Abstract
BackgroundThe 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.MethodsAmphiphilic 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.ResultsFibroblast 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.ConclusionTPL 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.Graphical
Highlights
The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy
Fourier transforms infrared (FT-IR) spectra and 1H nuclear magnetic resonance (NMR) spectrum confirmed the successful synthesis of PSN38 (Additional file 2: Fig. S2 and Additional file 2: Fig. S3a–d)
Chao Kong et al [36] reported the encapsulation efficacy of TPL in non-pH-sensitive micelles (NPSM) or ultra-pH-sensitive micelles (UPSM) was less than 20% due to the hydrophilicity of TPL and a hydrophobic esterase-responsive prodrug of triptolide, triptolide-naphthalene sulfonamide (TPL-nsa), designed with higher LogP could be successfully encapsulated in the hydrophobic inner core of nanoparticles with high encapsulation efficacy (> 90%)
Summary
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. CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. Despite the rapid development of chemotherapy and molecular targeted therapies, the survival of advanced GC patients was dismal owing to distant metastasis and resistance to concurrent systemic therapy [3,4,5]. The key feature of GC is the substantial molecular heterogeneity which defined complex heterotypic interactions of cancer cells with the tumor microenvironment (TME) [6]. CAFs induced chemoresistance of GC cells to cisplatin and fluoropyrimidine [9, 10], and a high
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