NIR-activatable Prodrugs for Treating Peritoneally Metastasized Ovarian Cancers

 描述(申请人提供)：卵巢癌(2014年估计有21,980例新病例和14,270例死亡)是最致命的妇科恶性肿瘤，通常在癌症已经转移到腹膜腔的晚期被发现。腹膜转移性卵巢癌的成功治疗的关键是在最佳去瘤手术后有效地根除残留的肿瘤。然而，目前的标准治疗(手术后化疗)未能显著提高总体存活率，仍然 会引起全身副作用。因此，迫切需要一种更有效、更安全的治疗方案。这项提案通过一种独特的多功能前药战略解决了这些问题。我们的长期目标是开发一种平台多功能前药战略，以实现定点化疗和光动力疗法(PDT，FDA批准的基于光化学的疗法)的协同组合，从而最大化治疗效果并将副作用降至最低。它也适用于多种转移性肿瘤。每种前药由抗癌药物、单线态氧(SO)不稳定连接体、荧光光敏剂和癌症靶向基团组成。一旦被可见光-近红外光照射，前药就会产生，从而直接损害癌细胞和肿瘤血管系统(PDT效应)。它还只在肿瘤中释放活性药物。PDT在机制上与化疗药物不同，也能有效地杀死耐药癌细胞。因此，光动力疗法和化疗的结合将提供最大的疗效。通过将非活性前体药物特定地递送到肿瘤后，仅在肿瘤中定位释放药物，可以避免副作用。为了通过可见-近红外光谱主动和外部控制药物的释放，我们使用了我们的新型不稳定的连接物。我们还利用生理协同效应来最大限度地减少特定部位释放的药物扩散到体循环。PDT造成的血管损伤和药物与靶点的紧密结合都限制了药物从肿瘤向血液循环的扩散， 避免药物的全身副作用。这些目标的实现有三个具体目标：(1)合成、优化和评价靶向化疗药物；(2)验证基于生理的药代动力学(PK)模型和肿瘤损伤机制；(3)确定腹膜卵巢肿瘤的肿瘤检测效率和抗肿瘤效果。这项建议的主要成果将是：(I)针对卵巢癌优化的靶向前体药物，(Ii)基于生理学的前体药物PK模型，它可以作为未来前体药物模型的基础，以及(Iii)验证我们的前体药物在光学检测和治疗方面的适用性 用于腹膜卵巢癌转移的原位小鼠模型。这项建议的结果将对转移性、耐药和晚期(II-IV期)卵巢癌患者的预后产生重大影响。这项提议的策略也将适用于广泛的转移性肿瘤。前药平台还将通过为时空给药工具提供新颖有效的前药策略，对科学研究产生影响。

 DESCRIPTION (provided by applicant): Ovarian cancer (estimated 21,980 new cases and 14,270 deaths in 2014) is the most lethal gynecologic malignancy, and is often discovered in advanced stages when the cancer has metastasized to the peritoneal cavity. Effective eradication of remaining cancers, after optimal debulking surgery, is the key to successful treatment of peritoneally metastasized ovarian cancers. However, current standard treatment (chemotherapy following the surgery) has failed to greatly improve overall survival rates and still causes systemic side effects. Thus, a more effective and safe treatment regimen is urgently needed. This proposal addresses these issues with a unique multifunctional prodrug strategy. Our long-term goal is to develop a platform multifunctional prodrug strategy to achieve synergistic combination of site-specific chemotherapy and photodynamic therapy (PDT, an FDA-approved photochemistry-based regime), which maximizes therapeutic efficacy and minimizes side effects. It is also applicable to a wide range of metastatic tumors. Each prodrug is comprised of an anticancer drug, singlet oxygen (SO)-labile linker, a fluorescent photosensitizer, and cancer- targeting group. Once illuminated by visible-NIR light, the prodrug generates SO that directly damages cancer cells and tumor vasculature (PDT effects). It also releases active drugs only in tumors. PDT is mechanistically distinct from chemotherapeutic drugs and also effectively kills chemo-resistant cancer cells. Thus, the combination of PDT and chemotherapy will provide maximum efficacy. Side effects are avoided by site-specifically releasing drugs only in tumors following specific delivery of inactive prodrugs to tumors. To actively and externally control the release of drug by visible-NIR, we use our novel SO-labile linker. We also employ physiological synergistic effects to minimize the diffusion of the site-specifically released drugs to the systemic circulation. Both vascular damage by PDT and tight binding of drugs to their targets limit the diffusion of the drugs from tumor to blood circulation, avoiding systemic side effects of the drugs. The goals will be realized with 3 specific aims: (1) Synthesize, optimize, and evaluate targeted prodrugs of chemotherapeutic agents, (2) Validate the physiologically-based pharmacokinetic (PK) model and mechanisms of tumor damage, (3) Determine tumor-detection efficiency and antitumor effects for peritoneal ovarian tumors. Major deliverables of this proposal will be (i) targeted prodrugs optimized for ovarian cancers, (ii) physiology-based PK models of prodrugs, which can be a foundation for models of future prodrugs, and (iii) validation of applicability of our prodrugs for optical detection and treatment for orthotopic mouse models with metastasized peritoneal ovarian cancers. The findings of this proposal will significant impact outcomes for patients with metastasized resistant and advanced (stages II-IV) ovarian cancers. The strategy of this proposal will also be adaptable to a wide array of metastatic tumors. The platform prodrugs will also impact scientific research by providing novel and effective prodrug strategy for spatio-temporal drug delivery tools.