NIR-activatable Prodrugs for Treating Peritoneally Metastasized Ovarian Cancers

 描述（由申请人提供）：卵巢癌（2014年估计有21，980例新发病例和14，270例死亡）是最致命的妇科恶性肿瘤，并且通常在癌症转移到腹膜腔时的晚期发现。在最佳减瘤手术后，有效根除剩余的癌症是成功治疗腹膜转移卵巢癌的关键。然而，目前的标准治疗（手术后化疗）未能大大提高总生存率， 会引起全身副作用因此，迫切需要更有效和安全的治疗方案。这一建议以独特的多功能前药策略解决了这些问题。我们的长期目标是开发一种平台多功能前体药物策略，以实现位点特异性化疗和光动力疗法（PDT，FDA批准的基于光化学的方案）的协同组合，从而最大限度地提高治疗效果并最大限度地减少副作用。它也适用于广泛的转移性肿瘤。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-NIR光照射，前药产生直接损伤癌细胞和肿瘤脉管系统的SO（PDT效应）。它也只在肿瘤中释放活性药物。PDT在机制上不同于化疗药物，并且还有效地杀死化学抗性癌细胞。因此，PDT和化疗的组合将提供最大的疗效。通过将无活性前药特异性递送至肿瘤后仅在肿瘤中位点特异性释放药物来避免副作用。为了通过可见-NIR主动地和外部地控制药物的释放，我们使用我们的新型SO-不稳定连接体。我们还采用生理协同效应来最小化位点特异性释放的药物向体循环的扩散。PDT引起的血管损伤和药物与其靶点的紧密结合都限制了药物从肿瘤扩散到血液循环， 避免了药物的全身副作用。本研究的主要目的是：（1）合成、优化和评价化疗药物的靶向前体药物;（2）建立基于生理学的药代动力学（PK）模型和肿瘤损伤机制;（3）确定肿瘤检测效率和对腹膜卵巢肿瘤的抗肿瘤作用。该提案的主要成果将是（i）针对卵巢癌优化的靶向前药，（ii）前药的基于生理学的PK模型，其可以是未来前药模型的基础，以及（iii）验证我们的前药用于光学检测和治疗的适用性 用于转移性腹膜卵巢癌的原位小鼠模型。该提案的发现将对转移性耐药和晚期（II-IV期）卵巢癌患者的结局产生重大影响。该建议的策略也将适用于广泛的转移性肿瘤。平台前药还将通过为时空药物递送工具提供新颖有效的前药策略来影响科学研究。

 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.