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

这个i-Corps项目的更广泛的影响/商业潜力是通过减少毒副作用和改善治疗指数来提高癌症化疗药物的临床利用率。关键技术是基于针对肿瘤酸中毒的化疗药物的控制释放。最初的产品是多柔比星(Dox)的一种酸敏性前药。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、肾母细胞瘤和神经母细胞瘤)。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)。临床上Dox应用的60%-70%是对可能是酸性的实体肿瘤的治疗。预计到2024年，Dox全球市场将达到13.8亿美元。这种对pH敏感的Dox前药可能被认为是Dox治疗酸性实体瘤的改进版本。此外，这项技术还可以扩展到除蒽环类药物以外的其他化疗药物。此外，酸性微环境不仅在癌症肿瘤中被发现，而且在其他疾病状态下也被发现，例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目标。这项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，来改善化疗药物的安全性。靶向药物释放将由肿瘤酸中毒触发。由于肿瘤的快速生长，许多肿瘤的细胞外pH(Phe)在6.5-6.9之间，而健康组织的Phe在7.2-7.4之间。肿瘤酸中毒可被认为是肿瘤微环境的通用生物标志物，并与预后不良相关(即，更多的酸性肿瘤通常在更具侵袭性的癌症中发现)。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，以回应酸性肿瘤Phe。通过使用酸敏连接子，从基础科学方面解决了开发能够区分Phe 7.4和6.7的超灵敏pH生物传感器的关键挑战。初步数据表明，在细胞培养环境中，这些前药在pH值为6.7时可以释放大约4倍于7.4的Dox。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 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.