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.
