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.