Engineering a supramolecular platinum nanoparticle for pediatric cancer

描述（由申请人提供）：铂类药物，如顺铂、卡铂和奥沙利铂，通常用于治疗儿科癌症，如CNS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，但它们在治疗剂量下具有耳毒性;事实上，多达60%的顺铂治疗儿童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，正在努力寻找一种方法来预防或减轻耳毒性效应而不降低其杀死癌细胞的有效性，但尚未完成。 实现了在一项初步研究中，我们观察到，铂类化疗药物可以重新设计，以促进超分子组装成纳米颗粒，从而产生优于母体分子的疗效和毒性特征。本项目旨在研究这些 纳米颗粒作为儿科癌症的新疗法，以减轻上述挑战，包括耳毒性。具体而言，我们将：（1）。合成两亲性铂（II）类似物，促进超分子自组装成纳米粒子。该研究的这一部分将测试这样的假设，即修饰铂化疗药物的离去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)在体外和体内测试超分子铂纳米颗粒在儿科癌症中的功效。在本节中，我们将检验超分子铂纳米颗粒与母体分子相比可以发挥增强的抗肿瘤功效的假设。我们将在本研究中使用两种儿科癌症模型，K7 M2骨肉瘤和B104-1-1神经母细胞瘤模型。(3)测试纳米颗粒的耳毒性特征以及与现有铂类化疗药物相比对听力的影响。我们将检验纳米颗粒不能穿过血迷路屏障（尺寸排阻）可以最大限度地减少耳毒性的假设。具体来说，我们将研究器官中Pt的浓度， 的Corti达到纳米粒子和免费药物治疗，并与毛细胞的损失。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化疗治疗儿科癌症的主要临床挑战之一，目前没有替代方案。我们预计，上述开发铂基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.