Stem Cell/Nanoparticle Constructs for Targeted Ovarian Cancer Therapy

用于卵巢癌靶向治疗的干细胞/纳米颗粒构建体

• 批准号: 9303321
• 负责人: Karen S Aboody
• 金额: $ 38.89万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303321
• 关键词: Abdomen; Abdominal Cavity; Address; Adverse effects; Animals; Behavior; Biodistribution; Biological; Blood Vessels; Brain; Cell Therapy; Cells; Chemotherapy-Oncologic Procedure; Cisplatin; Clinic; Clinical; Clinical Treatment; Clinical Trials; Coupling; Development; Disease; Drug Delivery Systems; Drug Targeting; Encapsulated; Enzymes; Extravasation; Formulation; Generations; Glioma; Goals; Healthcare; High Pressure Liquid Chromatography; Human; Hybrids; Hypoxia; In Vitro; Inductively Coupled Plasma Mass Spectrometry; Intravenous; Kinetics; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of abdomen; Malignant neoplasm of ovary; Mass Spectrum Analysis; Measures; Modeling; Monitor; Neoplasm Metastasis; Neurodegenerative Disorders; Normal tissue morphology; Paclitaxel; Paper; Patients; Pharmaceutical Preparations; Physiological; Platinum; Prodrugs; Property; Publishing; Recurrence; Safety; Scheme; Serous; Silicon Dioxide; Site; Spleen; Stem cells; Stroke; Surface; Survival Rate; Symptoms; System; Techniques; Therapeutic; Thermal Ablation Therapy; Thick; Time; Toxic effect; Tropism; Weight; Woman; cancer cell; cancer therapy; chemotherapy; drug efficacy; immunogenic; immunogenicity; improved; improved outcome; in vivo; intraperitoneal; intraperitoneal therapy; killings; mouse model; nano; nanocapsule; nanoparticle; nerve stem cell; novel; ovarian neoplasm; pre-clinical; prevent; public health relevance; targeted delivery; targeted treatment; taxane; tumor

 DESCRIPTION (provided by applicant): Targeted drug delivery is a critical goal for effective cancer therapy. While nanoparticles (NPs) have shown promise for targeting drugs to tumors, several major challenges remain for controlling the biodistribution of NPs. In general, NPs predominantly accumulate in the liver and spleen and have difficulty penetrating poorly vascularized regions like hypoxic tumor regions. Neural Stem Cells (NSCs) are appealing for use as carriers for NPs in order to overcome these biodistribution challenges. NSCs have demonstrated inherent tumor tropic properties in pre- clinical invasive and metastatic tumor models, migrating selectively to tumors and penetrating hypoxic tumor regions. NSCs must be modified in some way to exploit their tumor targeting abilities. We have been pioneers in genetically altering NSCs to express an enzyme that converts a prodrug into active drug; recently showing safety in a first in-human clinical trial. As NSC-based therapy moves into the clinic, there is a need for complementary techniques to enable NSCs to destroy tumors that cannot be addressed with the enzyme-prodrug strategy. We have shown that NSCs maintain their tumor tropism when transporting either surface-bound or internalized NPs. The combination of NSCs and NPs offers the potential to realize a modular and general drug targeting system. We have recently published several papers showing surface-bound NPs can slowly release chemotherapy drugs, while internalized NPs can be used for thermal ablation of tumors. Here we will further develop the surface conjugated NP system and apply it to the treatment of stage III ovarian cancer (metastasized only in the abdominal cavity). Intraperitoneal (IP) as compared to intravenous (IV) chemo improved survival rates for stage III ovarian cancer. While this demonstrates that concentrating chemotherapy at the tumors has therapeutic benefit, IP therapy was also accompanied by increased toxic side effects. We hypothesize that NSC/NP hybrids can be used to target chemotherapy to abdominal ovarian cancer, improving outcomes and decreasing side effects. Conjugation of the NPs to the NSCs will be optimized and potential immunogenicity will be evaluated in vitro. Novel NPs with the desired drug release kinetics will be prepared. Once the most promising NP formulation and conjugation is identified, the efficacy of NSC/NP-targeted chemotherapy will be evaluated in vivo. The results from these studies will not only significantly impact the treatment of ovarian cancer, but should also enable improved therapy for other cancers. The NSC/NP constructs could also be used for treating other conditions that have proved amenable to NSC-therapy, such as neurodegenerative diseases.

 描述（由申请人提供）：靶向药物递送是有效癌症治疗的关键目标。虽然纳米粒子 (NP) 已显示出将药物靶向肿瘤的前景，但控制纳米粒子的生物分布仍然存在几个主要挑战。一般来说，纳米颗粒主要积聚在肝脏和脾脏中，很难穿透血管化不良的区域，如缺氧的肿瘤区域。神经干细胞（NSC）作为纳米粒子的载体很有吸引力，以克服这些生物分布的挑战。 NSCs 在临床前侵袭性和转移性肿瘤模型中表现出固有的肿瘤特性，选择性地迁移到肿瘤并穿透缺氧肿瘤区域。神经干细胞必须以某种方式进行修饰才能发挥其肿瘤靶向能力。我们一直是基因改变 NSC 来表达将前药转化为活性药物的酶的先驱；最近在首次人体临床试验中显示出安全性。 随着基于 NSC 的疗法进入临床，需要补充技术来使 NSC 能够破坏酶前药策略无法解决的肿瘤。我们已经证明，NSC 在运输表面结合或内化的纳米粒子时保持其肿瘤趋向性。 NSC 和 NP 的结合提供了实现模块化和通用药物靶向系统的潜力。我们最近发表了几篇论文，表明表面结合的纳米颗粒可以缓慢释放化疗药物，而内部纳米颗粒可用于肿瘤的热消融。在这里，我们将进一步开发表面缀合的NP系统，并将其应用于III期卵巢癌（仅在腹腔转移）的治疗。与静脉内 (IV) 化疗相比，腹膜内 (IP) 化疗可提高 III 期卵巢癌的生存率。虽然这表明对肿瘤进行集中化疗具有治疗益处，但 IP 治疗也伴随着毒副作用的增加。我们假设 NSC/NP 混合体可用于针对腹部卵巢癌的化疗，改善结果并减少副作用。 将优化纳米粒子与 NSC 的结合，并在体外评估潜在的免疫原性。将制备具有所需药物释放动力学的新型纳米颗粒。一旦确定了最有前途的 NP 制剂和结合物，将在体内评估 NSC/NP 靶向化疗的疗效。这些研究的结果不仅将显着影响卵巢癌的治疗，而且还应该能够改善其他癌症的治疗。 NSC/NP 构建体还可用于治疗已证明适合 NSC 疗法的其他疾病，例如神经退行性疾病。