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 potteryGold 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 well2. Able to diffuse through the body well
LiposomesPolymeric nanoparticlesDendrimersFullerenesQuantum dotsMetal nanoparticlesMagnetic 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/managing/
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
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 timeHalf 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 SyndomeStomatitisFeverNeutropeniaNausea, vomiting, tiredness, weakness, rash, shortness of breath, or mild hair lossLoss of appetiteDiarrheaCardiotoxcity
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 sulciblock 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 L- Tyr)
Administered subcutaneously
Marketed by TEVA pharmaceuticals
Initiator: n-carboxyamino acid anhydrideGrowth : reaction with amino acidmonomersTermination: reaction with n-carboxyaminoacid anhydride
Length can be controlled by monomer/initiator ratioAs 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 T-suppressor cellsCompetes 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 symptomsinjection site rxnsmenstrual irregularitiesdecreased white blood cells elevated liver enzymes.
Approved by the FDA in 2005; protein therapeutic for the treatment of Hepatitis B, Ccovalent 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 cirrhosisautoimmune hepatitismajor, 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 propertiesTough 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.htmhttp://www.sciencedirect.com/http://www.weizmann.ac.il/ICS/booklet/1/pdf/copaxon.pdfhttp://www.rxlist.com/pegasys-drug.htmhttp://www.rsc.org/delivery/_ArticleLinking/DisplayArticleForFree.cfm?doi=b900374f&JournalCode=CChttp://www.unisa.edu.au/iwri/futurestudents/phdprojects/interfacialpropertiesofdendrimers.aspZhang, 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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