The Use of Nanoparticles in Drug Delivery Systems

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The Use of Nanoparticles in Drug Delivery Systems

• Ali Palejwala

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Overview

• Introduction to the nanoparticles
• Background on different types of nanoparticles

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History

• 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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The Idea

• 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.

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Current Trends in Nanomedicine

• The majority of progress of nanomedicine has been
  in the use of nanoparticles as drug delivery
  products

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What and Why

• 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

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Size and Shape

• 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

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Types of Nanoparticles

• Liposomes
• Polymeric nanoparticles
• Dendrimers
• Fullerenes
• Quantum dots
• Metal nanoparticles
• Magnetic nanoparticles

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Liposomes

• a self-closing spherical particle that is
  composed of natural or synthetic amphiphilic
  lipid molecules

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One can change the pharmacokinetic properties of
the drug by changing the liposome

• Size smaller liposomes have reduced
  immunogenicity
• Lipid composition give the membrane varied
  rigidity
• Stealth component reduces the immunogenicity
• The drug enclosed

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• 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

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• http//www.chemocare.com/managing/

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Doxil

• Developed in 1995
• Marketed by Ortho Biotech
• Liposome-PEG doxorubicin HCl
• Anti-cancer drug used
• in the treatment of HIV-related Kaposis 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 diastearoylphospatidylch
  oline 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
• 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

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Side effects

• 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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DepoCyt

• 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

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Neoplastic Meningitis

• 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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Cytarabine

• 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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Depofoam

• 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

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Other Liposomal Drugs
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Liposomes and Antibiotics

• 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.

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Polymeric Nanoparticles

• Nanoparticles synthesized from polymers

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The polymer can act as the active
ingredientCopaxone

• 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 L- Tyr)
• Administered subcutaneously
• Marketed by TEVA pharmaceuticals

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Multiple Sclerosis
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Polymer Synthesis

• 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)

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Mechanism of Action

• 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

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Side effects

• Flu-like symptoms
• injection site rxns
• menstrual irregularities
• decreased white blood cells
• elevated liver enzymes.

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The polymer can be conjugated to a drugPegasys

• 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

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• 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

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Side effects

• 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.

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The polymer can resemble a liposome

• 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

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Treatment of Type 1 Diabetes

• 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

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Dendrimer

• Highly branched, spherical nanoparticle
• Core, highly branched layers of repeating units
  (polymers), and multiple active terminal groups

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Pros and Cons

• 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

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Toxicity
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Conclusion

• The development of particles that are nanoscaled
  has created great opportunities in the
  development of improved drug delivery systems.

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Works Cited

• http//www.eperc.mcw.edu/fastFact/ff_135.htm
• ?http//www.sciencedirect.com/
• ?http//www.weizmann.ac.il/ICS/booklet/1/pdf/copax
  on.pdf
• ?http//www.rxlist.com/pegasys-drug.htm
• http//www.rsc.org/delivery/_ArticleLinking/Displa
  yArticleForFree.cfm?doib900374fJournalCodeCC
• http//www.unisa.edu.au/iwri/futurestudents/phdpro
  jects/interfacialpropertiesofdendrimers.asp
• Zhang, L. "Nanoparticles in Medicine."
  Translational Medicine.
• Patel, Priyal. "Nanotechnology." Drug Delivery
  Technology.
• Patel, Priyal. Nanoparticles in cancer research
  a novel drug deliverypharmacologicalapproach
  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.