NANOVESICLES

INORGANIC NANOPARTICLES
ORGANIC NANOPARTICLES
Quantum dots

VIRAL NON-VIRAL NANOPARTICLES

Silver NPs
NANOPARTICLES Superparamagnetic
iron oxide NP
Polymeric Nanoparticles (SPION)
Lipid Nanoparticles (LNPs)
(Chitosan, Alginate, PLGA)
Titanium
Synthesized LNPs Gold NPs Dioxide
NPs
Water-filled Lipid-filled
(Nanovesicles) OIL-in-WATER (O/W) SYSTEM
Cell derived LNPs Niosomes

Adeno-associated virus
Retrovirus Nanoemulsion
Adenovirus Liposomes Transferosomes Ethosomes
Solid lipid nanoparticles (SLN)
Exosomes Nanostructured lipid carriers (NLC)
Self-emulsifying Trans-ethosomes
Lipid based nanocarriers WATER-in-OIL-in-WATER
(W/O/W) SYSTEM

SNEDDS SMEDDS
Bacteriophage
Self-Nanoemulsifying Self-microemulsifying
Drug Delivery System Drug Delivery System
 Transport mechanism of nanosized lipid-based delivery
systems

Subramanian, Parthasarathi. "Lipid-Based Nanocarrier System for the

Effective Delivery of Nutraceuticals." Molecules 26.18 (2021): 5510.
 Summary of the lipid-based delivery system

System Definition Advantages

•Extensively studied lipid-based system.
•Employed for hydrophobic, hydrophilic, and amphiphilic
Phospholipid bilayered vesicular systems having an aqueous
bioactive compounds.
Liposomes core enclosed by one (unilamellar) or several (multilamellar)
•Improved pharmacokinetics.
concentric phospholipid membranes.
•Can be used for localized delivery.
•Commercialized for different nutraceutical formulations.
•Biodegradability, compatibility with biological systems, and
Similar to liposomes, but bilayers for the niosomes are made up
Niosomes vesicle characteristics.
of nonionic surfactants.
•Less expensive to formulate than the liposomes.
•Reduced leakage of the incorporated compound.
SLNs are matrix lipid particles formulated by replacing liquid •Protect the entrapped compound from harsh GI conditions.
Solid lipid nanoparticles (SLNs)
lipid portions in emulsion formula with solid lipids. •Application of organic solvents can be avoided.
•Large-scale production.
•Higher loading capacity.
•Affordable technique.
Second generation of lipid nanoparticles containing a mixture of •Application of organic solvents can be avoided.
Nanostructured lipid carriers (NLCs) •Minimal leakage of bioactives during storage.
solid and liquid lipids.
•Entrap both hydrophilic and hydrophobic bioactive
compounds.
•Simple formulation technique.
SEDDSs are isotropic mixtures of oil, surfactant, and
Self-emulsifying drug delivery •Thermodynamic stability.
cosurfactant that spontaneously form emulsion upon milk
system (SEDDS) •Spontaneous production of emulsion in the stomach motility.
agitation.
•Enhanced absorption and increase in bioavailability.

Subramanian, Parthasarathi. "Lipid-Based Nanocarrier System for the

Effective Delivery of Nutraceuticals." Molecules 26.18 (2021): 5510.
 Lipids and emulsifiers used for lipid nanoparticle production
Bioactive Compounds Lipids Emulsifier System Model Production Technique Research Findings Reference

Phosphatidylcholine, Prolonged and sustained release of curcumin was observed for 4 days with a low
Curcumin -- Liposome In vitro release Solvent dispersion and electrospray process [93]
cholesterol percentage (~37%) of curcumin release.
Bovine milk phospholipids, Thin-film evaporation and ultrasonic dispersion Liposomes prepared by krill phosphate were easily digestible and showed higher
Curcumin -- Liposome In vitro digestion [49]
krill phospholipids method bioavailability than the bovine milk phosphate liposomes.

Stearic acid and capric Tween 80 and Pluronic Nearly 41% of curcumin release from NLCs in simulated gastric medium up to 2 h
Curcumin NLC In vitro digestion Microemulsion + sonication [94]
triglycerides F127 and the drug release mechanism might be diffusion of curcumin from the matrix.

PEG100SE-stabilized SLNs were highly permeable across the intestinal

Curcumin Tristearin PEG10SE, PEG100SE SLN In vitro digestion High-shear homogenization and ultrasound epithelium and improved the oral bioavailability by 6-fold compared with [95]
PEG10SE-stabilized SLNs.
Precirol® ATO5 and In vivo pharmacokinetic Pharmacokinetic studies in mice revealed 4.48- and 3.41-fold increase in CMax for
Curcuminoids Poloxamer 188 NLC, SLN High-shear homogenization and ultrasound [96]
Compritol® 888 ATO study in mice SLN and NLC formulation, respectively.

Transferrin-attached lipid nanoparticles can enhance the permeability across the

Cell line studies in
Curcumin Cetyl palmitate Tween 60 NLC, SLN High-shear homogenization and ultrasound blood–brain barrier (BBB). Transferrin is a transporter present in the luminal side [97]
hCMEC/D3
of the brain and leads the receptor-mediated transcytosis across the BBB.

Compritol® 888 ATO and Poloxamer 188, Tween 80, In vivo antidepressant Curcumin NLCs can be a neuroprotective agent. An in vivo study in rats improved
Curcumin NLC Hot homogenization [98]
oleic acid Span 80 study in rats the behavioral despair and enhanced the antidepressant and anxiolytic activity.

The healing capacity of wounds by curcumin lipid formulations was assessed

Curcumin Triglycerides Lecithin, Kolliphor HS15 NLC, SLN In vitro release kinetics Hot homogenization through scratch assay. After 24 h of exposure, the healing effects for NLCs and [99]
SLNs are 10.61% and 4.06%, respectively.
No cytotoxic effects were recorded for the undigested nanostructures and SLN
Curcumin Beeswax Lecithin, Tween 80 NLC, SLN In vitro digestion Hot homogenization formulation. However, a decrease in cell viability of NLC was attributed to the MCT [100]
oil digestion products for the cytotoxicity effects.
Dispersion in aqueous phase followed by
Quercetin Phosphatidylcholine Liposomes Cell line study Eudragit-coated liposomes were safe in the intestinal cells without cytotoxicity. [101]
sonication
Liposomal formulations were showing poor stability (flocculated) in the simulated
Quercetin and linseed oil Phosphatidylcholine Liposomes In vitro digestion Ethanol injection method gastrointestinal digestion. However, hydrogel beads of liposomes were stable in [102]
the digestion environment.
In vitro release and in vivo In vivo study on mice bearing breast cancer showed 5 mg kg−1 of resveratrol was
Resveratrol Tripeptide lipid CDO Sucrose laurate Liposomes Thin-film hydration method [103]
antitumor activity more effective and 10 mg kg−1 completely inhibited the tumor growth.
During digestion, first, 10 min β-carotene was showing burst release, and then for
Vitamin C, β-carotene Cholesterol Yolk lecithin Liposomes In vitro digestion Ethanol injection method the next 110 min, over 70% of bioactive substances were slowly released in the [104]
intestinal phase.
The administered rutin SEDDSs spontaneously form O/O/W double emulsion in
Polyglycerol
SEDDS In vivo pharmacokinetic Mechanical stirring followed by dropwise the GI tract and improve the solubility and absorption process. A nearly 1.76-fold
Rutin Glycerol monostearate polyricinoleate, Span, and [105]
double emulsion study in rats addition of surfactant increase in bioavailability was observed for the SEDDS formulation compared with
Tween
the rutin suspensions.
SEDDS formulation improved the oral bioavailability of ferulic acid by 1.74-fold and
SEDDS In vivo pharmacokinetic strengthened the hypnotic efficacy. Brain tissues from the hippocampus and
Ferulic acid Labrasol Manual mixing of formulation ingredients [106]
Microemulsion study in rats hypothalamus showed an increase in levels of 5-HT and 5-HIAA, which regulate
sleep.
 Clinical trials on lipid-based formulations

BIOACTIVES FORMULATION TITLE STUDY AIM DISEASE/CONDITION REFERENCE

Evaluation of liposomal curcumin in healthy Safety and tolerability of increasing doses NCT01403545
Curcumin Liposomes Health volunteers
volunteers of intravenous liposomal curcumin (ClinicalTrials.gov)
Evaluate the bioavailability of curcumin of NCT03530436
Curcumin Liposomes Comparison of curcumin bioavailability Health volunteers
eight different formulations (ClinicalTrials.gov)
A phase 1 study establishing the safety of
Investigate the safety of administering
intrapleural administration of liposomal Patient with long-term ACTRN12620001216909
Curcumin Liposomes liposomal curcumin directly to the tumor
curcumin (LipoCurc) as a palliative treatment for chest drain (ANZCTR.org.au)
site
malignant pleural effusion
A randomized double-blind placebo-controlled Brain-derived
Investigate the bioavailable fraction of ACTRN12621000104853
Curcumin LipiSperse® study to evaluate the effect of curcumin on neurotrophic factor in
curcumin on BDNF levels in healthy adults (ANZCTR.org.au)
BDNF levels in otherwise healthy adults healthy adults
Patients with mild to
A comparison of the plasma levels and safety of
Evaluate the bioavailability of coenzyme moderate ACTRN12616001527459
Coenzyme Q10 Liposomes coenzyme Q10 from four different formulations
Q10 in liposomal formulation cardiovascular (ANZCTR.org.au)
in healthy adult volunteers
disease
The impact of micelle size and increased
Evaluate the bioavailability of Coenzyme
Coenzyme Q10 SEDDS absorption of ubiquinone using a novel delivery Healthy volunteers [40]
Q10 in SEDDS formulation
system (AquaCelle®)
A self-emulsifying omega-3 ethyl ester
Evaluate the bioavailability of omega-3 Healthy volunteers
formulation (AquaCelle) significantly improves
EPA, DHA SEDDS fatty acid concentrations of SEDDS under the low-diet [41]
eicosapentaenoic and docosahexaenoic acid
formulation condition
bioavailability in healthy adults
Trans- Trans-resveratrol oral bioavailability in humans Pharmacokinetics of resveratrol–
LipiSperse® Healthy volunteers [42]
resveratrol using LipiSperse™ dispersion technology LipiSperse® delivery complex
Schematic representation of popular solid lipid
nanoparticle production method
Region specificity and role of gastrointestinal tract during food digestion (left) and flow diagram of in vitro INFOGEST
digestion protocol (right).
Classification of vesicular systems
Production techniques of liposomes
Liposomes were first described by Bangham and Horne in
1961 at the Babraham Institute in Cambridge

Liposomal vesicles are made up of a lipid bilayer

surrounding the inner aqueous compartment that may be
filled with solutions of molecules of interest.

Hydrophobic systems can also be incorporated in

liposomes as they reside between the acyl hydrocarbon
chains of the vesicle membrane.
Liposomes appear as the simplest mimics of a biological
cell.
When phospholipids are dissolved in water and sufficient energy is provided to the solution by
sonication, heating, homogenization, or other methods, bilayered structures are formed

This phenomenon is thought to be related to the critical micelle concentration (CMC), defined as the
concentration of lipids in hydrophilic solvents above which lipids form vesicles or micelles, rather than
remaining soluble in their monomeric form.

The self-assembled nature of the lipid bilayer membrane renders it a complex and dynamic system,
which shows behavior and properties that are strongly dependent on composition and
temperature

Cholesterol is also a common component that stabilizes the liposome bilayer by reducing its
permeability in physiological fluids.
Typical for PC bilayers at low tem-
perature is the gel phase, also called the
solid-ordered (so) or Lb phase. In the
gel phase, the acyl side chains of the
lipids are well packed, leading to a low
lateral mobility of the phospholipids.

Upon heating, the lipids will “melt” above

their phase transition temperature (Tm)
and form a fluid, liquid-crystalline phase,
also called the liquid-disordered (ld) or
La phase, with much higher lateral
diffusion rates

Barba-Bon, Andrea, Mohamed Nilam, and Andreas

Hennig. "Supramolecular chemistry in the
biomembrane." ChemBioChem 21.7 (2020): 886-910.
Scheme of liposome classification

Ganganboina, Akhilesh Babu, et al. "Dual modality sensor using liposome-based signal
amplification technique for ultrasensitive norovirus detection." Biosensors and
Bioelectronics 157 (2020): 112169.
The following phospholipids are
more frequently encountered:
phosphatidylethanolamine (PE),
phosphatidylcholine (PC),
phosphatidylserine (PS),
phosphatidylglycerol (PG)
Figure 1. Laboratory
procedure for liposome
formation. A lipidic film is
formed after dehydration in
a rotary evaporator, and
subsequently rehydrated
with an aqueous solvent.
The formed vesicles
present different sizes and
lamellarity, and are then
further treated by sonication
or extrusion procedures to
achieve the desired
liposome characteristics.

Ganganboina, Akhilesh Babu, et al.

"Dual modality sensor using
liposome-based signal amplification
technique for ultrasensitive norovirus
detection." Biosensors and
Bioelectronics 157 (2020): 112169.
Structural representation of liposomes and different types of ethosomes
 Water-filled Colloidal Nanoparticles

The 1st The 2st The 3st

Generation Generation Generation
Phospholipid Bilayer Edge activator Edge activator
Hydrophylic Head & Lipophilic Tail (e.g. single chain (e.g. single chain
surfactant molecule) surfactant molecule)

Lecithin Tween80 Ethylalcohol

Liposomes Transferosomes Ethosomes

Transethosomes
 A non-ionic Surfactant-based Vesicle
Niosomes can be used for targeted drug delivery system
(increased bioavailability & reduced clearance), similar to
liposomes.
Single Chain Surfactant Molecule
(Non-ionic)

Niosomes

Span60

Liposomes Niosomes
Vesicles made up of concentric bilayer Vesicles made up of uncharged single-
of nutral or charged phospholipids chain surfactant molecules
Size ranges from 10-3,000 nm Size ranges from 10-100 nm

Comparatively expensive Inexpensive

Special storage condition Not require special storage and

handling
Comparatively more toxic Less toxic