Transcript There`s Plenty of Room at the Bottom

Ali Palejwala
 Introduction
 Background
to the nanoparticles
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
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Proposed by Richard
Feynman in his book titled
There’s 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
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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/managing/
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Developed in 1995
Marketed by Ortho Biotech
Liposome-PEG doxorubicin HCl
Anti-cancer drug used
in the treatment of HIV-related
Kaposi’s sarcoma
Also used to treat breast cancer,
ovarian cancer, and other solid
tumors
Administered intravenously
every 4 weeks
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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
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Doxil works through passing through fenestrations in
the vasculature and concentrating at tumor sites
- Leads to reduced accumulation in other tissues
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Able to deliver the drug at moderate concentrations
over a longer period of time
- Half life: 54 hours
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Result: An anticancer drug that is
delivered more effectively
- decreased side effects and dosage
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Doxil acts by the intercalation of DNA
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Hand-Foot Syndome
Stomatitis
Fever
Neutropenia
Nausea, vomiting, tiredness, weakness, rash, shortness
of breath, or mild hair loss
Loss of appetite
Diarrhea
Cardiotoxcity
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Approved by the FDA in 2004
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Marketed by SkyePharma
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Liposomal cytarabine
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Anticancer drug used in the
treatment of malignant
neoplastic meningitis
Administered intravenously
every 2 weeks
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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
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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
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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
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Marketed by TEVA
pharmaceuticals
Initiator: n-carboxyamino acid anhydride
 Growth : reaction with amino acid
monomers
 Termination: reaction with n-carboxyamino
acid anhydride
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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)
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Cop 1 polymer related to myelin binding protein (MBP)
Binding to MHC leads to the activation of T-suppressor
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.
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Approved by the FDA in 2005; protein
therapeutic for the treatment of
Hepatitis B, C
covalent conjugate of recombinant alfa2a 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
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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 insulinproducing 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
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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.
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http://www.eperc.mcw.edu/fastFact/ff_135.htm
http://www.sciencedirect.com/
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http://www.weizmann.ac.il/ICS/booklet/1/pdf/copaxon.pdf
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http://www.rxlist.com/pegasys-drug.htm
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http://www.rsc.org/delivery/_ArticleLinking/DisplayArticleForFree.cfm?doi=b900
374f&JournalCode=CC
http://www.unisa.edu.au/iwri/futurestudents/phdprojects/interfacialpropertiesofd
endrimers.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.