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.
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. This project aims to study the use of rationally designed supramolecular Pt (II) nanoparticles as a novel therapy for pediatric cancers that can not only exhibit greater antitumor efficacy but also decreased ototoxicity.