Nanoparticles in Drug Delivery Systems

Ali Palejwala
Introduction to the nanoparticles
Background on different types of

nanoparticles
Have been documented to in

use since the use 9th century
in Mesopotamia for ancient
pottery
Gold particles nanosclaed have optical properties

that cause the luster
Proposed by Richard
Feynman in his book titled
Theres Plenty of Room at
the Bottom
Feynman considered the

possibility of direct
manipulation of individual
atoms as a more powerful
form of synthetic chemistry
than those used at the
time.
The idea of nanotechnology

was born.
The majority of progress

of nanomedicine has been
in the use of nanoparticles
as drug delivery products
Nanoparticle any particle that is sized

between 1 and 100 nanometers (in terms
of diameter)
The use of nanoparticles

allows one to change the
pharmacokinetic properties
of the drug without
changing the active
compound
All matter has size and all size matters
General properties of nanoscaled

particles:
1. High surface area to volume ratio
-able to interact with biomolecules on the
surface of cells
-absorbs drugs well
2. Able to diffuse through the body well
Liposomes
Polymeric nanoparticles
Dendrimers
Fullerenes
Quantum dots
Metal nanoparticles
Magnetic nanoparticles
a self-closing spherical particle that is

composed of natural or synthetic
amphiphilic lipid molecules
Size smaller liposomes have reduced

immunogenicity
Lipid composition
give the membrane
varied rigidity
Stealth component reduces the

immunogenicity
The drug enclosed
Liposomes have been widely used in

anticancer drugs
Optimal antitumor activity occurs

when cancer cells are exposed to
moderate concentrations of a drug
over an extended period of time
http://www.chemocare.com/managin
g/
Developed in 1995
Marketed by Ortho Biotech
Liposome-PEG doxorubicin
HCl
Anti-cancer drug used
in the treatment of HIVrelated Kaposis sarcoma
Also used to treat breast
cancer, ovarian cancer, and
other solid tumors
Administered intravenously
every 4 weeks
Doxil is the drug doxorubicin HCl

encapsulated in an antibody
linked PEGylated liposome
Composed of multiple
monoclonal antibodies to target
cancer cells
PEG (polyethylene glycol)

makes the liposome less
vulnerable to immune system
Lipid composition: mainly

diastearoylphospatidylcholine
and cholesterol - increases
liposomal rigidity
Doxil works through passing through fenestrations

in the vasculature and concentrating at tumor
sites
- Leads to reduced accumulation in other tissues
Able to deliver the drug at moderate

concentrations over a longer period of time
- Half life: 54 hours
Result: An anticancer drug that is

delivered more effectively
- decreased side effects and dosage
Doxil acts by the intercalation of DNA
Hand-Foot Syndome
Stomatitis
Fever
Neutropenia
Nausea, vomiting, tiredness, weakness, rash,
shortness of breath, or mild hair loss
Loss of appetite
Diarrhea
Cardiotoxcity
Approved by the FDA in 2004
Marketed by SkyePharma
Liposomal cytarabine
Anticancer drug used in the

treatment of malignant
neoplastic meningitis
Administered intravenously
every 2 weeks
A common oncologic complication involving the

spread of tumor cells to the subarachnoid space
(SAS)
Cancer cells in the subarachnoid space can :

- Settle in the dependent portions of the base of
brain (cranial nerves, lower spinal canal)
- grow into the surface of the brain and fill the sulci
- block normal paths of CSF flow
Treatment options include chemotherapy and/or

radiation
Originally discovered in Europe in the

1960s
works by damaging the DNA in

cancerous cells
Short half-life in the body; requires

frequent dosage to attain cytotoxic levels
Clinical studies demonstrated that

encapsulation of cytarabine into
liposomes leads to sustained release of cytotoxic
cytarabine
- improved therapeutic efficacy in patients with
NM
Lipid composition: mainly

dioleoyl phospahtidylcholine,
triolein, and cholesterol
Depofoam results in a 55 fold

increase in the terminal half
life of cytarabine in the CSF
Composed of multiple
monoclonal antibodies to
target cancer cells
Larger liposome high drug

loading capacity; small enough
to cross the blood brain barrier
Drug targeting potential of liposomes

and nanoparticles in the treatment of
intracellular bacterial infections.
Poor penetration into cells and
decreased activity intracellularly major
reasons for limited activity of most
antibiotics in intracellular infections.
Nanoparticles synthesized from

polymers
Approved by the FDA in 1996

for the treatment of multiple
sclerosis (T-cell therapy)
Synthetic polymer of amino
amino acids (Cop1 composed
of L-Ala, L-Lys, L-Glu, and LTyr)
Administered subcutaneously
Marketed by TEVA
pharmaceuticals
Initiator: n-carboxyamino acid anhydride

Growth : reaction with amino acid
monomers
Termination: reaction with n-carboxyamino
acid anhydride
Length can be controlled by monomer/initiator ratio

As long as the composition of polymer is the same,
the physical and chemical properties will stay same
(regardless of sequence)
Cop 1 polymer related to myelin binding protein

(MBP)
Binding to MHC leads to the activation of Tsuppressor cells

Competes with several myelin-associated
antigens to bind to MHC class II molecules
Low toxicity; however, copaxone can only slow the

progression of the disease and reduce the relapse
rate
Flu-like symptoms
injection site rxns
menstrual irregularities
decreased white blood cells
elevated liver enzymes.
Approved by the FDA in 2005;

protein therapeutic for the
treatment of Hepatitis B, C
covalent conjugate of recombinant
alfa-2a interferon with a single
branched bis-monomethoxy
polyethylene glycol (PEG) chain
Administered through subcutaneous
injection
PEG can enhance plasma stability and

solubility of the drug while reducing its
immunogenicity
The protein therapeutic will have an

increased amount of time to act on the
virus
Pegasys is often used with Ribavirin in

the treatment of hepatitis C
decompensated cirrhosis
autoimmune hepatitis
major, uncontrolled depression
kidney, lung or heart transplants
known hypersensitivity (allergic reaction) to
pegylated interferon components.
Pegylated interferon should be used with
caution, preferably by a specialist, in people
with heart and thyroid problems, pulmonary
disorders, and autoimmune diseases.
How?
Amphiphilic
polymer
Polymer has specific responses that depend on

the stimulus and the environment
- in an aqueous environment, the polymer will
aggregate into a micelle
- upon binding to glucose, the compound
experiences a change in pka that dissociates the
polymer
Type I diabetes autoimmune

disorder that results in destruction of
insulin-producing beta cells of the
pancreas
- treatment includes insulin therapy
The polymer will hopefully be able to

provide the correct amount of insulin,
regardless of blood sugar levels
Highly branched, spherical

nanoparticle
Core, highly branched layers of

repeating units (polymers),
and multiple active terminal
groups
High level of activity as a result of

multiple functional groups at surface;
display strong surface activity with
cell and virus particle surfaces
limited information concerning

physicochemical properties
Tough to synthesize
The development of particles that are

nanoscaled has created great
opportunities in the development of
improved drug delivery systems.
http://www.eperc.mcw.edu/fastFact/ff_135.htm
http://www.sciencedirect.com/
http://www.weizmann.ac.il/ICS/booklet/1/pdf/copaxon.pdf
http://www.rxlist.com/pegasys-drug.htm
http://www.rsc.org/delivery/_ArticleLinking/DisplayArticleForFree.cfm?
doi=b900374f&JournalCode=CC
http://www.unisa.edu.au/iwri/futurestudents/phdprojects/interfacialpropertie
sofdendrimers.asp
Zhang, L. "Nanoparticles in Medicine." Translational Medicine.
Patel, Priyal. "Nanotechnology." Drug Delivery Technology.
Patel, Priyal. Nanoparticles in cancer research: a novel drug
delivery&pharmacologicalapproach Drug Delivery Technology.
Murry, R.Clinicalpharmacology of encapsulated sustained-release
cytarabine The Annals of pharmacotherapy.
Massing, U.Cancertherapy with liposomal formulations of anticancer
drugs. International journal of clinical pharmacology, therapy, and
toxicology.
Hashimoto, N. An approach to cancer chemotherapy by application of
monoclonal antibody-modified liposomesInternational congress series.
International congress series.

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Ali Palejwala

Introduction to the nanoparticles

Background on different types of

Have been documented to in

Gold particles nanosclaed have optical properties

Feynman considered the

The idea of nanotechnology

The majority of progress

Nanoparticle any particle that is sized

The use of nanoparticles

All matter has size and all size matters

General properties of nanoscaled

a self-closing spherical particle that is

Size smaller liposomes have reduced

give the membrane

Stealth component reduces the

The drug enclosed

Liposomes have been widely used in

Optimal antitumor activity occurs

Doxil is the drug doxorubicin HCl

PEG (polyethylene glycol)

Lipid composition: mainly

Doxil works through passing through fenestrations

- Leads to reduced accumulation in other tissues

Able to deliver the drug at moderate

Result: An anticancer drug that is

Doxil acts by the intercalation of DNA

Approved by the FDA in 2004

Anticancer drug used in the

A common oncologic complication involving the

Cancer cells in the subarachnoid space can :

Treatment options include chemotherapy and/or

Originally discovered in Europe in the

works by damaging the DNA in

Short half-life in the body; requires

Clinical studies demonstrated that

Lipid composition: mainly

Depofoam results in a 55 fold

Larger liposome high drug

Drug targeting potential of liposomes

Nanoparticles synthesized from

Approved by the FDA in 1996

Initiator: n-carboxyamino acid anhydride

Length can be controlled by monomer/initiator ratio

Cop 1 polymer related to myelin binding protein

Binding to MHC leads to the activation of Tsuppressor cells

Low toxicity; however, copaxone can only slow the

Approved by the FDA in 2005;

PEG can enhance plasma stability and

The protein therapeutic will have an

Pegasys is often used with Ribavirin in

Polymer has specific responses that depend on

Type I diabetes autoimmune

The polymer will hopefully be able to

Highly branched, spherical

Core, highly branched layers of

High level of activity as a result of

limited information concerning