Stem Cell/Nanoparticle Constructs for Targeted Ovarian Cancer Therapy

 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。虽然纳米颗粒（NPs）已经显示出将药物靶向肿瘤的前景，但控制NPs的生物分布仍然存在几个主要挑战。通常，NP主要积聚在肝脏和脾脏中，并且难以穿透血管化不良的区域，如缺氧肿瘤区域。神经干细胞（NSC）被用作NP的载体以克服这些生物分布挑战是有吸引力的。神经干细胞在临床前侵袭性和转移性肿瘤模型中表现出固有的肿瘤嗜性，选择性地迁移到肿瘤并穿透缺氧的肿瘤区域。必须以某种方式修饰神经干细胞以利用其肿瘤靶向能力。我们一直是基因改变NSC表达酶的先驱，该酶将前药转化为活性药物;最近在第一次人体临床试验中显示出安全性。 随着基于神经干细胞的治疗进入临床，需要补充技术来使神经干细胞能够破坏无法用酶-前药策略解决的肿瘤。我们已经表明，当运输表面结合或内化的NP时，NSC保持其肿瘤向性。神经干细胞和纳米粒的组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，而内化的纳米颗粒可以用于肿瘤的热消融。在这里，我们将进一步开发表面结合NP系统，并将其应用于治疗III期卵巢癌（仅在腹腔转移）。腹膜内（IP）化疗与静脉（IV）化疗相比，可提高III期卵巢癌的生存率。虽然这表明在肿瘤处集中化疗具有治疗益处，但IP治疗也伴随着增加的毒副作用。我们假设NSC/NP杂合体可用于腹部卵巢癌的靶向化疗，改善结果并减少副作用。 将优化NP与NSC的缀合，并在体外评价潜在的免疫原性。将制备具有所需药物释放动力学的新型NP。一旦确定了最有希望的NP制剂和缀合物，将在体内评价NSC/NP靶向化疗的功效。这些研究的结果不仅会显著影响卵巢癌的治疗，而且还可以改善其他癌症的治疗。NSC/NP构建体也可用于治疗已证明适合于NSC治疗的其他病症，例如神经退行性疾病。

 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.