Targeting Heterogeneous Tumors Using a Multifunctional Molecular Prodrug

Amit Sharma, Min Goo Lee, Miae Won, Seyoung Koo, Jonathan F. Arambula, Jonathan L. Sessler, Sung Gil Chi, Jong Seung Kim

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)15611-15618
Number of pages8
JournalJournal of the American Chemical Society
Issue number39
Publication statusPublished - 2019 Oct 2

Bibliographical note

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.

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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