Biofisica

BASIC SCIENCE
Nanomedicine: Nanotechnology, Biology, and Medicine

49 (2023) 102662
Review Article nanomedjournal.com
Insight on nano drug delivery systems with targeted therapy in treatment of

oral cancer
Kunj Vyas, B. Pharm., Maharshsinh Rathod, B. Pharm., Mayur M. Patel, PhD⁎
Institute of Pharmacy, Nirma University, SG Highway, Chharodi, Ahmedabad 382481, Gujarat, India
Revised 18 January 2023
Abstract
Oral cancer is a type of cancer that develops in the mouth and is one of the deadliest malignancies in the world. Currently surgical, radiation
therapy, and chemotherapy are most common treatments. Better treatment and early detection strategies are required. Chemotherapeutic drugs
fail frequently due to toxicity and poor tumor targeting. There are high chances of failure of chemotherapeutic drugs due to toxicity. Active,
passive, and immunity-targeting techniques are devised for tumor-specific activity. Nanotechnology-based drug delivery systems are the best
available solution and important for precise targeting. Nanoparticles, liposomes, exosomes, and cyclodextrins are nano-based carriers for drug
delivery. Nanotechnology is being used to develop new techniques such as intratumoral injections, microbubble mediated ultrasonic therapy,
phototherapies, and site-specific delivery. This systematic review delves into the details of such targeted and nano-based drug delivery systems
in order to improve patient health and survival rates in oral cancer.
© 2023 Elsevier Inc. All rights reserved.
Keywords: Colloidal carriers; Local delivery; Nanoparticulate system; Receptors; Targeted drug delivery
Introduction Oral cancer pathophysiology is quite intricate, with numer-

ous phases. Normal oral epithelial cells are transformed into
Cancer is now a relatively common disease all around the hyperproliferative epithelial cells during the initial stage, re-
world. Many people are killed by cancer each year. Various sulting in early adenoma that evolves into late adenoma. Mul-
forms of cancer have been discovered so far, and oral cancer is tiple tumor suppressor and proto-oncogene genes are deleted
one of them. Oral cancer alludes principally to diseases, oral during this process. On loss of the p53 suppressor gene, late
cavity cancer, and oropharyngeal cancer. 1 Oral cavity cancer adenoma develops into squamous cell carcinoma. Well-differ-
includes malignancies in the lips, hard palate, tongue, sublingual entiated squamous cell carcinomas mimic their parent tissue,
region, buccal mucosa, and retromolar trigons. Oral cancer is the maturation compartment of the epithelium, with morpho-
also classified as a subtype of head and neck cancer. According logical changes from basaloid-type cells to stratum spinosum
to the National Cancer Institute (NIH), the majority of oral cavity and increasing levels of keratin as they age. Keratin pearls are a
malignancies begin in squamous cells, hence they are referred to characteristic feature of well-differentiated SCC. Exophytic
as “oral squamous cell carcinoma” (OSCC). 90 % of oral and growth occurs when the tumor expands outwardly, whereas
oropharyngeal cancer cases are squamous cell carcinomas. 2 infiltration occurs when the tumor expands inwards. This
Abbreviations: DDSs, drug delivery systems; 5-FU, 5-fluorouracil; PTX, paclitaxel; DOX, doxorubicin; DTX, docetaxel; MTX, methotrexate; FA, folic
acid; HA, hyaluronic acid; RGD, peptides; VEGF, vascular endothelial growth factor; ALA, 5-aminolevulinic acid; PD-1, programme death; PD-L1,
programme death and its ligand; ADCC, antibody-dependent cell-mediated cytotoxicity; NIR-PIT, near-infrared photoimmunotherapy; HNSCC, head and
neck squamous cell carcinoma; Polymeric NPs, polymeric nanoparticles; PLGA, poly lactic-co-glycolic acid; PEG, polyethylene glycol; OSCC, oral
squamous cell carcinoma; α-TOS, α-tocopheryl succinate; QD, quantum dots; ROS, reactive oxygen species; EPR, enhanced permeability and retention;
PDPN Ab, podoplanin antibody; VCR, vincristine; QC, quinacrine; GI tract, gastrointestinal tract; SLNs, solid lipid nanoparticles; NLCs, nano lipid carrier;
DS-FUDR, distearoyl-floxuridine; HPMC, hydroxypropyl methylcellulose; PVA, poly (vinyl alcohol); HSC, hematopoietic stem cells; miRNA, microRNA;
BMSCs, bone marrow mesenchymal stem cells; hBMSCs, human bone marrow mesenchymal stem cells; COL10A1, collagen type X alpha 1 chain; miR-
101-3p, microRna-101-3p; EVs, extracellular vesicles; ISEV, International Society for Extracellular Vesicles; HPCD, hydroxypropyl—cyclodextrin; PDT,
photodynamic therapy; PTT, photothermal therapy; OTSCC, oral tongue squamous cell carcinoma; DFX, deferasirox; CCAM, cetuximab coated albumin
microbubbles; UTMC, ultrasound targeted microbubble cavitation; STAT3, signal transducer and activator of transcription-3; STAT3-LPX, STAT3-loaded
liposome-microbubble complexes.
⁎ Corresponding author.
E-mail address: mayurpatel@nirmauni.ac.in (M.M. Patel).
https://doi.org/10.1016/j.nano.2023.102662
1549-9634/© 2023 Elsevier Inc. All rights reserved.
Please cite this article as: Vyas K, et al, Insight on nano drug delivery systems with targeted therapy in treatment of oral cancer. Nanomedicine: NBM
2023;49:102662, https://doi.org/10.1016/j.nano.2023.102662
2 K. Vyas et al / Nanomedicine: Nanotechnology, Biology, and Medicine 49 (2023) 102662
Fig. 1. The multistage progression of oral cancer.
infiltration of deeper tissues confirms the OSCC and ultimately cancer. HPV is now a common cause, accounting for almost 60–
oral cancer. 3 The advancement in simple terms is shown in 70 % of oropharyngeal and 20 % of oral cancer. 14 Studies have
Fig. 1. shown that HPV is associated with both benign and malignant
In India, oral cancer has been found to be the most common lesions in the oral cavity. 15 Today, the cure for cancer is pre-
malignancy in men. 4 The predicted patients for Oral Cancer in posterous. However, appropriate therapy can slow malignant
India in 2020 are 188,969 which means 1 in 60 patients is at risk. growth. The fundamental therapies are chemotherapy, surgery,
For men, the number is 139,018. While females have a lower and radiation treatment. 16 Advancements have led to alternative
number of patients which stands at 49,951. 5 This form of cancer treatments like targeted therapy, hormone therapy, and immu-
is extremely widespread in south-central Asian countries such as notherapy, which are likewise accessible. There are several
India, Sri Lanka and Pakistan. 6 For example, death and inci- anticancer drugs (e.g., 5-fluorouracil, paclitaxel, cisplatin, and
dence rates in South Asian countries are almost double those in docetaxel) that are used either as a single drug or in combination
the rest of the world. 7,8 Globally, oral cancer accounts for for treatment. Current therapies are associated with severe side
377,713 cases, while the death toll is 177,757. While deaths effects and toxicities, and these therapies have been used for the
appear to be due to inadequate treatment, the main causes of past 50 years without substantial improvement. 12,17,18 Even after
death are a lack of knowledge in both patients and physicians advancements in the treatment of oral cancer, there are several
about the condition. There are also financial costs that not all flaws like toxicity issues, stability issues, physical impairment,
patients can afford. and functional deformities due to surgery. Another treatment is
Cancer is a disease also known as the silent executioner. At giving IV injections, which can prompt total bioavailability, but
the first stage, the majority of patients have no sensation or signs this also comes at a price. 19 Oral cancer is said to be an immu-
of deterioration, so they are exceptionally rarely considered. On nosuppressive disease that changes the immune system's re-
the other hand, routine examination of oral mucosa and primary sponse and makes them tumor cell escapers, which do not
oral malignancies by both dentists and physicians is given little detect tumor cells. 20 Immunotherapy has shown significant im-
or no importance. This leads to late detection of cancer, and by provement in treating patients as the success rate is very high in
this time cancer has developed to a dangerous stage with serious modulating immune responses in patients with refractory
complications: ulcers that do not heal, white patches, red lesions, solid tumors. This treatment essentially obstructs the pathways
abnormal lumps in the mouth, mouth Early signs, such as through which cancer cells target the immune system to escape,
bleeding from the mouth, can give doctors an indication of de- so the patient's immune system will target the tumor cells. 21,22
veloping oral cancer and improve the prognosis for tumor pa- This immune modulation mainly targets cytotoxic T-lympho-
tients. This may increase the chances of survival. 9 A greater part cyte-associated antigen-4 (CTLA4) and programme death (PD-
of survivors should be visible when malignant growth has been 1) and its ligand (PD-L1), as well as several other targets that
recognized during the early stages. 10 When cancer is identified at are under development. 23 Normally, immunotherapy has auto-
stage 1, the five-year survival rate is nearly 80 %, but when immune side effects and is costly, too, so to overcome this, nano-
cancer is detected at stage 4, the survival rate drops to <20 %. 11 based drug delivery systems (DDSs) are used via direct targeting
Oral cancer is usually diagnosed later because of OSCC, the and help in intracellular penetration. 24,25 Today, DDSs play a
deadliest disease with only a 50 % survival rate by disease. 12 vital role in the treatment of any cancer as they enhance the
Potentially malignant disorders such as inflammatory oral sub- current anticancer therapies with significant decreases in toxic
mucosa, fibrosis, erythroplakia, leukoplakia, candida leukopla- and adverse effects like less bioavailability in the case of oral
kia, dyskeratosis congenital, and lichen planus are considered the treatment, stability concerns, and non-specific biodistribution. 26
preclinical phase for oral cancer. 13 Tobacco is the leading cause Conventional techniques of chemotherapy are not suitable today
of mouth cancer. Consumption of smokeless tobacco (SLT), and improvement is required in bioavailability and targeted drug
betel-quid chewing, excessive alcohol consumption, poor oral delivery so that it cannot affect healthy cells or tissue. 27 These
hygiene, nutrient-deficient diet, and sustained viral infections, delivery methods have several drawbacks, including limited
i.e., human papillomavirus (HPV) are other aetiologies of oral efficacy and selectivity. They have a variable absorption rate,
K. Vyas et al / Nanomedicine: Nanotechnology, Biology, and Medicine 49 (2023) 102662 3
which when combined with a low pH can reduce absorption even nanoparticles were specifically distributed in the cytoplasm,
more because digestive enzymes can break down some of the mitochondria, and nuclei and could selectively target intracel-
drugs before they enter the bloodstream. Increased bioavail- lular organelles. Finally, high-speed Raman imaging with a
ability, bio-distribution, and targeted delivery at a sustained rate resolution of 50–50 pixels was accomplished in 30 s. 34
can be achieved at the primary tumor site by utilizing targeted Nanotechnology has even the capability to detect a single
DDS. In particular, the two most common contenders exploited cancerous cell in vivo. Some nanomaterials used for cancer de-
for the delivery of chemotherapeutic agents into tumor sites are tection are nanoscale cantilevers (a beam that binds with a cancer
naturally derived and synthetic polymers. Furthermore, for the link molecule), QD, nanopores (small holes through which DNA
release of bioactive molecules to specify the site targeted, DDS is can pass and can form DNA sequencing), multiplexing modality
key and is widely used in improving patient health outcomes for (biomolecular sensor), immunosensors, nanotubes, carbon
oral cancer. 28 Certain investigations and research have shown a nanotubes, and nanoparticles). 35,36 A recent study, for instance,
better half-life of drugs that otherwise degrade quickly, like produced a DNA biosensor that used a restriction-endonuclease-
peptides and proteins. 29 For these reasons, patients with oral assisted target recycling method using Pd-Au alloy nanocrystals
cancer can benefit from high compliance, increasing the efficacy to trap probe DNA on an electrode and catalyze the reduction of
of drugs, and cutting the period of treatment, so it becomes an H2O2, which amplified signal and improved detection sensi-
overall cost-effective therapy. tivity. This adaptable DNA biosensor demonstrated linear ranges
In this review, we are going to discuss the application of for the detection of p53 and oral cancer genes from 0.1 fmol L −1
nanotechnology in the first section, specific types of targeting to 0.1 nmol L −1 and 0.1 fmol L −1 to 1 nmol L −1, respectively.
used in the second part, different types of nano DDSs in the third The p53 and oral cancer genes' respective detection
segment, and targeted DDSs, finally, every one of them is uti- thresholds, which were set at 3σ, were calculated to be 0.03 and
lized in the therapy of oral malignant growth. 0.06 fmol L −1.37
There are many advances in immunosensors detection tech-
Current nanotechnology based diagnosis and treatment in niques. They are advanced and have a very precise diagnostic
oral cancer effect. In a study, a nanocomposite made of zinc oxide and re-
duced graphene oxide (ZnO-rGO) was used to make an elec-
Nanotechnology is the change of matter at a nano size. It is trochemical immunosensing test-bed for the noninvasive on-site
one billionth of a meter, which is 10 9. 30 It is an interdisciplinary detection of the biomarker IL8 for oral cancer. The immuno-
science including engineering, biology, chemistry, and physics. sensor detected IL8 at low concentrations, namely 100 fg/mL −5
In recent years, nanotechnology has made several advances in ng/mL, with a sensitivity of 12.46 ± 0.82 μA mL/ng and a de-
biomedical engineering through diagnosis, Molecular Imagin- tection limit of 51.53 0.43 pg/mL. In vitro experiments using
ing, Targeted DDS, synthesis of tissue modules, development of actual swabs spiked with IL8 supported these findings. 38 Simi-
biomaterials and improved surfaces for medical devices, in vitro larly, a personalized gold-NP-reduced graphene-oxide-based
and in vivo methodologies, biofiltration systems, robotic as- bioelectrode (AuNPs-rGO-) has been developed as an immu-
sembly, and many other areas. 31 nosensing platform for the electrochemical detection of oral
cancer. 39 The immunosensor detects Interleukin 8 (IL 8) fairly
Diagnosis quickly in almost 9 min. They demonstrated an experimental
linear dynamic range of 500 f. mL −1 to 4 ng mL −1, as well as a
The significant utilization of nanotechnology is in the diag- detection limit of 72.73 ± 0.18 pg mL-1. The developed
nosis of cancer. In the case of oral cancer, the detection of it is immunosensor has high specificity for detecting IL8 in human
mainly possible at a later stage, and patients do not visit the saliva samples. Furthermore, the immunosensor's reusability and
doctor until some nominal symptoms show up, such as pain and stability for up to three months highlight the market viability of
bleeding. The biopsy is the only method used to date. Because of this nanoplatform for the detection of other clinically relevant
this, early diagnosis is really important, and researchers are biomarkers. 39 All of these opens up a new area for research in
striving to find a diagnosis employing nanotechnology-based oral cancer detection and imagining techniques and can be
DDS. For example, magnetic resonance imaging (MRI), optical promising player for diagnostic technique.
coherence tomography (OCT), photoacoustic imaging, surface
plasmon resonance scattering, surface-enhanced Raman spec- Treatment
troscopy, diffusion reflection imaging, and quantum dots(QD)
imaging have all been used for oral cancer detection. 32 For Currently, chemotherapy is one of the preferred options for
example, in a metastatic murine model of OSCC, an ultrasound- the treatment of cancer. 40 There are several oral chemotherapy
guided spectroscopic photoacoustic imaging technique was in- drugs like cisplatin (cis-diamine-dichloro platinum), cetuximab,
troduced to detect lymph node micrometastases. After injecting 5-fluorouracil (fluoropyrimidine, 5-FU), bleomycin, paclitaxel
activated plasmonic nanosensors, significant ultrasound-guided (PTX), doxorubicin (DOX), docetaxel (DTX), and methotrexate
spectroscopic photoacoustic signals developed in micrometas- (MTX). MTX is one of the most often utilized chemotherapeutic
tases as small as 50 mm. 33 In another study, compact, round, drugs in patients with recurrent head and neck squamous cell
near-infrared region responsive and SERS active gold nanopar- carcinoma (HNSCC) for palliative care, with a response rate of
ticles with extremely narrow intra-nanogap nanostructures were 8–50 %. This drug is also utilized in phase III trials to compare
introduced for single oral cancer cell HSC-3 imaging. Gold with several other therapeutics. They increase MMP13 protein
expression, which is significantly linked to lymph node metas- Targeted DDS offers various advantages, including protecting
tasis in OSCC. Furthermore, the clinical efficacy of various healthy cells from harmful substances, reducing dose-limiting
chemotherapeutic drugs (paclitaxel/cisplatin/5-FU) was assessed side effects, and battling drug-resistant malignant cells. NPs fa-
in a study. The following drugs were administered to 56 patients. cilitate the transfer of sensitive treatments to their targeted areas
The findings revealed that these medications are quite successful, in active form, in appropriate concentration, and reduce the
with improved quality of life even in stage 4 cancer. Moreover, quantities that accumulate in unwanted organs/tissues due to
the patients experienced relatively few side effects and toxicity their unique cell uptake and transport processes. However, it has
difficulties. 41 become more evident that cytosolic ingestion of a therapeutic
Even though they are the simplest and somewhat convenient molecule does not imply contact with its subcellular target,
procedures, thanks to technological breakthroughs, we now have necessitating careful nanoparticle design and optimization to
nanotechnology-based treatments as well. Some of these treat- enable cellular/nuclear targeting. 42 Active targeting, passive
ments which are already tested against nano DDS for oral cancer targeting, and immune targeting are the main 3 types of targeting
are given in Table 1. Nano vectors for gene therapy, nonviral strategies.
gene delivery systems, drug delivery across blood-brain barriers,
and nanoparticles are very effective treatments with fewer side Passive targeting
effects and toxicity. 35,36
Because chemotherapeutic drugs have problems with un- Passive targeting is referred to as drug delivery, which is
wanted effects, bioavailability, and absorption mechanisms, based on the enhanced permeability and retention effect (EPR).
specific nano drugs have been developed that can quickly enter An EPR effect is nothing but the property of a molecule to
cancerous tissues due to cancer cells' fast vascularization and preferentially accumulate in tumor tissue rather than normal
inadequate lymphatic drainage. As a result, drug penetration and tissue. This is due to very high oxygen demand in tumor tissue
retention increase. Nanomedicine has the potential to become a and due to leaky vasculature and defective lymphatic drainage in
target carrier for cancer therapy. Nanotechnology has also found solid tumors. So, passive targeting can be defined as the depo-
its use in brachytherapy, photodynamic therapy (PDT), photo- sition of certain materials into a specific tumor site due to
thermal therapy (PTT), and gene therapy. Today, it is the trend pharmacological processes. Passive targeting is performed by
for treatment not only of cancer but of several other diseases also, nanoparticles as they permit them to pile up in tumor cells, which
and it has provided great hope for a possible cure for oral cancer. led to the discovery of the EPR effect. 43 The size of nanoparti-
cles has a significant impact on the EPR effect. The smaller the
Targeting methods for drug delivery size, the greater the penetration. 44 They do not have a ligand, as
in active targeting, but instead use extracellular drug diffusion to
Targeted nano DDS is defined as the action of any therapeutic deliver drugs into tumor cells, as shown in Fig. 2(A). 45 The
drug on any targeted organs, cells, or molecule using a nano- tumor microenvironment is also one of the influencers of passive
particle as a carrier. Nanoparticles have a huge surface area, high targeting. A study was conducted in which glycolysis, which is
surface reactivity, and a high adsorption capacity owing to their known as the powerhouse of cancer cells, was taken. This gly-
small size. Furthermore, we can achieve tailored therapy ac- colysis produces an acidic environment, resulting in a noticeable
cording to groups or substances by identifying target sites on the drop in pH in the tumor microenvironment. This can be advan-
surface of nanoparticles to be used, or by altering the charge or tageous for passive targeting because some nanoparticles are pH
space conformation on the surface of nanoparticles. Targeted sensitive and can easily release drugs in the area around cancer
therapy can be used by groups or substances that possess target cells at that pH. 46
site identification on the surface of nanoparticles, or it can even Today Doxil and Caleyx (PEGylated liposomes), Abraxane
be utilized by changing conformations on nanoparticle surfaces. (PTX), and Myocet (DOX) are DDS that are in the market and
Table 1
Summary of approved nano drug delivery system for oral cancer.
Name Particle type/drug Approval (year)
Abraxane Albumin-particle bound paclitaxel 2005
(Celgene)
Doxil (Janssen Products, LP (USA)) Caleyx Pegylated liposomal doxorubicin 1995
(Schering-Plough Corporation)
Myocet (Sopherion Therapeutics) Non-PEGylated liposomal doxorubicin 2000
BIND-014 (BIND Therapeutics) PSMA targeted (via ACUPA) docetaxel 2016
PEG-PLGA or PLA–PEG particle
Genexol-PM (Samyang Biopharmaceuticals) Paclitaxel polymeric micelle nanoparticle 2016
Docetaxel-PM Docetaxel micelle 2016
DOPNP201 (Samyang Biopharmaceuticals)
Feraheme (AMAG) Iron polyglucose sorbitol carboxymethylether colloid 2009
Rienso (Takeda)
Ferumoxytol
Fig. 2. (A) Passive targeting is represented where drug is released into tumor cells by EPR effect from nanoparticles through leaky vasculature. Drugs is released
from nanoparticles into extracellular matrix and then penetrates inside the tumor cells; (B) This depicts the active targeting in tumor cells. Nanoparticle's surface
possesses targeting ligand which binds with receptor and drug is released into tumor cells. This results into increased accumulation and cellular uptake via
receptor mediated endocytocis pathway; (C) New immune based therapy which induces antitumor T cells, Natural Killer cells and B cells rather than delivery of
drugs to tumor. Nucleic acid based nanovaccines targets dendritic cells which in turn activates the antibody cells and act on tumor cells by programming tumor
cell death.
Table 2
Summary of ligands with target receptors overexpressed in oral cancer.
Ligand Binding site Target receptor Reference
55,56
Folic Acid (FA) Folate Receptor Folate Receptor like FRα, FRβ and FRγ
57
Herceptin Human epidermal growth Human epidermal growth factor receptor 2 (HER-2)
factor receptor
Tripeptide arginine–glycine–aspar- Integrin Receptor Integrins like αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, α5β1, α8β1, and αIIbβ3 58,59
tic acid (RGD)

60,61
Epidermal growth factor (EGF), EGF Receptor, extracellular Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth
Neuregulin-1 (NRG1) domain Factor Receptor (VEGFR)
55,62,63
Transferrin Transferrin Receptor Transferrin Receptor
64
PB28 Sigma Receptor Opioid receptor family which includes Sigma 1 receptor (S1R) and Sigma 2
receptor (S2R)
65
Fibroblast Growth Factor (FGF) FGF receptor Fibroblast growth factor receptor (FGFR)
66
Platelet-derived growth factor PGDF receptor Platelet-derived growth factor receptor (PGDFR)
are successfully used in clinics for passive targeting in cancer. 43 targeting moiety. 50,51 Active targeting can also be possible via
PTX is a great anticancer drug but due to problems like poor liposomes. In the case of immunoliposome, RES uptake and
solubility, non-specific distribution and impenetrability can binding to the target are two major drawbacks, but polyethylene
create problems. 47 To overcome these, a study was conducted by glycol (PEG) has shown an effective mechanism that avoids RES
using core-shell nano capsules (NCs) and iRGD-modified NCs liposomal uptake and thus leads to increased blood concentration
(iRGD-NCs). PTX provides high drug penetration and distri- and target binding capacity. 52 The FA ligand uses a targeted
bution and an increase in its anticancer activities. The NCs membrane molecule called FAR, which is overexpressed in
loaded with PTX increased the area under the curve and mean head and neck cancers. Anti-vascular endothelial growth factor
resident time by about 4 to 8 folds, respectively, and reduced the (VEGF) shows its expression in oropharyngeal cancer. 53 Folate
elimination rate constant by >68-fold. 48 Hence, further investi- receptor is also overexpressed in human epithelial mouth carci-
gations and greater knowledge of these features of tumor tissues noma cells. 54 Table 2 shows various ligands and targeted re-
are essential to ensure a successful future for EPR effect-based ceptors along with their overexpression in several cancer cells.
chemotherapy of cancer with a passive drug-targeting strategy. A recent breakthrough has revealed evidence that PTX loaded
This indicates that more research and investigation into the EPR with RGD, Transferrin, and FA has an increasing anti-tumor
phenomenon and passive targeting can lead to more tailored effect due to the direct delivery of PTX into tumor cells. It has
anticancer drug DDSs. been seen that PTX shows increased targeting activity with RGD
and FA, but they have not yet been approved or even reached
Active targeting clinical trials. 67 Ultimately active targeting can greatly improve
drug delivery to the specific site upon further research progress.
Active targeted drug delivery (smart drug delivery) is based Aside from normal ligands, there has recently been increased
on ligand affiliation to receptors. Active targeting is the delivery interest in aptamers. The targeting effectiveness of nanomaterials
of a certain amount of therapeutic or diagnostic agents to the can be significantly increased by the use of aptamers. Aptamers
targeted diseased area by using the ligand. One or more drug- are single-stranded oligonucleotides that fold into certain struc-
loaded targeted nanoparticles along with ligands are used to tures and bind to specific targets like proteins. The aptamers used
recognize the specific receptor/antigen on targets. As represented generally in oral cancer are MUC1 and AS1411. In a recent
in Fig. 2(B), drugs are delivered to infected cells via receptor- study, MUC1 was silenced with short interfering RNA, which
mediated endocytosis, resulting in reduced toxicity and side ef- increased the amount of cell-cell aggregation in human oral
fects as well as a reduction in nonspecific distribution, which is epidermoid carcinoma cells. Further MUCI reduction resulted in
unattainable in chemotherapy. 49 This approach has the added EGFR mRNA and protein expression inhibition, but no recip-
benefit of being able to transfer nanoparticles to cells via a rocal effect was found. As a result, MUCI appears to modulate
specific pathway as soon as they reach the tumor's surrounding EGFR expression, suggesting that gene silencing may offer a
environment. Many receptors and antibodies have been discov- novel therapeutic approach. 68 They can be easily loaded into
ered in vitro and in vivo to date. Several tumor-specific small nucleic acids using a tetrahedral structure (tFNAs). Due to their
molecule ligands have also been found, such as folic acid (FA), superior cellular absorption, tFNAs have received a lot of at-
sugar residue (e.g., hyaluronic acid (HA)), peptides (RGD), tention as drug nanocarriers. However, tFNA primarily serves as
proteins (transferrin, cytokinin, lectins) and aptamers for specific a static delivery platform for oligonucleotide cargos created
delivery. 49 Ligands target the intravascular tumor cell to further through sticky-ended ligation. 69 The intrinsic ability of tFNA to
increase the delivery of nanoparticles within the disease site. scavenge reactive oxygen species, combined with exceptional
Furthermore, during the last decade, nanoparticle usage with enhancements in cellular endocytosis and tissue permeability due
targeted ligands has been tested under preclinical study. Active to its proper size and geometry, enhances cell-material interac-
targeting strategies can range from the attachment of an antibody tions to influence or investigate cell behavior. 70 Incorporating
to a specific cell surface protein or RGDs to the use of a synthetic AS1411 into the nanostructure, which assists tFNAs drastically
improves the cellular uptake efficacy. A tFNAs-based hybridi- drugs have separate and potentially complimentary effects on T
zation chain reaction (HCR) technology for cancer-related cells, and it was thought that using anti-CTLA4 and anti-PD1/PD-
targets was recently introduced, and its adaptability was L1 therapies together might induce synergy in HNSCC, as found
proved by identifying intracellular receptor miRNA 21 in melanoma. Despite insufficient evidence of anti-CTLA4 single-
and cellular membrane target nucleolin. The system was dubbed agent activity in HNSCC, combination studies combining anti-
the T-probe system. The T-probe technology effectively and CTLA4 drugs with anti-PD1/PD-L1 therapy progressed quickly.
precisely detects tumor-related biomarkers in vitro and in vivo, There are currently two ongoing clinical trials for durvalumab
showing tremendous promise for therapeutic and clinical monotherapy vs combination therapy, Condor and Eagle, in
applications. 71 phases II and III, respectively. 76
Immune tumor targeting entails the use of certain therapies
Immune targeting that aid in the stimulation of the immune system and the treat-
ment of cancer. These are referred to as immunotherapies. Active
Active and passive immunity are the two basic types of im- immunotherapy targets tumor cells by guiding the immune
munity. Active immunity is the immunity we obtain after being system's attack (tumor as target). Immune cells were extracted
exposed to a pathogen, while passive immunity is the immunity, from the patient's blood or tumor, cultivated in the lab, and then
we give purposely to prevent a person from contracting a disease. reintroduced into the body, where they target malignant cells.
In layman's terms, we name vaccines that have proven passive NK cells, dendritic cells, and cytotoxic T cells were extensively
immunity. Macrophages, natural killer (NK) cells, dendritic used in active immunotherapy. Passive immunotherapy, such as
cells, and eosinophils are examples of innate immunity, whereas ipilimumab, involves enhancing the immune system by targeting
B and T lymphocytes, also known as B and T cells, are examples cell surface receptors, which can result in antibody-dependent
of adaptive immunity. T cells make CD4+ and CD8+ cells, while cell-mediated cytotoxicity (ADCC). Examples of immunother-
B cells make antibodies. Cancer cells evade the immune system apies include antibody-based therapies (Checkpoint Inhibitors,
by lowering cell surface antigen expression, secreting antigens Targeted Monoclonal Antibodies), adaptive cell transfer, cancer
that inactivate the immune system, and encouraging the micro- vaccines, and cytokine immunotherapy (Interferon α, Interleukin
environment to release immune-suppressing chemicals, boosting 2). These treatments can aid in the stimulation of antibody re-
tumor growth. 72 Cancer immunity is defined as the ability of a sponses in cells, resulting in a more effective anticancer effect.
foreign material to stimulate an antibody response that can aid in Another study was conducted using near-infrared photo-
the fight against cancer. Cancer nano vaccines are thought to be immunotherapy (NIR-PIT), which uses anti-CD-44 monoclonal
the future of immune targeting in cancer. They are so small that antibodies that are fixed with the photo absorber IRD700DX.
they can easily penetrate the cell and aid in molecular or cellular This IRD700DX-anti CD-44 conjugate was given to mice, and
repairs. 73 Cancer nano vaccines are divided into four categories. an in-vivo and in-vitro study was conducted which demonstrated
Vaccines against antigens, Vaccines against dendritic cells, that this combination significantly decreases tumor growth and
DNA/RNA vaccines, and whole-cell vaccines. Cancer nano increases survival time in mice and could be a potential therapy
vaccines help in mimicking the antigen and expose them to for MOC cells. 77 Moreover, several minor trials have also looked
dendritic cells which in turn stimulates T cells, natural killer into the use of immune checkpoint inhibitors before surgery, and
cells, and B cells along with some antibodies. As shown in Fig. 2 the results are encouraging. Uppaluri et al. published preliminary
(C), all of the targeting cells are activated following the antigen findings from a single-arm phase II trial of 21 patients who
provided by the cancer vaccine. Due to the usage of a tumor cell received neoadjuvant pembrolizumab before surgery. They ob-
membrane, a polymeric nano-DDS with a tumor cell membrane served that neoadjuvant pembrolizumab was practical and safe,
was created, which demonstrated good stability and antigenicity. 74 and they also discovered that 43 % of patients responded to a
T cells are primary lymphocytes that fight pathogens and deter- single dose of the drug pathologically. 78 Numerous cutting-edge
mine the immune response to antigens. T cells are controlled by combinations of immune checkpoint inhibitors and other
the PD-1 receptor, which stops them from attacking normal cells. immunostimulatory drugs are now being tested. Immune
Some drugs like pembrolizumab (Keytruda) and nivolumab checkpoint inhibitors combination with TLR9 agonists, various
(Opdivo) target PD1 and inhibit it from controlling T cells. So, due therapeutic vaccines, the anti-EGFR antibody cetuximab, or the
to the blocking of the PD-1 receptor, T cells start attacking tumors anti-VEGF multiple kinase inhibitor lenvatinib have shown good
and slow their growth. A recent pre-clinical investigation using results in small phase I/II trials. Furthermore, co-stimulatory
a combination of cisplatin and PD-1 was conducted. The re- agonists like OX40, CD40L, CD137, STING, IDO1, and STAT3
searchers found that using cisplatin and anti-PD-L1/PD-1 together inhibitors are being explored. 76 The interaction of radiation
reduced tumor growth and improved survival in a syngeneic therapy with the tumor microenvironment is complex and may
mouse model of HNSCC without significantly lowering the both activate and suppress the immune system, but tests for the
quantity or function of tumor-infiltrating immune cells or en- combination of radiation therapy and immunotherapy are also
hancing cisplatin-induced toxicities. As a result, it was discovered underway. Radiation therapy may boost the anti-tumor immune
that a moderate dose is sufficient for increasing antitumor im- response in some cases by activating cytokines and tumor-
munity through mechanisms other than direct tumor cell killing, associated antigens. Immune checkpoint inhibitors are being
which can be boosted further by anti-PD-L1/PD-1 therapy. 75 studied in a variety of radiation-immune checkpoint inhibitors
Anti-CTLA4 therapy was one of the most expected drugs in combinations in both locally progressed and metastatic condi-
HNSCC when paired with anti-PD1/PD-L1 therapy. Anti-CTLA4 tions. This can clearly suggest that immune targeting is in
primary stage and requires much research to become a potential diseases has reached a new level. Many biomaterial-based delivery
therapy for oral cancer. vehicles or carriers have been developed and are currently being
used to treat cancer. Many nanoparticles, including polymeric,
Nanotechnology-based drug delivery system inorganic, combination, and gold, are utilized as delivery systems
in nanotechnology, while Liposomal, Hydrogels, and Exosomes
Nanotechnology has today become an inevitable part of sci- are also widely used as carriers for drug administration. Fig. 3
ence. From tiny to large disciplines of science, it has a peer. depicts the shape and structure of different delivery methods. The
Nanotechnology has made significant progress in the treatment of use of a nanotechnology-based delivery system has been imple-
oral cancer during the last decade. Oral cancer has been diagnosed mented to reduce cell cytotoxicity and provide tailored cancer
and treated using this method. After the development of Nano therapy. Table 3 shows a variety of studies and types of nano-
DDS, the use of nanotechnology in the treatment of a variety of delivery devices.
Fig. 3. (A) Polymeric Nanoparticle, (B) Magnetic Nanoparticle; (C) Solid Lipid Nanoparticle (SLN); (D) Liposome; (E) Nucleic Acid Nanoparticle;
(F) Exosome.
Table 3
Studies depicting the application of nano drug delivery systems.
Nano platforms Study Material Target cells/target tumor Type of study Outcomes/results References
168
Polymeric nanoparticles Study was conducted using PCL Curcumin was used with PCL SCC-9 human oral squamous In vitro There was reduction in viability of SCC-9 human
nanoparticle in which curcumin was nanoparticle and coated with chitosan carcinoma cell oral cancer cell line.
encapsulated to find out cytotoxicity as a mucoadhesive polymer Considerable decrease of toxicity and adverse
of SCC-9 cells. Pharmacological effects
effects and anti-cancer efficacy were
also tested.
99
Polymeric nanoparticles Evaluation of anti-tumor efficacy, PLGA-PEG-FA has co -encapsulated SCC-15 cells in Hamster In vitro and Considerable increase in stability, sustained drug
pharmacokinetics parameters and thymoquinone (TQ) and near-infrared model In vivo release was seen.
biodistribution for OSCC treatment plasmonic nanorods (AUNRs) into it. Cellular uptake of drug and cytotoxicity saw
in a hamster model was carried out improvement on SCC-15 cells.
by using PLGA-PEG nano capsules. There was reduction in tumor size and rise in
survival time of model was seen.
123
Magnetic nanoparticle Delivery of therapeutic siRNA using Polyethyleneimine (PEI)-modified B-cell lymphoma-2 (BCL2) In vitro Decline of 18 % in ca9–22 cells and 56 % in CAL
magnetic Fe3O4 to oral cancer cell in Magnetic Fe3O4 Nanoparticles for and siBIRC5 27 cells was found in
order to target and inhibit BCL2 and delivery of therapeutic siRNA mRNA level of BCL2 when therapeutic siRNA
BIRC5. Evaluate the cancer cell delivered with nanoparticles
apoptosis and gene silencing efficacy.
124
Magnetic nanoparticle To investigate the efficacy of magnetic Silica coated magnetic iron oxide Integrin αvβ6: oral squamous In vitro Direct targeting of αvβ6 over expressing cell was
hypothermia for treatment of oral nanoparticles was prepared which cell carcinoma biomarker observed with a surge
cancer by targeting integrin αvβ6 were combined with antibodies in tumor cell death. Also, upregulation of αvβ6
integrin in tissue
biopsies of OSCC was found
169
Gold nanoparticles Two nanocomposites conjugated Doxorubicin combined with both Cancer cells In vivo Doxorubicin pH resistant AuNP system has
with doxorubicin via pH sensitive AuNP. suggested a high tumor shrinkage
and resistant AuNP linkers was and survival time in hamster model. There was 2-
taken to identify the therapeutic role fold increment seen in
of gold nanoparticles in oral cancer. cellular apoptosis due to increased accumulation
Cytotoxicity as well as cellular and of AuNPs in the tumor cells.
nuclear uptake was also tested in a
hamster buccal pouch carcinoma
model.
170
Gold nanoparticles Study was conducted in order to Anti-EGFR conjugated Gold Nano- Cancer cells In vitro PTT when used with EGFR-AuNP conjugate
evaluate the efficacy and effects of particle with photothermal give higher selectivity and found that low laser
newly developed laser PTT by gold power was needed for killing of cancer cells.
nanoparticles. The ability of PTT
K. Vyas et al / Nanomedicine: Nanotechnology, Biology, and Medicine 49 (2023) 102662
with anti-EGFR conjugated AuNP

having lower laser power to induce
apoptosis was also tested. Study was
conducted on HSC 3 cells.
171
Solid lipid nanoparticles ɣ -Tocotrienol (c-T3), is considered ɣ -Tocotrienol (c-T3 along with Cancer cells In vitro and There was 10 folds higher permeability seen in
to be member of vitamin E family SLN In vivo SLN than mixed micelles as per in situ studies.
and several experiments claimed Also, during in vivo studies 3-fold higher oral
that it possesses anticancer activity. bioavailability was obtained. The ɣ-T3 uptake
This study was aimed to increase from SLN is 2-fold higher than MM. This uptake
(continued on next page)
9
10
Table 3 (continued)
Nano platforms Study Material Target cells/target tumor Type of study Outcomes/results References
permeability and bioavailability of was seen due to endocytosis in both formulation
ɣ-T3 nano formulation containing but reduction in NPC1L1in transportation of ɣ-
SLNs. In-situ rat model was used T3 and passive diffusion played a key role in
and some in vivo bioavailability greater uptake from SLN
studies were conducted. There was
also invitro experiments were done
to get information regarding cellular
uptake of ɣ-T3 from SLN
172
Liposomes To develop a new paste based Sodium alginate and liposomal Squamous cell carcinoma In Vitro Sustained release kinetics was found in the paste.
mucoadhesive delivery system. Study mucoadhesive paste. Doxorubicin (SCC) Increase in residence time at site of application
of in vitro drug release, mucoadhesive was also loaded into hybrid system was also noted. There was significant decrease in
assay, stability and toxicity along with as an anticancer drug cell viability was also seen. Decrease in toxicity
anticancer efficacy was performed on levels and increase in apoptosis was seen.
liposome-based alginate paste.
173
Liposomes Study of phototoxicity was carried Liposomes which were made up of HeLa Cervical carcinoma In Vitro The combination of liposome and phthalocya-
palmitoyloleoyphosphatidylcholine
out by using either free liposomes or and HSC-3 Oral Squamous nine was seen much more effective in reducing
liposomes encapsulated in the zinc and encapsulated in either zinc or Cell Carcinoma Cells cell viability than free liposomes.
phthalocyanine photosensitizer. aluminium phthalocyanine
174
Exosomes To prepare a OSCC specific eExo- Normal fibroblast was transfected Oral squamous cell carcino- In vivo and siLCP1 was easily transferred to the site of
somes (octExosomes) to assess the along with Epstein–Barr Virus ma (OSCC) cells In vitro OSCC with octExosomes while downregulating
loading capacity and effectiveness.Induced-3 (EBI3) and electroporation the LCP1 in OSCC and that led us to consider-
Anti-oral cancer activity was also of cDNA with siRNA of lymphocyte able tumor regenerative effect.
evaluated. cytoplasmic protein 1 (LCP1) as a
octExosome.
175
Exosomes Goal is to check effects of oral OCEXs is isolated from the oral Natural killer (NK) cell In vitro Natural Killer cells effects was enhanced by
cancer-derived exosomes (OCEXs) cancer cells. increased activity of type I interferon (IFN) gene
on natural killer (NK) cell and to and the chemokine (C-X-C motif) ligand
understand its mechanism. (CXCL) genes. The OCEXs promoted the ex-
pression of interferon regulatory factor 3(IFR-3)
along with its phosphorylation which in turn
activated IFN and CXCL genes.
176
Cyclodextrin To develop and evaluate a new type of CS and CM-β- CD was used as – In vitro Insulin was very fast released (84–97 % insulin
nanoparticles made of chitosan (CS) nanoparticles while insulin and within 15 min) whereas heparin remained highly
and carboxymethyl– cyclodextrin heparin were used as a model for associated to the nanoparticles for several hours
(CM-β- CD) for drug delivery of macromolecular drugs. (8.3–9.1 % heparin within 8 h)
macromolecular drugs. The release profiles were reliant on nanoparti-
K. Vyas et al / Nanomedicine: Nanotechnology, Biology, and Medicine 49 (2023) 102662
cles, and as a result, insulin was shown to be

highly quick release while heparin remained
sluggish. In the case of carriers, CS-CD (cyclo-
dextrin) nanoparticles were discovered to be
beneficial for both slow and quick drug delivery.
Nanoparticles drugs. Polymeric DDS also has its application as an intraoral site-
specific chemoprevention of oral cancer. Moreover, in vitro,
In the last decade, several advancements in various areas of ex vivo, and in vivo studies have suggested that intraoral site-
nano-systems have supported patients with better survival times specific drug delivery has the benefits of high efficiency, better
and healthier lives. From a simple nanoparticle to making highly therapeutic effect, patient friendliness, and good biocompatibil-
complex systems, it has evolved at a tremendous rate. For the ity. In the latest research, an n α-tocopheryl succinate (α-TOS)
treatment of cancer, drug resistance is a most common problem based polymeric NP was prepared, which was filled inside the
today, but nanoparticles like polymeric, inorganic, solid lipid hydrophobic core. They have targeted head and neck squamous
nanoparticles (SLN), gold nanoparticles (AuNPs), magnetic cell carcinoma (HNSCC). The in vitro three-dimensional (3D)
nanoparticles, along with liposomes, and hydrogels have solved experiment suggested that α-TOS-loaded nanoparticles suppress
the cause. 79,80 Nanoparticles are very small, sub-micrometers in angiogenesis by inhibiting the pro-angiogenic growth factor
size. They are ultra-dispersed solid supramolecular structures VEGF and decreasing the expression of its receptor. This sup-
with a 10–1000 μm size range. 81,82 Nanoparticles can be used to pression of angiogenesis is also caused by the accumulation of
alleviate the flaws and limits of traditional DDS. Nanoparticles ROS, which initiates cell death of surrounding endothelial cells.
have gained a lot of traction in oral cancer-targeted DDS due to For this reason, the α-TOS-loaded polymeric NPs could be a
their higher activity and therapeutic efficacy. They also have less promising candidate for HNSCC in the future. 95
systemic toxicity and chemical and physical properties that are A new method involving combination polymer was prepared
easily changed. 83 It can destroy cancer cells by delivering a drug by taking {[Cu(L1)] (H2O)1}n (1 .H2O) and {[Cu4Li(L2)2
that has been encapsulated directly to the damaged cell or (m3OH)2(H2O)2](NO3)(H2O)(DMA)2}n (2, DMA = N, N-
area. 19,83 The section below goes into greater detail regarding dimethylacetamide) along with their nanoparticles based on two
different types of nanoparticles and their applications in oral pyridine-carboxylate ligands 5-(30,50-dicarboxylphenyl) nicotic
cancer. acid (H3L2) as well as 3,3′-(pyridine-3,5-diyl) dibenzoic acid
(H2L1). In vivo and in vitro experiments suggested that there is
Polymeric nanoparticles high cancer activity on SSC-4 cancer cells in nanoparticle 2
Polymeric nanoparticles (Polymeric NPs) have emerged as a compared to nanoparticle 1. Also, nanoparticle 1 increased ROS
novel drug delivery technique in recent years. They are submi- accumulation and has helped in decreasing the tumor volume. 96
cron-sized particles with high biodegradability and biocompati- The ability to control the structural characteristics, functional
bility, making them ideal for increasing therapeutic impact while group modification, and physicochemical properties of novel
minimizing side effects. Polymeric NPs are primarily employed polymeric nanoparticles allowed for more effective targeting
for controlled or prolonged drug release, and they are easily delivery of cisplatin with lower toxicity. 97 The hydrophilic,
permeable across cell membranes, blood capillaries, and bio- biocompatible monomer N-vinyl pyrrolidone (NVP) is often
logical barriers (Fig. 3A). 84,85 In terms of preparation materials, used as a stabilizer and dispersant for polymeric NPs. Addi-
polymeric NPs are made up of surfactants comprising amphi- tionally, it can stop particle aggregation because of the steric
philic organic molecules, ionic and non-ionic surfactants, and structure of the pyrrolidone group. This property was used in a
polymers with low molecular weight. 86 There are also some study to create NPs from NVP and acrylic acid (AA) using two
disadvantages to employing polymeric NPs, such as the diffi- different techniques based on an emulsion polymerization reac-
culty in handling polymers, the fact that they become cytotoxic tion without the use of surfactants. Both synthesis methods
once, inside the cell, the protein antibodies cannot be transmitted, produced relatively spherical NPs with a negative charge that
and particle aggregation is more common. 87,88 Despite their ranged in size from 136 to 183 nm. With loading capacities of 4
flaws, polymeric NPs are widely recognized nowadays, and they mmol/g and 12–18 % entrapment efficiency, the ideal NPs to
have been used in a variety of compositions. Because of their cisplatin ratio was discovered to be 1:10. Depending on the pH of
total breakdown in aqueous media, polylactic-co-glycolic acid the release medium, 47–83 % of the cisplatin was released from
(PLGA) is one of the most commonly utilized polymeric NP. In the NPs in 7 days. The IC50 values of cisplatin-loaded NPs on
addition to PLGA, PEG is an approved polymeric NP for use in HN22 cells were just above 20 μg/mL. Additionally, the NPs that
treatments. 89,90 Poly (ethylene glycol)-poly (glutamic acid) had been given cisplatin showed a higher percentage of early
blocks copolymers and so they are effective in treating OSCC apoptotic death. The cisplatin-loaded NPs produced higher cel-
when loaded with cisplatin. 91 Another PTX-loaded polymeric lular cisplatin deposition at the earlier time point, indicating a
NP drug has been approved internationally for oral cancer and is slower but safer cancer-killing effect. Therefore, these novel NPs
being marketed as Abraxane. PTX induces cell death by com- may offer promise as cisplatin nanocarriers for the treatment of
bining with microtubules and maintaining the tubulin polymers oral cancer. 98 A combination of phytochemical anticancer thy-
unchanged. 92 PEGylated titanium dioxides were used to sup- moquinone (TQ) and near-infrared plasmonic gold nanorods
press proliferation, angiogenesis, and metastasis. 93 Polymers (GNRs) loaded inside folate-targeted pegylated poly (D, L-
such as poly (2-[methacryloyloxy] ethyl phosphorylcholine) lactide-co-glycolide) (PLGAPEG-FA) nano capsules were used
(PDPA) and poly [2diisopropylamino] ethyl methacrylate) in an in vitro and in vivo research. This combination demon-
(PMPC) were also effective in entrapping and delivering anti- strated high stability and cellular absorption in in vitro research.
cancer drugs against OSCC. 94 In Squamous cell carcinoma (SCC-15) cells, there was an in-
Polymeric micelles serve as novel DDS due to their target crease in cytotoxicity. In vivo studies revealed a considerably
specificity and controlled release of hydrophobic anticancer higher survival rate in rats due to tumor size reduction. After
more clinical research, this could have significant ramifications renders OSCC cells susceptible to its treatment. The inductively
in cancer therapy. 99 coupled plasma-mass spectrometry experiment demonstrates
that GPt increases Pt accumulation in cells, which significantly
Inorganic nanoparticles increases OSCC cell apoptosis and S-phase cell cycle arrest in
Inorganic nanoparticles are those that have an inorganic core both normoxia and hypoxia. Finally, in an OSCC xenograft
and an organic shell with a metallic content. They are utilized in mouse tumor model, GPt has a robust inhibitory effect on tumor
targeted therapy, where biomolecules are delivered and a development while causing less systemic drug toxicity than free
working site for the molecule's or anticancer agent's action is cisplatin. 111 Similarly, in another study, GQDs were employed
provided. 100,101 They possess properties such as a large surface as carriers to carry Evodiamine (EVO), a significant bioactive
area with a small size, easy synthesis, selective targeting of chemical. To target tumor cells, this nanocomposite was func-
molecules, and a large area-volume ratio. 102 They also have low tionalized with FA. Findings in tumor-bearing nude mice
toxicity, high tolerance, and better bioavailability compared to showed that after 18 days of therapy, the GQDs-FA-EVO
free drugs. QD, fullerene, graphene, carbon nanotubes, carbon composite laden with 10 % EVO dramatically reduced the tumor
dots, carbon nanoshells, gold nanorods, AuNPs, and magnetic burden by 19 % in comparison to the EVO group. 112
nanoparticles are some of the major inorganic nanoparticles. 103
QD is one of the important inorganic nanoparticles as they are Gold nanoparticles. AuNPs have long been utilized in cancer
efficient in treating and diagnosing oral cancer. QDs can act by treatment, diagnostics, and imaging. They're popular because of
targeting EPR effects or by surface cell biomarker recognition their high tissue permeability, biocompatibility, and bioconju-
methods. QDs have extensive use in PDT as they form QD-PS gation. They feature exceptional colloidal stability, precise size
complexes that can induce targeted cell destruction. Because of control, and tunable optical characteristics. They are also rela-
their ability to connect with antibodies on the cell surface, they tively simple to manufacture. Transferring a significant amount
will produce reactive oxygen species (ROS) when exposed to of AuNPs to the tumor site is required for precision treatment. It
UV light. 104 To increase the tissue penetration using near-in- is crucial to selectively transport sufficient AuNPs to tumor tis-
frared light (NIR) lucky et al. made a PEGylated titanium dioxide sue for proper diagnosis or therapy. They can be selectively
(TiO2) loaded with up-conversion nanoparticles (UCN). In vivo transported and precisely targeted using both active and passive
study was conducted to know the inhibitory effect on tumor targeting approaches. AuNPs accumulate in the tumor due to the
growth, angiogenesis and metastasis by using anti- epidermal EPR effect and are subsequently taken up by cells through the
growth factor receptor (EGFR)-antibody conjugated with endocytosis process, which is largely reliant on their nanoscale.
PEGylated TiO2-UCNs and selectively targeting the EGFRs. However, passive targeting has a considerably smaller absorp-
After the clinical investigation it was found that anti-EGFR- tion of AuNPs. They can even be coupled with an EGFR-based
PEG-TiO2-UCNs has no side effect nor toxicity while enhancing antibody for immune-targeted therapy. 113 Further benefits of
the apoptosis and angiogenesis. 105 Further studies also stated the AuNPs include ease of preparation in various ranges of sizes,
nanoparticle's information by an energy dispersive X-ray (EDX) easy functionalization, and their inherent ability to conjugate
spectroscopy. There was the formation of Na (Sodium), Y (Yt- with other biomolecules without altering their biological prop-
trium), F (Fluorine), Yb (Ytterbium), and Tm (Thulium) from erties. 114
the core nanocrystals and Ti (Titanium), Si (Silicon), and O Drug absorption by cells during chemotherapy is an area of
(Oxygen) from the shell. 106 AuNPs and magnetic nanoparticles concern. Even with a significant EPR effect, there is a low rate of
are two of the most common inorganic nanoparticles. They have absorption. As a result, active tumor-targeting research has in-
a wide range of applications in the treatment of various malig- creased. In numerous squamous cells, PDPN, a tiny mucin-like
nancies. Graphene-based nanomaterials, such as graphene oxide transmembrane protein, was discovered to be highly expressed.
(GO), reduced graphene oxide (rGO), graphene nanoribbons So, a polyethylene glycol-stabilized, podoplanin antibody
(GNRs), graphene quantum dots (GQDs), graphene nanopores, (PDPN Ab) conjugated with AuNP loaded with DOX was pre-
and graphene nanoplatelets 107,108 which are also potential op- pared and evaluated. AuNP is known for increasing its targeting
tions for oral cancer therapy. They can act as tunable carriers or efficacy if combined with any type of laser irradiation. The
active agents for enhanced chemotherapeutics administration and (PDPN Ab)-AuNP-DOX system was evaluated for targeted de-
cancer therapy due to their unique physicochemical and optical livery, cytotoxicity, and synergistic anticancer activity. In vivo
features, which include an extraordinarily wide surface area, and in vitro studies suggest that it has low toxicity and a high
good thermal and electrical conductivity adjustable active drug-loading capacity. An antitumor effect was found due to
groups, high biocompatibility, and powerful photothermal im- (PDPN Ab)-AuNP-DOX and AuNP having no role in it. The
pact. 109,110 Graphene quantum dots have recently been investi- targeting efficiency of this system was greatly increased because
gated as a drug delivery carrier due to their exceptional drug of AuNP. It was found that the tumor was highly targeted when
loading capacity via strong π–π stacking interactions and func- AuNP was combined with PTT. 115 A diagnostic method was
tional modification. Researchers created a PEG-modified GQDs- developed to detect OSCC in which AuNP was mixed with
Pt (GPt) nanocomposite in a study that is specifically targeted at serum samples obtained from the OSCC patient to capture this
treating tumors. It was shown that GPt could significantly in- into high-quality SERS spectra. After the Raman spectral anal-
crease the chemotherapeutic efficacy for OSCC both in vitro and ysis, there were major peaks in the OSCC candidate seen in the
in vivo, suggesting that this approach could be helpful for future molecular structure of nucleic acids and proteins. Ultimately,
tumor-targeted therapy. Both in normoxia and hypoxia, GPt PCA-LDA analyzed the result and the readings from it were
accurate. This demonstrated that SERS spectra based on AuNP nanoparticles, are required for translation of lab work into clin-
have a high potential for diagnosing OSCC. 116 AuNPs can im- ical research. 103
prove OSCC's radio sensitization in addition to enhancing its
chemo sensitization. According to research by Teraoka et al., the Combination nanoparticles
presence of AuNPs can improve the in vitro effectiveness of X- Combinational nanoparticles are made up of numerous
ray radiation treatment on oral cancer cells. Apoptosis induction nanoparticles that when mixed have a greater therapeutic impact.
was the fundamental reason for this cytotoxicity. 117 Most polymeric and inorganic nanoparticles are blended to
provide a combinational therapy that improves clinical effec-
Magnetic nanoparticles. Magnetic nanoparticles are referred tiveness while lowering systemic toxicity. In a recent study, a
to as iron oxide due to their innate magnetic response and con- chemo-PTT was prepared and vincristine (VCR) was used as an
trollable release. They are intelligent, small-sized, and possess anticancer agent. An amphiphilic PLGA-PEG polymer was
magnetic and superparamagnetic properties as shown in Fig. 3 taken and encapsulation of VCR into the polymer through a
(B). 118 Magnetic nanoparticles have been synthesized using a silica-coated plasmonic GNR was done. This combination
variety of methods, including coprecipitation, microemulsion, helped in the sustainable release of drugs into the acidic intra-
thermal decomposition, hydrothermal, combustion, sol-gel, and cellular environment, and so there is the possibility of targeted
polyol syntheses. 119,120 However, because of the possibility of therapy after further clinical investigation. 126
reticuloendothelial system adoption and agglomeration, the uses An anticancer drug named quinacrine (QC) has shown a
of magnetic nanoparticles remain limited. Polymeric coatings act positive therapeutic outcome in breast, lung, colon, and renal cell
as a barrier, preventing reticuloendothelial system absorption and carcinoma. It's also an antimalarial drug. Despite this, the drug's
nanoparticle agglomeration. 113 Organic polymers such as dex- side effects and limited availability outweigh its benefits. There
tran, chitosan, polysorbate, PEG, and organic surfactants such as is a nanoparticle called Inorganic silver-based nanoparticles
sodium oleate and dodecyl amine are often used to coat iron (AgNPs) that is also a potential anticancer treatment, but it has
oxide magnetic nanoparticles, which have excellent stability, drawbacks because higher dosages cause toxicity in healthy
enhanced half-life, and biocompatibility. cells. To address both of these issues and make the most out of
These magnetic nanoparticles normally absorb heat by using this, a combinational therapy combining QC with AgNPs was
electromagnetic waves in an alternating magnetic field. They are developed, which resulted in improved anticancer efficacy.
normally present in a superparamagnetic state and the most PLGA-based quinacrine (QC)–silver hybrid nanoparticles
commonly used nanomaterial is iron oxide nanoparticles like (QAgNP) were prepared. They were highly stable and were
Fe3O4 and γ-Fe2O3. 121,122 In a recent study, polyethyleneimine made by using oil in water emulsion. The size was found to be in
(PEI)-modified magnetic Fe3O4 nanoparticles were prepared for the range of 50-100 nm and a positive zeta potential of 0.523 ±
the delivery of therapeutic small interfering RNA (siRNAs) 0.09 mV was obtained from dynamic light scattering (DLS). 93
targeting B-cell lymphoma-2 (BCL2) and baculoviral IAP re- They were given to various oral cancer cell lines and the
peat-containing 5 (BIRC5) into Ca9–22 oral cancer cells. The antitumor activity was evaluated. There was an increase in
results suggest that nanoparticles targeting BCL2 and BIRC5 are cell cytotoxicity and OSCC-derived stem cells were destroyed
found to be effective in inhibiting Ca9–22 cells. 123 For the also a reduction in neo-angiogenesis was seen which suggested a
treatment of oral cancer, a magnetic hyperthermia technique was new possible treatment for oral cancer treatment. 127,128 Another
applied, in which magnetic nanoparticles with heating properties study used combination nanoparticles that comprised cationic
were used and thermal ablation of the tumor location was polymer polyethyleneimine (PEI) which were employed to
achieved using an alternating magnetic field. Magnetic iron modify mesoporous silica nanoparticles (MSNs) to construct a
oxide particles with a biocompatible silica coating were paired carrier for delivering DOX and MDR1-siRNA. In vivo, MSNP-
with antibodies to target integrin αvβ6, and thermal ablation of PEI-DOX/MDR1-siRNA significantly decreased tumor size and
the tumor site was produced through the above technique to delayed tumor growth rate when compared to a control group.
either give a negative effect or overexpress the integrin αvβ6. As This has brought up the possibility of therapeutic use for
a result, the anti-αvβ6 silica coating gave direct targeting to OSCC. 129
overexpressed cells, which ultimately leads to apoptosis of
cancerous cells. 124 To alleviate the toxicity difficulties caused by Solid lipid nanoparticles
oxidative stress on the OSCC, a superparamagnetic iron oxide Solid lipid nanoparticles (SLNs) have been used as a delivery
nanoparticle (SPION) was used to assess its effect on the OSCC mechanism for water-soluble drugs. They are colloidal particles
mitochondria. There is a substantial increase in ROS and mito- made up of biodegradable physiological lipids and surfactants
chondrial membrane potential, as well as swelling and cyto- at a safe temperature. Their size varies between 50 and
chrome complex release. On top of that, it also decreases cell 1000 nm, 130,131 and they encapsulate drugs in their core, as
viability and increases the lipid peroxidation level and caspase-3 drawn in Fig. 3(C). The core is composed of a lipid phase
activity in OSCC cells. 125 comprising fats and oils, while surfactants are utilized as stabi-
Although the potential of inorganic nanoparticles can im- lizers to avoid aggregation. Homogenization procedures are
prove current imaging and diagnostic techniques, a simple, commonly used to prepare them. SLNs are less toxic and have
safe, cost-effective, and environmentally friendly mode of biocompatibility that is comparable with other nanoparticles. 132
synthesis, as well as a better understanding of the safety mech- The advantages of SLNs are that they can be prepared without
anisms, biodistribution, and pharmacokinetics of inorganic using organic solvents, drug encapsulation is possible, which
decreases the side effects on the gastrointestinal tract (GI tract), Liposomes are mostly well-suited for cytotoxic agents. Some
SLNs do not degrade in acidic environments, and lipophilic drug reports suggest that cationic liposomes are most well-suited for
loading has always been a problem, but this can be solved by gene delivery in oral cancer. 143 Cisplatin interacts with the DNA
SLNs. 133,134 This was investigated in a study where paclitaxel process and initiates cell cycle arrest at the G2 Phase. Despite
was administered orally using SLN. Together with poloxamer several benefits, side effects and toxicity issues are hindering the
188, SLN showed significant and rapid aggregation after being application of cisplatin as an anticancer drug. In this study, li-
incubated in the gastric medium. Due to SLN's ability to remain posomes containing cisplatin nanoparticles were prepared. The
unaffected by the low pH and form a protective barrier around liposomes contained anionic lipids and cationic lipids with cis-
the nanoparticles, there was very little lipid degradation in the platin as a chemotherapeutic agent. To further enhance the effect,
gastric medium. 135 Another study used SLNs loaded with PTX, liposome nanoparticles are combined with PDT that work by
5-FU, and ascorbic acid (AA) for OSCC combination treatment. giving PDT after successful administration of LPC. This ex-
SLNs were created using high-speed homogenization and perimental treatment was evaluated in-vivo by using a xenograft
ultrasonication techniques, and their effectiveness against mouse model with OSCC. The treatment was found to be safe
OSCC-induced animal models was evaluated both individually and had negligible side effects in terms of toxicity. This com-
and in combination. The SLN exhibits biphasic drug release in bined effect increased the tumor growth inhibition time while
both the in-vitro and in-vivo systems. Finally, it was determined cutting the dose. It promoted anticancer activity while cytotox-
that PTX and AA entrapped in SLN may be employed suc- icity significantly improved its chemotherapeutic efficacy. The
cessfully to treat oral cancer. 136 Moreover, FA was substituted author also mentioned that in the future, other anticancer drugs
for 5-FU and prepared similarly. The outcome was nearly can be incorporated and combined treatment can be scruti-
identical to the previous one and proposes a new delivery nized. 144 As mentioned, liposomes can be excellent delivery
method. 137 vehicles, but the reticuloendothelial system poses a serious
However, SLNs have both benefits and drawbacks. They challenge. The reticuloendothelial system easily eliminates drug-
have issues with encapsulation during storage, as well as less loaded liposomes. Therefore, the surface of the liposomes has
drug loading capacity. To alleviate the issues produced by SLNs, been coated with a variety of biocompatible polymers, including
a novel nano lipid carrier (NLC) identical to SLNs was devel- PEG, to make up for this. One such research was carried out to
oped. NLCs were made from solid-liquid lipids which remain in increase the apoptosis in OSCCs CAL-27 cells, and a liposome-
a solid state at room temperature. Because NLCs have a large coated nano platform with DOX as the anti-tumor drug was
drug-loading capacity and a lower number of drug content is lost studied. Liposomes were coated with PEG polymer and DOX
during the storage of encapsulated drugs, they have solved the was encapsulated in them. This formula is known as “pegylated
problems. 138,139 The composition of SLNs includes a lipid phase liposomal DOX” (Doxil), which contains uni-lamellar liposomes
(solid fat), surfactants, and drugs. NLCs also contain the same with a coating of methoxy polyethylene glycol (mPEG) attached
ingredients, but the lipid phase is made up of both solid (fat) and to the liposomal bilayer. The analysis clearly states a surge in
liquid (oil) and they form the matrix. 140 Some in vivo advantages apoptosis on CAL-27 cells compared to only the DOX drug.
of both are high tumor suppression, increased animal survival Doxil also has a high percentage of inhibition of CMyc mRNA
time, marked positivity in oral bioavailability, and high lym- and an increase in caspase-3 level. 145 However, although PLD
phatic uptake and targeting. 139 has good safety, long-term use in some patients has been related
to the development of OSCC or precancer lesions. 146
Liposomes Meanwhile, liposome-based gene therapy formulations hold
great promise for the treatment of oral cancer. A simple way to
Liposomes are microscopic lipid, phospholipid, and choles- deliver therapeutic genes to target cells is by using liposomes, a
terol-containing particles. They might be multi-layered or single- promising alternative to viral vectors. Buccal mucoadhesive
layered. Liposomes are normally non-toxic to normal tissues, patches have also attracted a lot of interest for local delivery, and
thus they can operate on tumors by accumulating at the target recent research indicates that when combined with liposomes,
site, giving liposomal drug delivery a boost. 28 An aqueous they have an enhanced anticancer effect. Dr. Feng He Zhang and
volume is encapsulated by a lipid bilayer into a liposome. This colleagues created a mucoadhesive buccal patch with MTX en-
multi-layered lipid has hydrophobic interaction with the lipid capsulated in liposomes. This study was mainly conducted to
layer and hydrophilic interaction with the aqueous layer which achieve a controlled release rate of drugs. The major issue with
gives liposomes an advantage of having both hydrophobic and the buccal mucoadhesive patch is the permeation of the formu-
hydrophilic drugs as given in Fig. 3(D). 141 Some advantages of lation. This was solved by increasing the residence time in the
using liposomes as DDS include reduced toxicity, targeted drug mucosa so that sustained permeation and controlled drug
delivery, biocompatibility, and ease of preparation. The disad- delivery could be achieved. Its anticancer activity was greatly
vantages of using liposomes include their high production costs, enhanced when combined with the liposomal carrier. Cytotox-
their short half-lives, stability issues, and the potential for icity, along with mitochondrial depolarization and pro-oxidant
chemical reactions inside of them. 142 Most commonly, lipo- effects, was observed in hematopoietic stem cells (HSC)-3 cells.
somes fall into one of five categories: conventional liposomes, A significant decrease in cytotoxicity was found as the IC50
pH-sensitive liposomes, cationic liposomes, immune liposomes, value dropped in M-LP-F7. ROS levels were examined for their
and long-circulating liposomes. They can all be utilized in var- pro-oxidant effect. When using M-LP-F7, there was an elevated
ious ways to deliver the drug. 142,143 ROS level. MTX struggles with cellular uptake and site
specificity, along with toxicity issues. A cell apoptosis assay was specifically targeting oral squamous cell cancer. The FA-
performed in HSC-3 cells, and a 3-fold increase was found in cell conjugated tetrahedron was discovered to have the highest level
apoptosis, which solved the MTX problem. Finally, increased of gene silencing. 155 Nucleic acid nanoplatforms with varied
bio-adhesive properties were obtained and a controlled DDS was functionalities offer enormous potential for use in biomedicine
formulated. 147 because of their superior biocompatibility, degradability, and
programmable self-assembly. Not to mention, research on
Nucleic acid RNA delivery based on nucleic acid nanoplatforms is still in
the lab. The assembly speed and purification requirements for
RNAs have become intriguing therapeutic and diagnostic nucleic acid nano assemblies prevent their mass manufactur-
possibilities due to their multiple functions in the genesis and ing. To deepen and widen the study of nucleic acid nanoas-
progression of the disease. Gene expression can be upregulated, semblies, additional research can be done in the following
downregulated, or altered by adding a certain nucleic acid se- areas.
quence to the targeted tissue. Even though RNA molecules offer
bright futures in the treatment and diagnosis of disease, their Exosomes
clinical uses have been impeded by some challenges. 148 RNA
molecules may be prevented from reaching the target tissues by Extracellular vesicles (EVs) are nano-sized lipid bilayer
intracellular and extracellular obstacles, such as breakdown, vesicles that are naturally obtained from cells to ECM, according
immune system clearance, nonspecific interactions with proteins to the International Society for Extracellular Vesicles (ISEV)
or nontarget cells, and renal clearance. 149,150 The delivery of any (Fig. 3F). 156 Exosomes, microvesicles, and apoptotic bodies are
drug to a gene also necessitates the use of nanomaterials based on considered EVs. 157 Exosomes are small, membranous, extra-
nucleic acids. Currently, lipid, polymer, peptide, and exosome- cellular vesicles that are formed by endocytosis, MVB creation,
based nanomaterials have been studied for genetic delivery. 151 and exosome secretion. Morphologically, it is a classic dish or
Given their cytotoxicity and immunological response, nucleic cup formed in a transfer electron microscope (SEM). The density
acid nanomaterials with improved biocompatibility, structural is 1.13–1.19 g/mL, and the size (is 30–100 nm in diameter). 158
programmability, and easy access to alterations are garnering a Several studies have shown that targeting tissues or organs is
lot of interest as potential delivery systems for nucleic acid possible by using exosomes. 159 Exosomes are used primarily as
therapeutics. The intrinsic nuclease in nucleic acid-based nano- diagnostic biomarkers and as effective drug carriers. They may
particles can destroy them in contrast to polymer- or lipid-based load both small lipophilic compounds and big molecules such as
ones, preventing toxicity of the delivery vehicle. 152,153 The DNA, RNA, and proteins. Exosomes have the advantage of
creation of nucleic acid nanoplatform using DNA and RNA being able to easily cross the biological barrier, allowing the
nanotechnology has long been driven by the desire to create contents to be actively transported to the tumor location. 160 They
effective drug delivery systems, molecular biology tools, and are great for delivery but have multiple drawbacks such as the
nanodevices for diagnosis. There are multiple types of nucleic Exosome's capacity to deliver substantial dosages of therapeutic
acid nanoplatforms such as DNA nanoplatforms (DNA origami, substances being restricted. Exosome separation with high purity
DNA polyhedrons, peptide nucleic acids), and RNA nanoplat- is a time-consuming and labor-intensive technique that yields
forms (RNA origami, RNA-protein nucleic acid). When func- little quantities of exosomes. Purification, analysis, and delivery
tionalized with particularly targeted ligands, nucleic acid of these substances are also difficult and therefore they are not
nanoparticles have shown effective cell uptake and recognition widely used. To treat cancer tissues like OSCC, it's critical to
of some molecules and membrane signals. Moreover, nucleic target the tumor microenvironment. As a result, a pH/light-
acid nanoassemblies can be used as theranostic carriers to deliver sensitive bovine milk-based DDS was created for OSCC therapy.
multifunctional payloads, high detection rates, and adjustable It was discovered that exosomes generated from bovine milk
pharmacological profiles. The nucleic acid nanoparticles are contain both synthetic and cell-mediated nano-carrier properties.
shown in Fig. 3(E). There were also nucleic acid delivery vehi- They prepared a milk exosome and loaded it with DOX, which is
cles prepared for oral cancer. For instance, in a recent study, anti- an anticancer drug by imine bond, and mixed it with an an-
miRNA was specifically delivered to malignancies using RNA thracene endoperoxide derivative and named it exosome–DOX–
micelles. Micelles were built using the phi29 packaging RNA anthracene endoperoxide derivative (Exo@Dox–EPT1, NPs).
three-way junction (pRNA-3WJ) as a scaffold. As an interfer- Along with these, chlorin e6 (Ce6) was also used. In vitro and
ence molecule for the prevention of cancer, an oligo with an 8 nt in vivo results showed that ce6 produced plasmonic heat and
locked nucleic acid (LNA) corresponding to the seed region of ROS generation started from EPT1 under NIR irradiation when
microRNA21 (miR21) was added to the micelles. The studies the nanoparticles started accumulating in the tumor site. Endo-
were carried out on oral squamous cell carcinoma. These anti- peroxides undergo thermal cycloreversion and release singlet
miR21-carrying RNA micelles strongly attracted and internal- oxygen to induce apoptosis. This carrier was so set up that it
ized cancer cells, blocked the activity of oncogenic miR21, in- started releasing its action in an acidic environment, and due to
creased the production of the pro-apoptotic protein, and triggered the acidic tumor microenvironment, it started releasing its effect
cell apoptosis. Animal studies showed that xenograft models for at the tumor site. This gave a controlled drug release and also
tumor-targeted therapy and suppression were effective. 154 In made it biocompatible, along with enhancing the antitumor ac-
another study, DNA polyhedron technology was employed to tivity of DOX, which was found effective in treating OSCC. 161
create oligonucleotide nanoparticles. Several ligands were In a new investigation, menstrual mesenchymal stem cell
(MenSC)-derived exosomes were taken and evaluated for treat- formulations. A plethora of anticancer drugs, such as PTX, DTX,
ing OSCC. The study was conducted on hamster buccal carci- cisplatin, and MTX, can readily be combined with cyclodextrin
noma. An intratumoral injection was given to a hamster, which to increase their targeting and effects. 165 The features of cyclo-
showed an increase in anticancer effects and blood vessel loss in dextrins can be used in formulations through various routes of
the tumor. In the same study, an anti-angiogenic effect was also administration after the major difficulties of the drug that de-
seen, which has been said to be more advantageous in OSCC velop as a part of the complex are removed. 19 Wang et al. pre-
treatment. This effect is something new and unique to exosomes. pared a soluble supramolecular complex of two curcuminoids
Endothelial cells are said to be responsible for the anti-angio- wherein phospholipid compound technology and hydroxypro-
genic effect. They had a significant effect on a decrease in tumor pyl–cyclodextrin (HPCD) were integrated. This was done to
volume after four injections were given to the hamster cheek remove the limitations like poor aqueous solubility and bio-
pouch. This in vivo study has given a new exosome-based availability of curcumin and demethoxycurcumin. Curcumin is a
nanoplatform a boost for future OSCC-related treatment. 162 natural analog of phenol that is extracted from turmeric and has
MicroRNA (miRNA) plays a crucial part in oral cancer. several pharmaceutical uses and benefits. There is an obvious
When the miRNA is downregulated, the progress of oral cancer improvement in solubility, drug release mechanism, GI tract
is hindered, but the question is which miRNA will be most ef- absorption, and oral bioavailability by using PC-HPCD supra-
fective and in which mode will it be effective. To find the answer molecular complexes. The study suggested that particle size
to the question, human bone marrow mesenchymal stem cells played a significant role as it was <200 nm in raising bioavail-
(hBMSCs)-derived exosomes are identified and scrutinized for ability along with the charge, which was found to be on the
their possible effect on oral cancer. Bone marrow mesenchymal neutral side. Another interesting thing reported is the in vivo
stem cells (BMSCs) possess anti-apoptotic and anti-inflamma- bioavailability of both curcumin and demethoxycurcumin
tory properties. Due to their small size (40–100 nm) and high without any complex is completely different from each other.
impact on cancer cells, exosomes are considered for this. Also, They are found feasible for oral delivery as an anticancer drug
the regulatory mechanism of BMSCs with Collagen Type X because of their low cost of preparation and ease of formula-
Alpha 1 Chain (COL10A1) and microRNA-101-3p (miR-101- tion. 166 pH is a barrier in targeted drug delivery and can cause
3p) was taken into consideration. COL10A1 is a human protein several problems, including the early release of drugs. Some
that encodes the alpha-type chain of X collagen as it belongs to researchers used an acetylated α-cyclodextrin based pH-re-
the collagen family. The outcome of using exosomes with sponsive nanoplatforms to overcome this. The pH of the tumor
hBMSCs isolated from oral cancer on the tumor microenviron- is 5.7–7.8 and this system was prepared to reach the tumor
ment was evaluated. In-vivo and in-vitro studies suggest that targeting site by bearing the pH of the tumor. As a result of their
miR-101-3p secreted by hBMSCs inhibits the proliferation of resistance to pH, this complex has an advantage over them. This
TCA8113 cells and tumor growth by downregulating COL10A1 formulation was subjected to in-vivo testing. Results suggested
as suggested via in-vivo and in-vitro studies. Furthermore, the that the α-cyclodextrin pH-sensitive system suggested good
inhibitory effect was also seen when hBMSCs-derived exosomes biocompatibility in vivo and in vitro studies, and also an in-
loaded with miR-101-3p were given to nude mice and confirmed crease in cytotoxic activity was seen in tumor cells. Also, the
by a tumorigenicity assay. 163 major benefit of these systems is that they can reverse the
multidrug resistance of PTX-resistant cancer cells. 167 Although
Cyclodextrins cyclodextrin has many advantages, getting it from the lab to the
clinic would be a financial challenge. Furthermore, the prepa-
Cyclodextrins are another nanotechnology-based delivery ration is a time-consuming procedure, and if they are not em-
system used for targeting oral cancer cells. They are of cyclic ployed in a controlled environment, they may cause major
shape, having an oligosaccharide family. They contain at least toxicity.
six units of glucose and are derived from the enzymatic degra-
dation of starch, which can contain hydrophobic drugs in- Targeted therapeutics for oral cancer
side. 28,164 Their cyclic form is commonly referred to as a cage, in
which drug molecules are confined due to the complexation There are few treatments for OSCC, and traditional methods
action. Any lipophilic drug molecule can readily lure inside and (surgery, radiation, and chemotherapy) have a major influence
block any hydrophilic molecule from entering. Cyclodextrin's on the quality of life. Therefore, there is a need to develop new
exterior surface contributes to solubilizing effects when in an strategies for drug delivery that can aid in the targeted distribu-
aqueous solution. 165 Because of their advantages in increasing or tion of drugs, reducing the number of side effects and toxicity in
changing the poor physicochemical qualities of drugs, cyclo- patients. Some of these approaches are intra-tumoral drug
dextrins are getting an edge over competitors. Cyclodextrins delivery, local drug delivery, phototherapy approaches, and
provide increased stability, bioavailability, and stability. Tar- microbubbles-mediated ultrasound. Each system has its mecha-
geting efficiency can also be improved while reducing the danger nism of action and plays different roles in drug delivery as given
of unfavorable outcomes and harmful effects. Concerns about in Fig. 4. 177 These are all novel strategies that can be utilized in
pharmacokinetic characteristics and pharmacological activity conjunction with nanotechnology to improve the treatment of
can be addressed, while therapeutic efficacy is maintained. 141 oral cancer while also lowering adverse effects. However, just as
For these features, cyclodextrins are a good multifunctional ex- a coin has two sides, there are advantages and disadvantages to
cipient for targeted DDS and have a lot of uses in pharmaceutical employing this approach as shown in Table 4.
Fig. 4. (A) Represents Intra-Tumoral drug delivery system. Drugs loaded nanoparticles are directly given to the tumor site and via injection method and are
released via passive targeting directly to tumor and thus reducing unwanted effects; (B) Tumor cells are targeted by applying a mucoadhesive patch or pastes
near buccal cavity at the site of tumor. Therapeutic agents directly produce anticancer effect on the infected part leaving the rest and hence reducing side effects;
(C) Photothermal therapies include two therapies PDT and PTT. A near infrared laser irradiation is used and heat is dissipated which depicts direct killing of
cancer cells via PTT. When excitation of cells occurs, it moves between excited and ground state. This leads to release in ROS from biomolecules and hence cell
death. (D) Typically, a microbubble with a drug load is inserted into the patient's system. When they get close to the tumor site, an ultrasound is used to break
down the microbubble and effectively deliver the drug to the tumor site.
photosensitizer pheophorbide a (Pa) derived from chlorophyll-a

Targeted drug delivery system in oral cancer
was taken and the therapeutic effect was studied using PDT.
Intra-tumoral drug delivery Pheophorbide (Pa) possesses independent cytotoxic activity and
Solid tumors have different biological features than normal is identified as a second-generation photosensitizer. Synthetic
cells. These can be defective lymphatic systems and defective photosensitizer Pa was administered via intratumoral delivery in
blood vessels. An anticancer drug should ideally reach the core an in vivo murine OSCC in mice. To find out the antitumor ac-
of tumors and destroy the cell itself by damaging the molecule tivity in vivo study of IT Pa-PDT on AT-84 Cell-Bearing CH3
residing in the tumor but most drugs can only reach the periphery mice was performed. It was determined that after intratumoral
and so DDSs come to the rescue which can directly reach the delivery of Pa successful penetration was found as observed in
center of the tumor and can damage the cell. Furthermore, the IVIS imagining system. The IT Pa-PDT in vivo antitumor effect
problem of tumor resurgence which happens in many cases can was tested on mice bearing AT-84 cells. Everyday testing was
be solved. Direct delivery of drugs inside the tumor shell is carried out using a laser diode and regression of about 60 % was
known as intra-tumoral drug delivery. To overcome drawbacks found in comparison with the control group without any system
and limitations scientists have made new nanoparticulate intra- toxicity and other adverse events as seen by fluorescence
tumoral DDS as shown in Fig. 4(A). It can easily accumulate in imagining. Thus, Intratumoral treatment of Pa-PDT (IT Pa-PDT)
solid tumors and have an effect inside the tumor owing to its inhibited the growth of OSCC, and also there was induced ap-
submicronic size. 185 To prove the accumulation in a recent study optosis which showed potent antitumor activity. IT Pa-PDT can
Table 4
Merits and demerits demonstrated by various targeted delivery systems.
Drug delivery systems Merits Demerits Reference
Intratumoral • High Dose administration • There can be needle track metastasis 178,179
• It is directly given to tumor site

• Minimal Systemic Toxicity • Discomfort to patient
Local/site specific • Increase Bioavailability • Nano Toxicity 180
• No first pass metabolism

• Entry into systemic circulation is limited • Systemic toxicity
• Less side effect • Removal of nanomaterial during reticuloendothelial system
Phototherapy • Increased drug concentration in tumor • Poor accumulation in tissues 181–183
• Superficial tumor types

• High apoptosis rate • Tumor cell targeting
• Penetration rate is very high • Metastasis
Microbubble mediated utlrasound • Size change can be possible • Accumulation in spleen and liver can occur 184
• Improves efficacy of drug

• High drug loading capacity
• Improves imagining technique • Toxicity can be a concern
• Targeted to specific tumor site • Shorter half life
also be used as a diagnosis for OSCC via fluorescence spec- favorable site for drug delivery because of the ease of drug ad-
troscopy or molecular imagining. 186 A peptide-based immuno- ministration and the ability to bypass first-pass metabolism. The
therapy which is an injectable, biomaterial-based platform for major problem of any buccal drug delivery is the acting duration
intratumoral drug delivery named synerGel was evaluated. It at the site of application. This has led to the development of a
helped in the removal by immune-mediated treatment in oral new mucoadhesive delivery system in which polymeric NPs
tumors of the murine model. 187 Soluble microneedles (MN), were combined. A study was conducted by using Curcumin
which are simple to release into tumor cells, are one type of loaded with polycaprolactone nanoparticles and coating with
intratumoral injection. They are collections of incredibly small chitosan as a mucoadhesive polymer wherein the drug delivery
needles, typically in the micrometer range (<1000 m), made of was by the buccal route. It aimed to assess the cytotoxicity in
water-soluble materials. They make pores in the skin, and when SCC-9 cells along with the diffusion profiles on porcine oeso-
the microneedles dissolve, the drug payload is released. This phageal mucosa. The results of in vitro permeability studies
method was applied in a recent study where MN was used for suggested an increased residence time at the delivery site and
immunotherapy in a murine HNSCC model with a tobacco elevated therapeutic activity. Also, during the study of PCL
signature. Results indicated that >90 % tumor response was nanoparticles, it was noted that there was no response in the
achieved with both systemic and local anti-CTLA-4 therapy. The sensorgram when the drug was given without coating chitosan.
distribution of anti-CTLA-4 antibodies from regions far from Cur-NP CSL showed a reduction in toxicity to almost 45 % of
draining lymphatic basins was, however, constrained by local- viable cells and it was found due to drug encapsulation in
MN delivery. In the end, the study recommended an enhanced nanoparticles. Ultimately it was observed that Cur-NP-CSL gave
intratumoral and immunotherapy-based treatment for SCC. 188 reduced SCC-9 human oral cancer cell viability by inducing
apoptosis. 168 Recently in-vitro research was conducted by using
Local drug delivery Ellagic acid which was loaded with chitosan nanoparticles.
As the name suggests delivery of a drug directly to the in- Several benefits are observed for using biopolymeric NPs such
fected region (tumor in case of cancer) is local drug delivery. as high drug loading capacity, protection against drug degrada-
Direct delivery can result in reduced drug absorption into the tion, and easy administration of the drug. Ellagic acid is a
systemic circulation, lowering the risk of a drug overdose. For promising anticancer agent but has a low bioavailability and
oral cancer, local delivery is usually done with a patch or paste sustainability which can be easily compensated by using chito-
that is put to a tumor location in the buccal cavity as depicted in san as the carrier. The in-vitro results exhibited controlled drug
Fig. 4(B). For an instance, a liposome and alginate combined release for up to 48 h in a Phosphate buffer medium. This helped
mucoadhesive paste for local DDS was prepared for the treat- in stopping the addition of the human oral cancer cell line (KB).
ment of oral cancer. This combination gave a 20 % controllable Cytotoxicity was observed at a very low concentration of 0.953
release rate in 2 h when they are cross-linked and also 80 % of g/mL which gave a possible hint of greater intracellular uptake of
the paste was retained in the tongue tissue. Due to the success of positive charge area. The best ratio suitable for effective drug
the paste, it was used for therapeutic agent delivery in an ex- delivery with high drug loading capacity was identified as the 4:1
periment where DOX was inserted into liposomes and the same chitosan to TPP ratio. 189 Mucoadhesive patches are used sig-
alginate paste was created. This delivery technique was found to nificantly for local drug delivery. In accordance, a new liposomal
be extremely effective in the treatment of cancer cells. This re- nanoparticle along with chitosan, poly (vinyl alcohol) (PVA),
solved the issue of degradation, absorption, and poor mucoad- and hydroxypropyl methylcellulose (HPMC) is developed for
hesive property completely. 172 The buccal route is considered a local delivery of MTX anticancer drug. This nanoformulation
was encapsulated into an optimized mucoadhesive patch having cells. 5-aminolevulinic acid is considered a second-generation
a sustained release profile. Liposome was considered favorable photosensitizer and it is an endogenous 5 carbon compound. It
because of their biodegradability, low toxicity, and high bio- can produce strong protoporphyrin IX (PpIX). This combination
compatibility. The patch prepared was given by buccal route due can easily and very quickly penetrate cancerous tissue without
to increased residence time and improved drug release. In vitro affecting normal ones. There was inhibition in the growth of
and cell, apoptosis studies were conducted by various methods SCC25 cells when 5-ALA mediated laser irradiation was per-
but majorly with flow cytometry. Result gave a clue of increased formed in vitro. It showed a major effect on cell apoptosis as the
cell apoptosis by almost 3-fold when the M-LP-F7 system was concentration of the drug was increased. Indication of 5-ALA
used. By DCFDA assay it was confirmed that M-LP-F7 exerted a regulating the growth of OSCC was seen during in vitro and
high ROS level which gave a pro-oxidant effect in HSC-3 cells. in vivo studies and is also governing the metabolism and pro-
There was a significant drop seen in IC50 which was 75 g/mL M- liferation of SCC25 cells. 194 5-ALA has become prominent in
LP-F7 against 142 g/mL M-LP and 180 g/mL MTX and this was PDT and they both are combined with iron chelator deferasirox
attributed to the increased permeability of MTX. It was con- (DFX) to evaluate their synergistic effects on oral tongue squa-
cluded that CH-HPMC-PVA-based MTX-LP-F7 was suitable mous cell carcinoma (OTSCC) by both in vivo and in vitro
for controlled and sustainable drug delivery with decreased testing. Deferasirox is approved by USFDA for the prevention of
toxicity and adverse effect. 147 Another study was conducted by iron chelation during blood transfusion and also has its part in the
incorporating oxaliplatin (OXPt) into mucoadhesive chitosan anticancer effect. Accordingly, a female BALB/c nude mouse
nanoparticles. These nanoparticles were prepared as a topical was used for in vivo experiments. Laser irradiation at 635 nm
agent for ex vivo evaluation of porcine mucosa under passive and was given and in vivo study suggested that SCC-25 cells were
iontophoretic treatment and provided a controlled delivery after a suppressed by 5-ALA and combined 5-ALA/DFX system even
burst effect. As a result, the drug penetration increased 3 folds on tumors having a very small size. Due to DFX accumulation of
and oral tumor cell apoptosis also exceeded the normal amount PpIX which is a precursor of 5-ALA was increased which ulti-
of drug when given with iontophoretic. 190 To treat a variety of mately promoted 5 -ALA-based PDT and iron chelation on
disorders with local or systemic effects, buccal drug delivery OTSCC. After the laser radiation mixture of DFX/5-ALA in-
may be the preferred therapeutic method. In a new study, re- creased the production of ROS in SCC-25 which led to further
searchers suggest creating a thermosensitive hydrogel with chi- oxidative damage of the mitochondrial membrane. According to
tosan-coated lipid-core nanocapsules that are loaded with both in vivo and in vitro studies DFX enhanced the 5-ALA-
curcumin to promote mucoadhesion and get around some of the based PDT activity against OTSCC and it also drastically
drawbacks of this mode of administration. Poloxamer® 407 and inhibited the cell growth of OTSCC. 195 5 ALA is commonly
hydroxypropylmethylcellulose were combined to create hydro- used in the treatment of OSCC. Another study was conducted
gel. In vitro testing of formulations against an oral squamous utilizing 5 ALA as a photosensitizer to evaluate the PDT impact
carcinoma cell line revealed a significant decrease in cell via- in OSCC. The study was primarily concerned with the impact of
bility across the board for all groups tested. These results showed 5 ALA on the phenotypes of cancer stem cells and the mainte-
that the suggested nanosystem is mucoadhesive and has the nance of stem cell features. The viability and migration of the
ability to provide medicines to the buccal cavity. 191 OSCC cell lines significantly decreased after PDT. The
clonogenic and tumor sphere formation assays, along with RT-
qPCR, were used to evaluate the CD44 high/ESA high, CD44 high/
Targeted treatment in oral cancer
ESA low, and CD44 low populations. Following PDT, there was a
Phototherapy based treatment drop in the percentage of CD44high/ESAhigh cells, which was
Phototherapy mainly consists of two types photodynamic accompanied by an increase in CD44low cells and a functional
therapy (PDT) and photothermal therapy (PTT). PDT has been reduction in the potential for sphere and colony formation. PpIX
used because of its specific and sensitive targeting of tumor cells. levels were higher in CD44 high/ESA high cells, which contributed to
PDT works by eliminating tumor cells or damaging the leaky their increased sensitivity to PDT. Overall, their findings show that
vasculature, which can trigger a variety of immunological re- 5-ALA-mediated PDT reduces oral CSC percentage while also
sponses. 192 PDT is a non-invasive approach to anticancer ther- impairing their functional capacity and causing differentiation. 196
apy. The PDT consists of a photosensitizing agent which is the Also, as Ahn et al. suggested Intratumoral treatment of Pa-
most essential element after which the irradiation is given which PDT (IT Pa-PDT) inhibited the growth of OSCC, and also there
is absorbed by the agents at a specific wavelength. Photosensi- was induced apoptosis which showed a potent antitumor activ-
tizer normally generates ROS which are the primary cause and ity. 186 PDT is still constrained by photosensitizer's poor tumor
effective cancer cell assassins, but photosensitizers are poorly targeting capabilities and low stability, despite a few compounds
accumulated in tumor cells. 183,193 This mechanism is well rep- being approved for clinical usage. This difficulty is readily
resented in Fig. 4(C) PDT has uses in topical therapy, adjuvant handled if we employ nanomaterials in conjunction with PDT.
therapy, palliative treatment, and surveillance modality. Nano- Small molecular photosensitizers can be incorporated into
particles have proven to be important in PDT treatment, either functional nanomaterials to improve the photosensitizer stability
actively participating or passively acting as carriers for photo- and tumor-targeted delivery, and some functionalized nanoma-
sensitizers. 192 terials can also be deployed as photosensitizers on their own. 197
There was a study conducted on 5-ALA mediated photody- PTT, on the other hand, is less invasive, toxic, and has local
namic study which resulted in a decrease in the growth of SCC25 treatment effects. PTT uses a near-infrared laser (NIR) to target
Fig. 5. Drawbacks of nanomedicine.
tumor cells through an optical fiber, and light energy is converted thermal ablation in the cancer cells when they were exposed
to heat by this optical fiber as shown in Fig. 4(C). 198 This process under 980 nm NIR. 200
is called hyperthermia. This therapy does not depend on ROS as
in PDT, and so oxygen is necessary to increase the temperature Microbubble-mediated ultrasound treatment
of the milieu but does not generate a cytotoxic effect on cancer Microbubbles are microscopic gas bubbles that are utilized as
cells. 199 PTT is not employed in clinical settings because the ultrasonic contrast agents. Ultrasound imaging is a valuable tool
laser's intensity is so strong that it can harm normal tissues for cancer detection and treatment. By infusing microbubbles
around tumor cells. 183 Because the heat it emits can readily kill into the bloodstream, ultrasound pictures can be considerably
normal cells, this therapy is only used in specific situations. enhanced. This combination is also employed for local drug
DDSs incorporated into PTT can easily solve the limitations delivery for the treatment of cancer, as given in Fig. 4(D). Tar-
related to it. Darwish et al. prepared a chemo PTT in which they geted therapy can be created by combining ligands and mono-
employed VCR integrated into gold nanorods as a photothermal clonal antibodies that bind to specific receptors expressed on
reagent for OSCC therapy. 126 In another study polyethylene, cancer cell membranes with microbubbles. Anticancer drugs
glycol-stabilized PDPN antibody (PDPN-Ab) combined with combined with microbubbles work on the principle of sono-
DOX and AuNPs were prepared to evaluate the antitumor effect poration, which improves biodistribution and reduces the tox-
in Chemotherapy and PTT. The (PDPN Ab)-AuNP-DOX icity of drugs. 201 Combining ultrasound with microbubbles
showed an increased antitumor effect in both in vitro and in vivo increases cell membrane permeability, which aids in drug dis-
experiments, but when they were combined with laser irradiation tribution and intracellular drug delivery, nanoparticle drug de-
or PTT it enhanced the antitumor effect even to a greater ex- livery, and other therapeutic agent delivery, as evidenced by
tent. 115 A recent study on mesoporous nitrogen-doped carbon various pre-clinical trials. Sonoporation has shown increased
quantum dots (NCQD) has captured carbon spheres (NCQD- microvascular permeability and it usually occurs through inertial
HCS) and when an in vitro experiment was conducted on a cavitation that causes tremendous growth and collapse of
human cancer cell line, the NCQD-HCS were internalized due to microbubbles. 202 It is a DDS used for the intracellular delivery of
anticancer drugs that cannot reach cancer cells under normal patients. Several adverse effects, such as nausea and vomiting, as
conditions. 203 well as drug aggregation and toxicity, have hampered the tran-
Recently, cetuximab-coated albumin microbubbles (CCAM) sition from research to bedside treatment. These controlled DDSs
were used for ultrasound irradiation of OSCC cells (HSC-2) and have been around for a while, but side effects continue to be an
it was found that CCAM increased apoptosis by nearly 5 times issue, necessitating more research. For breast, ovarian, and
(154). The signal transducer and activator of transcription-3 pancreatic cancer 205 there are various FDA-approved nano-
(STAT3) transcription factor have been linked to the treatment of formulations, such as Abraxene (calgene) and Doxil, but there is
head and neck cancer. This STAT3 decoy microbubble was a need to develop similar formulations for oral cancer. As a
previously used with ultrasound-targeted microbubble cavitation result, with continued research and development of nanotech-
(UTMC) to decrease tumor growth in murine squamous cell nology, nanomedicine will play a better and larger role in the
carcinoma. In this experiment, they loaded STAT3 decoys on treatment of oral cancer in the future.
cationic lipid microbubbles (STAT3-MB) or loaded them on
liposome-conjugated lipid microbubbles to form STAT3-loaded Declaration of competing interest
liposome-microbubble complexes (STAT3-LPX). An in vivo
study of this UTMC combined drug was done on the CAL33 The author declares no conflict of interest.
(human HNSCC) tumor murine xenograft model and results
suggested that UTMC with STAT3-MB had strong anti-tumor Acknowledgement
effects, with fewer tumors and increased chances of survival
compared to that of UTMC with microbubbles loaded with a The authors are thankful to Nirma University for providing
mutant control decoy and untreated control groups. 204 the required assistance in the preparation of this manuscript.
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BASIC SCIENCE

Nanomedicine: Nanotechnology, Biology, and Medicine

Review Article nanomedjournal.com

Insight on nano drug delivery systems with targeted therapy in treatment of

Introduction Oral cancer pathophysiology is quite intricate, with numer-

Fig. 1. The multistage progression of oral cancer.

tic acid (RGD)

with anti-EGFR conjugated AuNP

cles, and as a result, insulin was shown to be

photosensitizer pheophorbide a (Pa) derived from chlorophyll-a

• It is directly given to tumor site

• No first pass metabolism

• Superficial tumor types

• Improves efficacy of drug

Fig. 5. Drawbacks of nanomedicine.

Conclusion and future prospects References

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