Poly (amino acid) as an Integrin Targeted Drug Carrier

University Of The Pacific-Stockton, Stockton CA

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Abstract

DESCRIPTION (provided by applicant): Integrins are found to play an important role in the adhesion of cancer cells to the extracellular matrix during cancer metastasis. This adhesion occurs via interactions or binding between small peptide sequences located in the extracellular matrix and specific binding sites on integrins. It is hypothesized that this interaction or specific binding can be utilized to design drug carriers for the treatment of cancer. Melanoma cells possess an over-expression of the alpha4beta1 integrin on the cell surface. It is reported that the recognition of the tripeptide sequence, leucine-aspartic acid-valine, (LDV) is limited only to the a4a1 integrin. In this proposal, a random polymer of LDV and a polymer with ordered LDV sequence are designed to serve as a drug carrier by which anticancer agents can be conjugated to the carrier via a labile covalent linkage. Due to the binding specificity between melanoma cells and the LDV sequence in the copolymer, the anticancer agent will be targeted to the melanoma cells. The anticancer agent will be released and exert pharmacological effects after the poly (LDV)-drug conjugate is internalized by melanoma cells. Random copolymers of LDV were chosen in the design of this integrin targeted drug carrier because of achievable high molecular weight with less ordered structure (to avoid immunogenicity of the carrier) at low costs. The goal of this proposal is to design, synthesize, characterize, and test random copolymers of LDV for alpha4beta1 integrin specific targeted drug delivery. This goal will be achieved by conducting a series of studies with the following specific aims: 1) to synthesize novel random terpolymers containing leucine, aspartic acid, and valine and covalently link doxorubicin to this integrin targeted drug carrier, 2) to verify the target specificity of the carrier to malignant melanoma cells, and 3) to test if the conjugation of doxorubicin to poly (LDV) could improve its efficacy by targeting to malignant melanoma cells both in vitro and in vivo. The study of this targeting drug carrier will explore the integrins as targeting site for drug delivery and design the integrin targeted drug carriers to deliver anticancer agents. These novel polymers of LDV would not only serve as a drug carrier but also could potentially act as an inhibitor of cancer metastasis, thus providing a synergetic effect in cancer therapy. Therefore, the polymers of LDV may be a promising target specific carrier to cancers that express the alpha4beta1 integrin. Additionally, when the objective of the proposed study is achieved, specific carriers can also be developed to target other integrins and deliver drugs to cancer cells that express a specific type of integrin. The proposed studies in this AREA grant proposal will provide a solid training to a graduate student in the area of drug delivery and strengthen the research environment at the Univ. of the Pacific, a primarily baccalaureate training institution.