Development of targeting nanotherapeutics against bladder cancer

描述（由申请人提供）： 该项目的目标是开发一种可以特异性靶向膀胱癌的纳米胶束药物递送系统。在VA职业发展奖-2（CDA-2，PI：Pan）的资助下，开发了一种名为PLZ 4的膀胱癌靶向配体。PLZ 4结合人和狗膀胱癌细胞系以及来自临床标本的癌细胞，这表明可以在患有自发性膀胱癌的狗中进行临床前研究。PLZ 4不与正常的尿路上皮细胞、发炎的膀胱细胞、血细胞、血管内皮细胞和成纤维细胞结合。最近，Kit Lam，MD，PhD（潘博士的VA CDA-2导师）开发了生物相容性和生物可降解的纳米胶束。 化学试剂和成像剂可以装载在纳米胶束内。当它们在表面上用PLZ 4修饰时，这些靶向纳米胶束与药物负载一起被递送到膀胱癌细胞中。靶向PLZ 4-纳米胶束优先集中在体内膀胱癌异种移植部位，与非靶向纳米胶束相比，可以显著延长存活期。在本项目中，我们将优化PLZ 4-纳米胶束的结构，以实现最大的药物负载和递送，并确定在携带从人类临床标本开发的膀胱癌异种移植物的小鼠中的体内靶向和药物分布。将在患有自发性膀胱癌的犬患者中进行初步研究，以获得初步毒性和疗效数据。

DESCRIPTION (provided by applicant): The goal of this project is to develop a nanomicelle drug delivery system that can specifically target bladder cancer. With the funding of the VA Career Development Award-2 (CDA-2, PI: Pan), a bladder cancer-targeting ligand named PLZ4 was developed. PLZ4 binds to both human and dog bladder cancer cell lines and cancer cells from clinical specimens, suggesting that the pre-clinical studies can be performed in dogs with spontaneous bladder cancer. PLZ4 does not bind to normal urothelial cells, inflamed bladder cells, blood cells, vascular endothelial cells an fibroblasts. Recently, Kit Lam, MD, PhD, (Dr. Pan's VA CDA-2 mentor) developed biocompatible and biodegradable nanomicelles. Chemotherapeutic and imaging agents can be loaded inside the nanomicelles. When they are decorated with PLZ4 on surface, these targeting nanomicelles together with the drug load are delivered into bladder cancer cells. Targeting PLZ4-nanomicelles preferentially concentrate at the bladder cancer xenograft sites in vivo and can significantly prolong survival when compared to non-targeting nanomicelles. In this project, we will optimize the structure of the PLZ4-nanomicelles to achieve the maximal drug loading and delivery, and determine the in vivo targeting and drug distribution in mice carrying bladder cancer xenografts developed from human clinical specimens. A pilot study will be conducted in dog patients carrying spontaneous bladder cancer in order to obtain the preliminary toxicity and efficacy data.