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 re-growth 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.
The long-term goal of this investigation is to research and develop a novel biodegradable delivery system for anticancer drugs to localize drug to tumors for greater anti-tumor effects and to reduce toxic side effects. 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 doxorubicin as well as for other anti tumor drugs.
| Cammarata, Christopher R; Hughes, Mitchell E; Ofner 3rd, Clyde M (2015) Carbodiimide induced cross-linking, ligand addition, and degradation in gelatin. Mol Pharm 12:783-93 |
| Wu, Darren C; Ofner 3rd, Clyde M (2013) Adsorption and degradation of doxorubicin from aqueous solution in polypropylene containers. AAPS PharmSciTech 14:74-7 |
| Wu, Darren C; Cammarata, Christopher R; Park, Hyun Joo et al. (2013) Preparation, drug release, and cell growth inhibition of a gelatin: doxorubicin conjugate. Pharm Res 30:2087-96 |
