Combined delivery of salinomycin and docetaxel by dual-targeting gelatinase nanoparticles effectively inhibits cervical cancer cells and cancer stem cells

Abstract

Intra-tumor heterogeneity is widely accepted as one of the key factors, which hinders cancer patients from achieving full recovery. Especially, cancer stem cells (CSCs) may exhibit self-renewal capacity, which makes it harder for complete elimination of tumor. Therefore, simultaneously inhibiting CSCs and non-CSCs in tumors becomes a promising strategy to obtain sustainable anticancer efficacy. Salinomycin (Sal) was reported to be critical to inhibit CSCs. However, the poor bioavailability and catastrophic side effects brought about limitations to clinical practice. To solve this problem, we previously constructed gelatinase-stimuli nanoparticles composed of nontoxic, biocompatible polyethylene glycol-polycaprolactone (PEG-PCL) copolymer with a gelatinase-cleavable peptide Pro-Val-Gly-Leu-Iso-Gly (PVGLIG) inserted between the two blocks of the copolymer. By applying our "smart" gelatinaseresponsive nanoparticles for Sal delivery, we have demonstrated specific accumulation in tumor, anti-CSCs ability and reduced toxicity of Sal-NPs in our previous study. In the present study, we synthesized Sal-Docetaxel-loaded gelatinase-stimuli nanoparticles (Sal-Doc NP) and confirmed single emulsion as the optimal method of producing Sal-Doc NPs (Sal-Doc SE-NP) in comparison with nanoprecipitation. Sal-Doc SE-NPs inhibited both CSCs and non-CSCs in mice transplanted with cervical cancer, and might be associated with enhanced restriction of epithelial-mesenchymal transition (EMT) pathway. Besides, the tumorigenic capacity and growing speed were obviously suppressed in Sal-Doc-SE-NPstreated group in rechallenge experiment. Our results suggest that Sal-Doc-loaded gelatinase-stimuli nanoparticles could be a promising strategy to enhance antitumor efficacy and reduce side effects by simultaneously suppressing CSCs and non-CSCs.

Targeted Codelivery of Prodigiosin and Simvastatin Using Smart BioMOF: Functionalization by Recombinant Anti-VEGFR1 scFv

“…The goal of co-delivery systems is to combine two or more drugs with different properties and mechanisms, which in turn can improve therapeutic effects and/or reduce their adverse effects in cancer therapy ( Meng et al, 2020 ; Wang et al, 2021 ). In recent years, many efforts have been made to overcome MDR such as P-glycoprotein (P-gp) through various drug strategies ( Sharom, 2008 ).…”

In situ gelatinase-responsive and thermosensitive nanocomplex for local therapy of gastric cancer with peritoneal metastasis

“…As we previously reported [ 14 ], SAL and DOC were initially loaded into gelatinase-responsive nanoparticles. The average diameter of NPs was 192.0 ​± ​0.7 ​nm (average and standard deviation of 4 independently prepared batches) with a zeta potential of −2.53 ​± ​0.33 ​mV (average and standard deviation of 3 independently prepared batches) at pH 7.4 ( Fig.…”

“…PEG-pep-PCL copolymers were prepared as we previously described [ 14 ]. Nanoparticles were prepared using a double-emulsion method.…”

Synthesis and Characterization of Salinomycin-Loaded High-Density Lipoprotein and Its Effects on Cervical Cancer Cells and Cervical Cancer Stem Cells

“… 15 Combined delivery of salinomycin and docetaxel by dual-targeting gelatinase nanoparticles can enhance anti-cervical cancer efficacy and reduce side effects by simultaneously suppressing CCCs and CCSC. 16 …”

“…15 Combined delivery of salinomycin and docetaxel by dual-targeting gelatinase nanoparticles can enhance anti-cervical cancer efficacy and reduce side effects by simultaneously suppressing CCCs and CCSC. 16 High-density lipoprotein (HDL) is a kind of lipoproteins that carry lipids as multifunctional aggregates in plasma. HDL can be used as an effective carrier for many drugs because its phospholipid core can be combined with hydrophobic drugs.…”