Bladder Cancer Patient-derived Xenograft Research Articles

Abstract A80: Cancer-specific targeting nanomicelles for diagnosis and treatment of bladder cancer.

Abstract Background: We previously developed a bladder cancer-specific targeting ligand named PLZ4 (amino acid sequence: cQDGRMGFc) that can specifically bind to both human and dog bladder cancer cells in vitro and in vivo. We have also developed a nanoscale micellular drug delivery platform. To minimize premature drug release during circulation, disulfide crosslinks are introduced to the micelles, which are cleaved under the intracellular reducing environment, where the drugs are released. Here, we assess the antitumor activity and toxicity of the PLZ4-coated and paclitaxel (PTX)-loaded micelles, with or without disulfide crosslinks. Materials and Methods: Micelle-building monomers (ie, telodendrimers) are synthesized through conjugation of polyethylene glycol with cysteine (for disulfide crosslink) and a cholic acid cluster at one end and PLZ4 at the other. Such monomers self-assemble under aqueous condition to form micelles. Human bladder cancer cell line 5637 and patient-derived xenografts (PDX) are used for in vitro and in vivo drug delivery studies. Results: PLZ4-coated micelles are about 20 nm in diameter. The PTX loading capacity is approximately 5 mg/ml in 20 mg of telodendrimers. PLZ4 confers cancer-specific drug delivery both in vitro and in vivo. Formulation of PTX in micelles significantly decreases the toxicity and allows intravenous administration of three times the maximum tolerated dose without increasing the toxicity, and improves the overall survival of mice carrying patient-derived bladder cancer xenografts to 64 days (without PLZ4 on micelle surface) and 76 days (PLZ4 targeting micelles) when compared to free parental PTX at 27 days (p<0.0001). In contrast to free paclitaxel in Cremophor (Taxol®), the micelle formulation of PTX does not induce mast cell degranulation. To determine the minimal requirement of PLZ4 for targeted drug delivery, we compared and found that micelles with 2% and 50% of PLZ4 on surface exhibited similar antitumor activity in mice carrying patient-derived xenografts. Conclusion: Micellular formation of PTX coated with PLZ4 shows promising antitumor activity with decreased toxicity in the treatment of bladder cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A80. Citation Format: Amy Wang Pan, Tzu-yin Lin, Hongyong Zhang, Neal Goodwin, Chong-xian Pan, Yuanpei Li, Kit Lam. Cancer-specific targeting nanomicelles for diagnosis and treatment of bladder cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A80.