Development of targeting nanotherapeutics against bladder cancer

膀胱癌靶向纳米疗法的开发

• 批准号: 8442030
• 负责人: CHONG-XIAN PAN
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442030
• 关键词: Binding; Biocompatible; Bladder; Blood Cells; Calmette-Guerin Bacillus; Cancer Control; Cancer cell line; Canis familiaris; Cells; Chronic Cystitis; Clinical; Companions; Data; Detection; Development; Doctor of Medicine; Doctor of Philosophy; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Fibroblasts; Funding; Goals; Homing; Human; Image; Immunocompromised Host; K-Series Research Career Programs; Knowledge; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Mentors; Monitor; Mus; Names; Organ; Paclitaxel; Patients; Peptides; Pharmaceutical Preparations; Pharmacology and Toxicology; Pilot Projects; Site; Specimen; Structure; Surface; System; Therapeutic; Therapeutic Effect; Time; Toxic effect; Treatment Efficacy; Treatment outcome; Urothelial Cell; Vascular Endothelial Cell; Work; Xenograft procedure; cancer cell; density; drug distribution; drug efficacy; improved; in vivo; intravenous injection; nanotherapeutic; novel; outcome forecast; peptide analog; preclinical study; public health relevance; targeted delivery; tumor xenograft

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. PUBLIC HEALTH RELEVANCE: This project aims to develop a multi-functional nanomicelle drug delivery system that can specifically deliver the chemotherapeutic drug paclitaxel to bladder cancer. The nanomicelle system can possibly improve treatment efficacy and lower therapy-associated toxicity.

描述(由申请人提供)： 该项目的目标是开发一种能够特异性靶向膀胱癌的纳米胶束给药系统。在退伍军人管理局职业发展奖-2(CDA-2，PI：PAN)的资助下，开发了一种名为PLZ4的膀胱癌靶向配体。PLZ4可以与人和狗的膀胱癌细胞株以及临床标本中的癌细胞结合，这表明临床前研究可以在自发性膀胱癌的狗身上进行。PLZ4不与正常的尿路上皮细胞、炎症的膀胱细胞、血细胞、血管内皮细胞和成纤维细胞结合。最近，Kit Lam，医学博士，博士，(潘博士的VA CDA-2导师)开发了生物兼容和可生物降解的纳米胶束。化疗和显像剂可以被加载到纳米胶束中。当它们表面修饰PLZ4时，这些靶向纳米胶束与药物一起被输送到膀胱癌细胞中。靶向PLZ4-纳米胶束在体内优先集中在膀胱癌异种移植瘤部位，与非靶向纳米胶束相比，可以显着延长生存期。在本项目中，我们将优化PLZ4纳米胶束的结构，以实现最大的载药量和递送，并确定体内靶向性和药物在携带人类临床标本发展的膀胱癌异种移植瘤小鼠体内的分布。将在携带自发性膀胱癌的犬患者中进行初步研究，以获得初步的毒性和疗效数据。 公共卫生相关性： 本项目旨在开发一种多功能纳米胶束给药系统，能够特异性地将化疗药物紫杉醇输送到膀胱癌。纳米胶束系统有可能提高治疗效果并降低治疗相关毒性。