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

这个i-Corps项目的更广泛的影响/商业潜力是开发用于腹膜转移癌治疗的光疗法。目前，美国每年诊断出的腹膜转移病例超过7.5万例，存活率低，复发率高。光免疫疗法最近已被批准用于治疗原发肿瘤，几项临床试验正在进行中。然而，有相当数量的患者死于转移，因此需要组合策略来最大限度地发挥癌症免疫治疗的好处。拟议的技术旨在同时靶向并提供多种协同联合药物，从而有效地改善治疗结果。此外，药物的光激活可能会介导靶向癌症损伤，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。这可能会为癌症患者提供最有效的治疗，同时减少与毒性相关的住院治疗。这项i-Corps项目是基于开发用于癌症光疗的靶向、光激活纳米颗粒。拟议的纳米技术旨在实现多种药物的同时释放和顺序激活，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。它可用于联合传递三种方案以提高治疗效果，包括治疗性抗体(例如西妥昔单抗)，该抗体选择性地靶向于膜结合的受体(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)有效地光动力去极化胞浆细胞器(例如线粒体)，以及随后释放DNA损伤剂(例如拓扑异构酶抑制剂伊立替康)以诱导有效的核DNA损伤以实现协同结果。拟议的技术将应用于导致腹膜转移的癌症，如卵巢癌和晚期阑尾、胃肠道和结直肠癌。将这项技术成功地转化到临床上可能有助于改善患者的无进展存活率和总体存活率。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.