Engineering a supramolecular platinum nanoparticle for pediatric cancer

设计用于治疗儿科癌症的超分子铂纳米颗粒

• 批准号: 8692268
• 负责人: Shiladitya Sengupta
• 金额: $ 21.57万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-16 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692268
• 关键词: Aging; Bilateral Hearing Loss; Binding; Biodistribution; Blood; Bypass; Cancer Biology; Carboplatin; Cause of Death; Cells; Central Nervous System Neoplasms; Charge; Child; Childhood Cancer Treatment; Chloride Ion; Chlorides; Cisplatin; Clinical; Clinical Oncology; Complex; Cyclobutanes; DNA; DNA Adduction; Data; Dose; Dose-Limiting; Drug Kinetics; Drug toxicity; Effectiveness; Engineering; Environment; Exclusion; Exhibits; Germ cell tumor; Goals; Guanine; Hair; Hair Cells; Health; Hearing; Hepatoblastoma; In Vitro; Journals; Kinetics; Labyrinth; Learning; Learning Disabilities; Left; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Methods; Modeling; Morphology; Mus; Myelosuppression; Nanotechnology; Nature; Neuroblastoma; Organ of Corti; Organic Cation Transporter; Outcome; Parents; Pharmaceutical Preparations; Pharmacodynamics; Platinum; Property; Reaction; Reflex action; Regimen; Reporting; Resources; Retinoblastoma; Risk; Testing; Therapeutic; Toxic effect; Translating; Work; X-Ray Crystallography; analog; base; cancer cell; cancer pharmacology; chemotherapy; comparative efficacy; design; dicarboxylate; efficacy testing; hearing impairment; improved; in vivo; killings; learning ability; nanoparticle; neoplastic cell; nephrotoxicity; novel; osteosarcoma; ototoxicity; oxaliplatin; prevent; public health relevance; response; self assembly; treatment effect; tumor; tumor growth

DESCRIPTION (provided by applicant): Platinum-based drugs, such as cisplatin, carboplatin and oxaliplatin, are routinely used in treatment of pediatric cancers, such as CNS tumors, osteosarcoma, hepatoblastoma, neuroblastoma, germ cell tumors, and retinoblastoma. While the dose-limiting toxicities of these drugs are nephrotoxicity and myelosuppression, they are oto-toxic at therapeutic doses; indeed, as many as 60% of children treated with cisplatin suffer from permanent bilateral hearing loss, leading to learning disabilities. As described recently in the Journal of Clinical Oncology, efforts to find a method to prevent or mitigate the ototoxic effect without diminishing its effectiveness in killing cancers cells are ongoing but are yet to be realized. In a preliminary study, we observed that platinum-based chemotherapeutics can be re-engineered to facilitate supramolecular assembly into nanoparticles, resulting in superior efficacy and toxicity profile than the parent molecule. This project aims to study the use of these nanoparticles as a novel therapy for pediatric cancers to mitigate the above challenges, including ototoxicity. Specifically we will: (1).Synthesize amphiphilic platinum (II) analogs that facilitate supramolecular self-assembly into nanoparticles. This part of the study will test the hypothesis that modifying the leaving group of platinum chemotherapeutics can generate analogs that are not only more potent than the parent molecule, but confer an amphiphilic property that facilitates self-assembly into nanoparticles via hydrophobic-hydrophilic interactions. (2) Test the efficacy of the supramolecular platinum nanoparticles in pediatric cancer in vitro and in vivo. In this section we will test the hypothesis that the supramolecular platinum nanoparticles can exert enhanced anti-tumor efficacy as compared with the parent molecules. We will use two models of pediatric cancer, the K7M2 osteosarcoma and B104-1-1 neuroblastoma model in this study. (3) Test the ototoxicity profile of the nanoparticles and impact on hearing as compared with existing platinum chemotherapeutics in vivo. We will test the hypothesis that the inability of nanoparticles to cross the blood labyrinth barrier (size exclusion) can minimize otoxicity. Specifically, we will study the concentration of Pt in the organ of Corti attained with nanoparticles and free drug treatments, and correlate that to the loss of hair cells. Additionally, we will use the Preyer reflex and startle response to quantify the effectof treatment on hearing loss and learning ability in mice. Hearing loss and impaired learning abilities are one of the major clinical challenges of platinum chemotherapy for pediatric cancers, for which there are currently no alternatives. We anticipate that the above approach to develop a platinum-based nanoparticle may overcome these challenges while improving antitumor outcome.

描述（由申请人提供）：铂类药物，如顺铂、卡铂和奥沙利铂，常规用于儿科癌症的治疗，如中枢神经系统肿瘤、骨肉瘤、肝母细胞瘤、神经母细胞瘤、生殖细胞肿瘤和视网膜母细胞瘤。虽然这些药物的剂量限制性毒性是肾毒性和骨髓抑制，但在治疗剂量下它们是耳毒性的；事实上，接受顺铂治疗的儿童中有多达60%患有永久性双侧听力损失，从而导致学习障碍。正如《临床肿瘤学杂志》（Journal of Clinical Oncology）最近所描述的那样，人们正在努力寻找一种方法，既能预防或减轻耳毒性作用，又不降低其杀死癌细胞的有效性，但仍有待完成