Engineering a supramolecular platinum nanoparticle for pediatric cancer

描述(申请人提供)：以铂为基础的药物，如顺铂、卡铂和奥沙利铂，通常用于治疗儿童癌症，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毒性是肾毒性和骨髓抑制，但在治疗剂量下它们是耳毒性；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，导致学习障碍。正如最近在《临床肿瘤学杂志》上所描述的那样，正在努力寻找一种方法来预防或减轻耳毒性效应，同时又不会削弱其杀死癌细胞的有效性，但还没有做到 意识到了。在一项初步研究中，我们观察到基于铂的化疗药物可以被重新设计，以促进超分子组装成纳米颗粒，从而产生比母分子更好的疗效和毒性。本项目旨在研究这些技术的使用 纳米粒子作为一种治疗儿童癌症的新疗法，以缓解上述挑战，包括耳毒性。具体来说，我们将：(1).合成促进超分子自组装成纳米颗粒的两亲性铂(II)类似物。该研究的这一部分将检验这样一种假设，即修饰铂类化疗药物的离开基团可以产生不仅比母体分子更有效的类似物，而且赋予两亲性，通过疏水-亲水相互作用促进自组装成纳米颗粒。(2)检测超分子铂纳米粒在体内外对儿童肿瘤的治疗效果。在这一部分中，我们将检验超分子铂纳米颗粒与母体分子相比可以发挥更强的抗肿瘤效果的假设。我们将使用两种儿童癌症模型，K7M2骨肉瘤模型和B104-1-1神经母细胞瘤模型。(3)与现有铂类化疗药物进行体内比较，测试纳米粒的耳毒性及对听力的影响。我们将检验这样一种假设，即纳米颗粒无法穿过血液迷宫屏障(大小排除)可以将卵巢毒性降至最低。具体地说，我们将研究器官中铂的浓度 使用纳米颗粒和免费药物治疗获得的Corti的比例，并与毛细胞的损失相关。此外，我们将使用Preyer反射和惊吓反应来量化治疗对小鼠听力损失和学习能力的影响。听力损失和学习能力受损是铂类化疗治疗儿童癌症的主要临床挑战之一，目前尚无替代方案。我们预计，上述开发基于铂的纳米颗粒的方法可以克服这些挑战，同时改善抗肿瘤结果。

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.