Grant: $223,780 - National Institutes of Health - May. 12, 2009
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Award Description: The long-term goal of this investigation is to research and develop a novel macromolecular delivery system for anticancer drugs to produce greater anti tumor efficacy and less toxicities compared to non-biodegradable polymer delivery systems as well as to the free drug. The proposed delivery system is based on three sequential concepts: (1) Biodegradable conjugates, of greater molecular weight than safely used in non-biodegradable polymer conjugates, are expected to produce an enhanced tumor accumulation due to a longer circulation time and leaky tumor vasculature; (2) After tumor accumulation, enzymatic degradation in the interstitial tumor space into lower molecular weight species is expected to enhance tumor cell uptake; (3) After cell uptake of conjugate fragments into acidic lysosomal compartments, drug release is expected by cleavage of an acid labile conjugate bond. Specific aim one is to develop and characterize a soluble macromolecular conjugate composed of a gelatin carrier at different molecular weights covalently linked to doxorubicin HCl (DOX) by an acid labile hydrazone bond with appropriate drug release characteristics. Previously published methods of synthesis, characterization, and release from this lab and others will be used. Specific aim two is to determine the effect of in vitro intra tumor enzymatic degradation of the gelatin-DOX conjugate (G-DOX) on cellular uptake and anti-proliferative effects. Cathepsin B will be used for enzymatic degradation. Uptake in three cell lines will be measured by HPLC and FACS while cell effects will be measured by growth inhibition. Specific aim three is to evaluate tumor DOX accumulation and tumor response of treatment with different molecular weight G-DOX against an EL4 T cell lymphoma in mice. Tumor uptake will be measure by HPLC while response will be measured by tumor size regrowth delay and percent survival. The in vitro and in vivo results will be evaluated for a molecular weight correlation. If the aims and goals of this proposal are achieved, the feasibility of this system will be established with good prospects for therapeutic advantages of tumor treatment and reduced systemic toxicity in clinical practice for this drug as well as other anti tumor drugs.
Project Description: Quarter Ending: September 30, 2009 Work towards specific aim one includes the following. Different gelatin – doxorubicin conjugate (G-Dox) preparation procedures are being explored to obtain desirable characteristics of drug load, solubility, reduced side reactions, and purity of conjugate. Five G-Dox versions were prepared with Dox content estimates ranging from 2 to 10%. Method development continues for assay of Dox, gelatin, and design of experiments to evaluate drug release from G-Dox.
Infrastructure Description: `
Jobs Summary: Quarter Ending: September 30, 2009 Funds were used for salary for the PI at 5% effort. Funds were used to pay a student worker who used different procedures and reagent amounts to make five versions of G-Dox. Funds were used to purchase supplies for these procedures (chemicals and reagents, glassware, pH probes and buffers, SEC column peristaltic pump, pipettes and tips, disposable test tubes and vials). Funds were used for method development of Doxorubicin assay (HPLC column, HPLC fluorescent lamp, solvents, UV cuvets, polypropylene volumetric flasks), gelatin assay (Bradford assay kit, modified coumassie blue assay kit) and preliminary drug release studies (dialysis cassettes, buffers, mini cassettes, microcentrifuge tubes, disposables and reagents). Funds were used for the position of a lab technician to carry out experiments. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on May. 12, 2009. Help expand these official descriptions using the wiki below.