TY - JOUR
T1 - Targeting Heterogeneous Tumors Using a Multifunctional Molecular Prodrug
AU - Sharma, Amit
AU - Lee, Min Goo
AU - Won, Miae
AU - Koo, Seyoung
AU - Arambula, Jonathan F.
AU - Sessler, Jonathan L.
AU - Chi, Sung Gil
AU - Kim, Jong Seung
N1 - Funding Information:
This work was supported in part by a Creative Research Initiatives project (grant no. 2018R1A3B1052702, J.S.K.) and a grant from the National Research Foundation of Korea (NRF-2018R1A2A1A05020236, S.-G.C., and 2017R1D1A1B03030062, M.W.). Funding from the National Cancer Institute (RO1 CA68682, J.L.S., and R15 CA232765, J.F.A.) and the Robert A. Welch Foundation (F-0018, J.L.S.) is also acknowledged.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/10/2
Y1 - 2019/10/2
N2 - Reported here is a molecular construct (K1) designed to overcome hurdles associated with delivering active drugs to heterogeneous tumor environments. Construct K1 relies on two cancer environment triggers (GSH and H2O2) to induce prodrug activation. It releases an active drug form (SN-38) under conditions of both oxidative and reductive stress in vitro. Specific uptake of K1 in COX-2 positive aggressive colon cancer cells (SW620 and LoVo) was seen, along with enhanced anticancer activity compared with the control agent SN-38. These findings are attributed to environmentally triggered drug release, as well as simultaneous scavenging of species giving rise to intracellular redox stress. K1 serves to downregulate various cancer survival signaling pathways (AKT, p38, IL-6, VEGF, and TNF-α) and upregulate an anti-inflammatory response (IL-10). Compared with SN-38 and DMSO as controls, K1 also displayed an improved in vivo therapeutic efficacy in a xenograft tumor regrowth model with no noticeable systematic toxicity at the administrated dose. We believe that the strategy described here presents an attractive approach to addressing solid tumors characterized by intratumoral heterogeneity.
AB - Reported here is a molecular construct (K1) designed to overcome hurdles associated with delivering active drugs to heterogeneous tumor environments. Construct K1 relies on two cancer environment triggers (GSH and H2O2) to induce prodrug activation. It releases an active drug form (SN-38) under conditions of both oxidative and reductive stress in vitro. Specific uptake of K1 in COX-2 positive aggressive colon cancer cells (SW620 and LoVo) was seen, along with enhanced anticancer activity compared with the control agent SN-38. These findings are attributed to environmentally triggered drug release, as well as simultaneous scavenging of species giving rise to intracellular redox stress. K1 serves to downregulate various cancer survival signaling pathways (AKT, p38, IL-6, VEGF, and TNF-α) and upregulate an anti-inflammatory response (IL-10). Compared with SN-38 and DMSO as controls, K1 also displayed an improved in vivo therapeutic efficacy in a xenograft tumor regrowth model with no noticeable systematic toxicity at the administrated dose. We believe that the strategy described here presents an attractive approach to addressing solid tumors characterized by intratumoral heterogeneity.
UR - http://www.scopus.com/inward/record.url?scp=85072848863&partnerID=8YFLogxK
U2 - 10.1021/jacs.9b07171
DO - 10.1021/jacs.9b07171
M3 - Article
C2 - 31509395
AN - SCOPUS:85072848863
SN - 0002-7863
VL - 141
SP - 15611
EP - 15618
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 39
ER -
