Smart Packaging: A Novel Technique for Localized Drug Delivery for Ovarian Cancer

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DESCRIPTION (provided by applicant): The main challenge of the proposed research is to develop a novel drug delivery system that apart from providing targeted and better control over the drug release and dosage, will also aid in reducing the toxic side effects associated with administration of chemotherapeutic drugs. The design strategy is based on a 'Smart Packaging' system in which the chemotherapeutic drugs are encapsulated in non-ionic surfactant vesicles (niosomes) embedded in a cross-linked hydrogel network. The 'Smart Packaging' is applied directly to the affected site thus enabling the stabilization of the drug and preventing systemic exposure to healthy cells. It also assists in sustained drug delivery over extended periods and eliminates the need for frequent administration. The accomplishment of this work includes four aims. Aim 1 is to immobilize the drug/dye encapsulated niosomes in cross-linked chitosan polymeric networks having different molecular weights, degree of deacetylation, cross-link density, niosome loading and to characterize the behavior of the chitosan- niosome system. Characterization of the system will be done using Surface Forces Apparatus(SFA) and Atomic Force Microscopy (AFM). Aim 2 is to compare the stability, encapsulation efficiency and the release rate of two niosomal systems: i) where a hydrophobic drug (Paclitaxel) and a hydrophilic drug (Carboplatin) are encapsulated in the same niosome and ii) where the drugs are encapsulated in separate niosomes and then mixed together. TEM/ DLS will be used to determine the stability and HPLC/ UV-VIS spectrometer to determine the release rate. Aim 3 is to study the cytotoxicity of the chitosan- niosome system in normal and cancer cells and determine the selectivity, biocompatibility, and adhesion of the system to cancer cells. Cytotoxicity will be determined by the standard MTT dye reduction assay. Selectivity will be determined by exposing normal and cancer cells to the proposed system and measuring the drug intake by the cells. Aim 4 is to determine the release rate of drugs from the chitosan-niosome system in in-vivo mice models, analyze the implementation of our system in real tumor-like conditions, and to test the biodegradability and biocompatibility of our system. Xenogen and Fluorescent Spectrometer will be used to determine the release rate of the drugs tagged with a fluorescent tracer. PUBLIC HEALTH RELEVANCE: The main purpose of the proposed research is to develop a drug delivery system which allows targeting and control over the drug release and dosage process. Such a delivery system is expected to aid in the reduction of the toxic side effects associated with administration of chemotherapeutic drugs. The design strategy is based on a 'Smart Packaging' concept in which the chemotherapeutic drugs are encapsulated in non-ionic surfactant vesicles (niosomes) embedded in a cross-linked hydrogel network. The 'Smart Packaging' is applied directly to the affected site, enabling stabilization of the drug and preventing systemic exposure to healthy cells. It also assists a sustained drug delivery over extended periods and eliminates the need for frequent administration. The novelty of this system is in its high ability to control time release and dosage of chemotherapy drugs to allow judicious manipulation to treat many different types of tumor sites. For instance, if a tumor is removed surgically, it may be desirable to administer a low dosage of chemotherapy drugs for a short period of time (3-7 days) to allow a successful recovery of the cells that have been subjected to the surgical trauma. In that case, an outer layer of the polymer network can be tuned to be more compact and the niosomes to contain small concentrations of the drug cocktails. After this short period, the treatment may require to administer a high dosage and quick release to fight any cancer cells left behind. In that case, a middle layer can be constructed to be loose and the niosomes to contain high concentrations. Then, an inner layer can be constructed tight containing niosomes with systemic concentrations to allow sustained release of chemotherapy drugs for larger periods of time (3-9 months). Many other layers with different capabilities for delivery can also be constructed as needed depending on the oncologist experience and tissue integrity of the patient. A potential application would be in intra-cavitary drug delivery in ovarian cancer tumors and in the administration of labile drugs. Toxicities associated with systemic administration of much larger quantities of the drug are avoided, by the direct administration of chemotherapeutic agents directly to the tumor or to body cavities created after surgical removal of the tumor. The therapeutic system is a clear viscous solution, which, upon injection (at contact with warm tissue, 37:C) undergoes a phase transition to a semi-solid gel. This gel which conforms to the shape of the cavity, quickly blends with the surrounding tissue, and allows setting position for the delivery.