I-Corps: Targeted light activatable nanoparticle to treat metastasized cancer cells

I-Corps项目更广泛的影响/商业潜力是开发用于腹膜转移性癌症治疗的光疗。目前，美国每年确诊的腹膜转移病例超过75000例，生存率低，复发率高。光免疫疗法最近被批准用于治疗原发性肿瘤，一些临床试验正在进行中。然而，大量的患者死亡是由转移引起的，因此需要联合策略来最大化癌症免疫治疗的益处。该技术旨在同时靶向和递送多种协同联合药物，从而有效改善治疗效果。此外，药物的光激活可能介导靶向癌症损伤，同时保留周围的健康组织。通过将这些功能与荧光成像相结合，外科医生和肿瘤学家可以监控药物输送并根据需要定制剂量。这可能为癌症患者提供最有效的治疗，减少毒性相关的住院治疗。这个I-Corps项目是基于开发靶向的、光激活的纳米粒子用于癌症光疗。所提出的纳米技术旨在实现多种药物的同时递送和顺序激活，这些药物针对癌细胞的所有主要区域，包括质膜、细胞质和细胞核。它可以用于共同递送三种方案，通过控制递送不同的治疗物品，包括治疗抗体（例如，西妥昔单抗），选择性地靶向膜结合受体（例如，表皮生长因子受体，EGFR），使用可光激活的光敏剂（例如，苯并卟啉衍生物）对细胞质细胞器（例如，线粒体）进行有效的光动力去极化，随后释放DNA损伤剂(例如，拓扑异构酶抑制剂伊立替康)诱导有效的核DNA损伤的协同结果。该技术将适用于卵巢癌、晚期阑尾癌、胃肠道癌、大肠癌等导致腹膜转移的癌症。将该技术成功应用于临床可能有助于提高患者的无进展生存期和总生存期。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is the development of phototherapy for peritoneal metastatic cancer treatment. Currently, more than 75,000 cases of peritoneal metastasis are diagnosed in the U.S. each year with poor survival and high recurrence rates. Photoimmunotherapy has recently been approved for treatment of primary tumors and several clinical trials are in progress. However, a significant number of patient deaths result from metastasis, and there is a demand for combination strategies to maximize the benefits of cancer immunotherapy. The proposed technology is designed to simultaneously target and deliver multiple synergistic combination drugs, thus effectively improving treatment outcomes. In addition, light activation of the drug may mediate targeted cancer damage while sparing surrounding healthy tissues. By integrating these capabilities with fluorescence imaging, surgeons and oncologists may monitor drug delivery and customize dosing as needed. This may provide cancer patients with access to the most effective treatment with fewer toxicity-associated hospitalizations.This I-Corps project is based on the development of targeted, light-activated nanoparticle for cancer phototherapy. The proposed nanotechnology is designed to achieve simultaneous delivery and sequential activation of multiple drugs that target all major regions of a cancer cell including the plasma membrane, cytoplasm, and nucleus. It may be used to co-deliver three regimens to enhance therapeutic efficacy through controlled delivery of diverse therapeutic cargoes including therapeutic antibodies (e.g., Cetuximab) that selectively target membrane-bound receptors (e.g., epidermal growth factor receptor, EGFR) for effective photodynamic depolarization of cytosolic organelles (e.g., mitochondria) using light-activatable photosensitizers (e.g., benzoporphyrin derivative), and subsequent release of DNA damaging agents (e.g., topoisomerase inhibitor irinotecan) to induce potent nuclear DNA damage for synergistic outcomes. The proposed technology will be applied to cancers that lead to peritoneal metastasis, such as ovarian cancer and late-stage appendix, gastrointestinal, and colorectal cancers. A successful translation of this technology to the clinic may contribute to improving progression-free survival and overall survival in patients.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.