I-Corps: pH-sensitive Prodrug for Targeted Cancer Chemotherapy

I-Corps项目更广泛的影响/商业潜力是通过减少毒副作用和提高治疗指数来增加癌症化疗药物的临床应用。肿瘤酸中毒的关键技术是基于化疗药物的控释。最初的产品是阿霉素（Dox）的酸敏感前药。Dox是一种重要的化疗药物，通常用于治疗乳腺癌、膀胱癌和其他癌症（包括儿童癌症Wilms肿瘤和神经母细胞瘤）。目前，Dox的全球年市场规模约为8亿美元（美国约为4亿美元）。治疗可能呈酸性的实体肿瘤约占阿霉素临床应用的60-70%。到2024年，Dox全球市场预计将达到13.8亿美元。这种对ph敏感的Dox前药可能被认为是治疗酸性实体瘤的Dox的改进版本。此外，这项技术可以扩展到蒽环类药物以外的其他化学药物。此外，酸性微环境不仅存在于癌性肿瘤中，也存在于其他疾病状态中，如炎症部位和心脏病发作时的缺血心肌，这代表了未来ph敏感前药技术的其他潜在靶点。I-Corps项目旨在开发一种技术，通过抑制药物在健康组织中的释放，同时优先在肿瘤部位释放药物，从而提高化疗药物的安全性。肿瘤酸中毒可触发靶向药物释放。由于生长迅速，许多癌性肿瘤的胞外pH值（pHe）在6.5-6.9之间，而健康组织的pHe为7.2-7.4。肿瘤酸中毒可以被认为是癌症微环境的一种普遍的生物标志物，并与不良预后相关（即，更强的酸性肿瘤通常出现在更强的侵袭性癌症中）。为了将肿瘤酸中毒转化为癌症，该团队开发了超酸敏感的小分子前药，以选择性地释放Dox，以响应酸性肿瘤pHe。开发一种能够区分pHe 7.4和6.7的超灵敏pH生物传感器的关键挑战已经通过使用酸敏感连接剂从基础科学方面解决了。初步数据表明，在细胞培养条件下，这些前药在pH为6.7时比在pH为7.4时多释放约4倍的Dox。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 to increase the clinical utilization of cancer chemotherapy drugs by reducing toxic side effects and improving the therapeutic index. The key technology is based on the controlled release of chemo-drugs in response to tumor acidosis. The initial product is an acid-sensitive prodrug of Doxorubicin (Dox). Dox is a prominent chemo-drug commonly used in the treatment of breast, bladder, and other cancers (including the childhood cancers Wilms tumor and neuroblastoma). The current global annual market for Dox is ~$800M (~$400M in the US). Treatments of solid tumors that are likely to be acidic account for ~60-70% of Dox applications in the clinic. The Dox global market is projected to reach $1.38B by 2024. This pH-sensitive prodrug of Dox may be considered an improved version of Dox for treating acidic solid tumors. Also, this technology could be expanded to other chemo-drugs outside of the anthracycline class. Furthermore, acidic microenvironments are found not only in cancerous tumors, but also in other disease states, such as sites of inflammation and the ischemic myocardium during heart attacks, which represent other potential targets of the pH-sensitive prodrug technology in the future.This I-Corps project aims to develop a technology for improving the safety profile of chemo-drugs by suppressing drug release at healthy tissues, while preferentially releasing drugs at tumor sites. The targeted drug release would be triggered by tumor acidosis. Due to rapid growth, many cancerous tumors have extracellular pH (pHe) in the range of 6.5-6.9, compared with pHe of 7.2-7.4 in healthy tissues. Tumor acidosis can be considered as a universal biomarker of the cancer microenvironment and correlates with poor prognosis (i.e., more acidic tumors are usually found in more aggressive cancers). To turn tumor acidosis against cancer, this team developed ultra-acid-sensitive, small molecule prodrugs to selectively release Dox in response to acidic tumor pHe. The critical challenge of developing an ultra-sensitive pH biosensor that can distinguish between pHe 7.4 and 6.7 has been met from the basic science side by using an acid-sensitive linker. Preliminary data indicate that these prodrugs can release ~ 4-fold more Dox at pH 6.7 vs. 7.4 in cell culture settings.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.