| For the treatment of cancer, peptides hold great potential as both targeting and therapeutic agents. One particularly promising anti-cancer strategy is peptides derived from the third Bcl-2 homology domain (BH3), which antagonize pro-survival Bcl-2 proteins and induce apoptosis. Unfortunately, before the clinical potential of peptides can be realized, a number of drug delivery barriers must be overcome. Namely, peptides have short circulation half-lives, are susceptible to degradation by extracellular proteases, and are unable to cross cell membranes and access intracellular targets.;An antibody-targeted, pH-responsive polymeric system was recently developed and implemented for the intracellular delivery of the pro-apoptotic BH3 peptide BIM1. Unfortunately, the delivery properties of this system were limited by the poor stability of the disulfide-linkage used for conjugating BIM to the polymeric carrier. It was the objective of this thesis to develop highly stable polymer-peptide conjugates for the targeted and intracellular delivery cancer drugs.;Initially, steric hindrance was investigated for enhancing the stability and delivery properties of disulfide-linked polymer-BIM conjugates. Two methyl groups were introduced onto the peptide's disulfide-adjacent carbon by substituting BIM's C-terminal cysteine with pencillamine and conjugating the peptide to the polymeric carrier via disulfide exchange. In a murine xenograft model of B-cell lymphoma, steric hindrance significantly enhanced conjugate stability, peptide half-life and peptide deposition into tumors. However, benefits were relatively minor with much left to be desired.;Next an enzyme-labile peptide linker was developed that is highly stable in human serum and efficiently cleaved in cancer cells to release active BIM peptide. A methacrylamido-peptide macromonomer containing BIM capped with a four amino acid (FKFL) cathepsin B substrate was synthesized and directly integrated into the polymeric delivery vehicle via RAFT polymerization. The resulting cathepsin-B cleavable BIM prodrug system demonstrated potent apoptotic activity in ovarian cell cultures and is currently being investigated for apoptotic activity and therapeutic efficacy in intraperitoneal ovarian cancer xenograft model.;Lastly, peptide monomer technology was alternatively implemented for tumor-specific targeting. A peptide monomer containing the EGFR-targeting sequence GE112 was polymerized into a hydrophilic polymeric drug delivery system in combination with an ester-linked camptothecin prodrug monomer. GE11 was shown to enhance targeting and activity of the polymeric prodrug in ovarian cancer cell cultures.;[1] Berguig GY, Convertine AJ, Frayo S, Kern HB, Procko E, Roy D, Srinivasan S, Margineantu DH, Booth G, Palanca-Wessels MC, Baker D, Hockenbery D, Press OW, Stayton PS. Intracellular delivery system for antibody-Peptide drug conjugates. Mol Ther. 2015 May;23(5):907-17. .;[2] Li Z, Zhao R, Wu X, Sun Y, Yao M, Li J, Xu Y, Gu J. Identification and characterization of a novel peptide ligand of epidermal growth factor receptor for targeted delivery of therapeutics. FASEB J. 2005 Dec;19(14):1978-85.. |
