The Use of Nanoparticles in Drug Delivery Systems

The Use of Nanoparticles in Drug Delivery Systems Ali Palejwala

Overview �Introduction �Background to the nanoparticles on different types of nanoparticles

History • Have been documented to in use since the use 9 th century in Mesopotamia for ancient pottery • Gold particles nanosclaed have optical properties that cause the luster

The Idea � 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.

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

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

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

Types of Nanoparticles �Liposomes �Polymeric nanoparticles �Dendrimers �Fullerenes �Quantum dots �Metal nanoparticles �Magnetic nanoparticles

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

One can change the pharmacokinetic properties of the drug by changing the liposome �Size –smaller liposomes have reduced immunogenicity �Lipid rigidity composition – give the membrane varied �Stealth �The component –reduces the immunogenicity 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

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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 Kaposi’s 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

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 �

Depo. Cyt � Approved by the FDA in 2004 � Marketed by Skye. Pharma � Liposomal cytarabine � Anticancer drug used in the treatment of malignant neoplastic meningitis � Administered intravenously every 2 weeks

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

Cytarabine � Originally discovered in Europe in the 1960 s � 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

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

Other Liposomal Drugs

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.

Polymeric Nanoparticles �Nanoparticles synthesized from polymers

The polymer can act as the active ingredient Copaxone � Approved by the FDA in 1996 for the treatment of multiple sclerosis (T-cell therapy) � Synthetic polymer of amino acids (Cop 1 composed of L-Ala, L-Lys, L-Glu, and L- Tyr) � Administered subcutaneously � Marketed by TEVA pharmaceuticals

Multiple Sclerosis

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) �

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

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

The polymer can be conjugated to a drug Pegasys Approved by the FDA in 2005; protein therapeutic for the treatment of Hepatitis B, C � covalent conjugate of recombinant alfa 2 a interferon with a single branched bismonomethoxy 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

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.

The polymer can resemble a liposome �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

Treatment of Type 1 Diabetes �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

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

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

Toxicity

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

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