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 journalArticle

1 Citation (Scopus)

Abstract

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
Volume141
Issue number39
DOIs
Publication statusPublished - 2019 Oct 2

Fingerprint

irinotecan
Prodrugs
Tumors
Pharmaceutical Preparations
Neoplasms
Scavenging
Dimethyl Sulfoxide
Heterografts
Interleukin-10
Vascular Endothelial Growth Factor A
Toxicity
Interleukin-6
Anti-Inflammatory Agents
Chemical activation
Cells
Colonic Neoplasms
Oxidation-Reduction
Oxidative Stress
Up-Regulation
Down-Regulation

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Targeting Heterogeneous Tumors Using a Multifunctional Molecular Prodrug. / Sharma, Amit; Lee, Min Goo; Won, Miae; Koo, Seyoung; Arambula, Jonathan F.; Sessler, Jonathan L.; Chi, Sung Gil; Kim, Jong Seung.

In: Journal of the American Chemical Society, Vol. 141, No. 39, 02.10.2019, p. 15611-15618.

Research output: Contribution to journalArticle

Sharma A, Lee MG, Won M, Koo S, Arambula JF, Sessler JL et al. Targeting Heterogeneous Tumors Using a Multifunctional Molecular Prodrug. Journal of the American Chemical Society. 2019 Oct 2;141(39):15611-15618. https://doi.org/10.1021/jacs.9b07171
Sharma, Amit ; Lee, Min Goo ; Won, Miae ; Koo, Seyoung ; Arambula, Jonathan F. ; Sessler, Jonathan L. ; Chi, Sung Gil ; Kim, Jong Seung. / Targeting Heterogeneous Tumors Using a Multifunctional Molecular Prodrug. In: Journal of the American Chemical Society. 2019 ; Vol. 141, No. 39. pp. 15611-15618.
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