Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer.

Abstract

BACKGROUND:

The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy.

METHODS:

Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo.

RESULTS:

Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC.

CONCLUSION:

TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC.

• Authors: Sheng Zheng, Jiafeng Wang, Ning Ding, Wenwen Chen, Hongda Chen, Meng Xue, Fei Chen, Jiaojiao Ni, Zhuo Wang, Zhenghua Lin, Haiping Jiang, Xiangrui Liu, Liangjing Wang
• Journal: Journal of nanobiotechnology (J Nanobiotechnology) Vol. 19 Issue 1 Pg. 381 (Nov 21 2021) ISSN: 1477-3155 [Electronic] England
• PMID: 34802453 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Antineoplastic Agents
• Diterpenes
• Epoxy Compounds
• Micelles
• Phenanthrenes
• Prodrugs
• triptolide

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Cancer-Associated Fibroblasts (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Diterpenes (chemistry, pharmacokinetics, pharmacology)
• Drug Synergism
• Epoxy Compounds (chemistry, pharmacokinetics, pharmacology)
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Micelles
• Phenanthrenes (chemistry, pharmacokinetics, pharmacology)
• Prodrugs (chemistry, pharmacokinetics, pharmacology)
• Stomach Neoplasms (metabolism)
• Tumor Microenvironment (drug effects)