NIR-activatable Prodrugs for Treating Peritoneally Metastasized Ovarian Cancers

用于治疗腹膜转移性卵巢癌的近红外激活前药

• 批准号: 9207769
• 负责人: Youngjae You
• 金额: $ 30.34万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207769
• 关键词: Address; Adjuvant Chemotherapy; Adverse drug effect; Adverse effects; Antineoplastic Agents; Binding; Blood Circulation; Blood Vessels; Bystander Effect; Cancer Patient; Cancer Survivor; Cells; Cessation of life; Clinical; Coupled; Custom; Data; Detection; Diagnosis; Diffusion; Disease; Dose-Limiting; Drug Controls; Drug Delivery Systems; FDA approved; Failure; Folic Acid; Foundations; Future; Goals; Greater sac of peritoneum; In Vitro; Light; Lighting; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Modeling; Neoplasm Metastasis; Normal tissue morphology; Operative Surgical Procedures; Optics; PUVA Photochemotherapy; Parents; Patient-Focused Outcomes; Patients; Peritoneal; Peritoneum; Pharmaceutical Preparations; Photochemistry; Photosensitization; Physiological; Physiology; Prodrugs; Regimen; Research; Resistance; Scheme; Singlet Oxygen; Site; Survival Rate; System; Time; Tissues; Treatment Efficacy; Treatment Protocols; Tumor Debulking; Validation; active control; antitumor effect; base; cancer cell; chemotherapeutic agent; chemotherapy; controlled release; image guided; imaging detection; improved; killings; mouse model; novel; optical imaging; ovarian neoplasm; pharmacokinetic model; public health relevance; radiation resistance; radioresistant; spatiotemporal; standard care; success; tool; tumor

 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.

 描述（由适用提供）：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，并且在癌症已转移到腹膜腔时经常在晚期阶段发现。在最佳的脱毛手术后，剩余癌症的有效放疗是成功治疗腹膜转移卵巢癌的关键。但是，当前的标准治疗（手术后的化疗）未能大大提高总体生存率，但仍在 引起全身副作用。这是迫切需要一种更有效，更安全的治疗方案。该建议通过独特的多功能前药策略来解决这些问题。我们的长期目标是制定平台多功能前药策略，以实现特定地点化疗和光动力疗法（PDT，基于FDA批准的基于光电化学的制度）的协同组合，从而最大程度地提高了治疗效率并最大程度地降低了副作用。它也适用于多种转移性肿瘤。每个前药都由一种抗药物，单氧（SO） - 轻度接头，荧光光敏剂和癌症靶向组组成。一旦被可见光照明，前药会产生，从而直接损害癌细胞和肿瘤脉管系统（PDT效应）。它还仅在肿瘤中释放活性药物。 PDT在机械上与化学治疗药物不同，也有效地杀死了化学抗性的癌细胞。这是PDT和化学疗法的组合将提供最大的有效性。仅在特异性地递送非活性前药向肿瘤的特定肿瘤中，仅在肿瘤中释放药物来避免副作用。为了积极和外部控制可见的nir释放药物的释放，我们使用了新型的So-babile接头。我们还采用了物理协同作用，以最大程度地减少特定于现场释放的药物对系统循环的扩散。 PDT的血管损伤和药物与目标的紧密结合限制了药物从肿瘤到血液循环的扩散， 避免药物的全身副作用。该目标将通过3个特定目的实现：（1）合成，优化和评估的化学治疗剂前药，（2）验证肿瘤损伤的基于物理的药代动力学（PK）模型和机制，（3）确定肿瘤检测效率和抗肿瘤效应对腹膜蛋白腹膜卵巢的效应。该提案的主要可交付成果将是（i）针对卵巢癌优化的目标前药，（ii）基于生理的前药模型，这可以成为未来前药模型的基础，以及（iii）验证我们的前药的适用性用于光学检测和治疗方法 用于与转移腹膜卵巢癌的原位小鼠模型。该提案的发现将对具有转移性和晚期（II-IV阶段）卵巢癌的患者产生重大影响。该提案的策略也将适应各种转移性肿瘤。该平台前药还将通过为时空药物输送工具提供新颖有效的前药策略来影响科学研究。