Different Strategies to Improve Drug Tissue Selectivity for Better Efficacy/Toxicity Profile

Abstract

Despite tremendous efforts being devoted to improving drug discovery and development, the clinical failure rate remains high (>90% phase I onwards), particularly due to efficacy and safety issues. Based on the current strategies, drug candidates with optimized pre-clinical efficacy or toxicity and favorable plasma pharmacokinetics (PK) parameters are preferred for clinical studies. However, drug plasma exposure is not sufficient to represent the in vivo behavior and may mislead the selection of drug candidates for clinical trials. Furthermore, the importance of drug tissue exposure or selectivity, which is related to drug accumulation in disease- or toxicity-related tissues, continues to be ignored. In this study, we attempted to improve drug discovery from the perspective of altering drug tissue exposure and selectivity. In the first project (Chapter II), an albumin-based nanoformulation was prepared for BCL-2/BCL-XL inhibitors to improve tissue targeting, reduce platelet toxicity, and enhance anticancer efficacy in myeloproliferative neoplasms (MPNs) and lymphoma. Since the BCL-XL pathway is critical to the survival of platelets in blood, dual BCL-2/BCL-XL inhibitors can cause rapid thrombocytopenia in the circulation system. By altering the formulation of the compound, we aimed to alter its biodistribution via 1) a lower exposure in the blood to reduce platelet toxicity, and 2) similar or even a higher exposure in the target tissues (spleen and bone marrow, BM) to maintain or increase its efficacy. Subsequently, an albumin-based nanoformulation was successfully developed; owing to its high formulation stability, large amounts of nanoparticles were trapped in the spleen and BM, resulting in their high accumulation in these tissues and low concentration in the circulation system. Nanomedicine comprising the BCL-2/BCL-XL inhibitor substantially decreased platelet toxicity, prolonged the survival rate, delayed paralysis occurrence, and reduced tumor infiltration in the spleen and BM compared to the clinical formulation. In the second project (Chapter III), the anti-SARS-CoV-2 small molecule remdesivir was optimized to improve lung targeting and enhance its efficacy against COVID-19. Although approved by the FDA in October 2020, the controversial efficacy of remdesivir in several clinical studies (GS-US-540-5773, GS-US-540-5774, WHO Solidarity trial) limited its wide administration. To improve the clinical potential of remdesivir, we modified its structure to increase lung accumulation without altering its anti-viral activity. Our lead compound, MMT5-14, achieved a 200-fold higher parent drug concentration in the target tissues (e.g., lung) and approximately 5-fold higher amount of active form (triphosphate form) than remdesivir. Moreover, owing to its high chemical stability, MMT5-14 showed a 4- to 7-fold higher uptake by HUVECs and lung epithelial cells (Calu-3) than remdesivir, with 4- to 8-fold enhanced anti-SARS-CoV-2 activities in Vero-E6 cells survival assay and virus titer reduction assay. In the third project (Chapter IV), the structure-tissue exposure or selectivity relationship (STR) was studied using a series of selective estrogen receptor modulators (SERMs). Results showed that drug exposure in the plasma was not correlated with drug exposure in the target tissues (tumor, fatpad, and bone), which was associated with clinical efficacy and safety. A slight structural modification altered drug exposure and selectivity in tissues despite similar drug exposure in the plasma. The STR may be correlated with clinical efficacy and safety, which might impact the success rate of drug development. Overall, this study highlights the importance of employing tissue selectivity as a parameter in the early stages of drug discovery and development.