αvβ3 integrin-specific exosomes engineered with cyclopeptide for targeted delivery of triptolide against malignant melanoma

Abstract

Background Melanoma is the most malignant skin tumor and is difficult to cure with the alternative treatments of chemotherapy, biotherapy, and immunotherapy. Our previous study showed that triptolide (TP) exhibited powerful tumoricidal activity against melanoma. However, the clinical potential of TP is plagued by its poor aqueous solubility, short half-life, and biotoxicity. Therefore, developing an ideal vehicle to efficiently load TP and achieving targeted delivery to melanoma is a prospective approach for making full use of its antitumor efficacy. Results We applied exosome (Exo) derived from human umbilical cord mesenchymal stromal cells (hUCMSCs) and engineered them exogenously with a cyclic peptide, arginine-glycine-aspartate (cRGD), to encapsulate TP to establish a bionic-targeted drug delivery system (cRGD-Exo/TP), achieving synergism and toxicity reduction. The average size of cRGD-Exo/TP was 157.34 ± 6.21 nm, with a high drug loading of 10.76 ± 1.21%. The in vitro antitumor results showed that the designed Exo delivery platform could be effectively taken up by targeted cells and performed significantly in antiproliferation, anti-invasion, and proapoptotic activities in A375 cells via the caspase cascade and mitochondrial pathways and cell cycle alteration. Furthermore, the biodistribution and pharmacokinetics results demonstrated that cRGD-Exo/TP possessed superior tumor targetability and prolonged the half-life of TP. Notably, cRGD-Exo/TP significantly inhibited tumor growth and extended survival time with negligible systemic toxicity in tumor-bearing mice. Conclusion The results indicated that the functionalized Exo platform provides a promising strategy for targeted therapy of malignant melanoma. Graphical Abstract

Engineering Extracellular Vesicles as Delivery Systems in Therapeutic Applications

“…This system possessed superior tumor targetability and prolonged the half-life of TPL, obviously inhibiting tumor growth and extending the survival time of the mouse model of malignant melanoma via the caspase cascade and mitochondrial pathway. [102] A disease strongly associated with hepatocellular carcinoma is cirrhosis, and thus cancer-associated fibroblasts (CAFs) play an important cellular communication function in HCC. Wang et al found that miR-335-5p was downregulated in HCC cells cocultured with CAF.…”

Extracellular Vesicles-Based Cell-Cell Communication in Melanoma: New Perspectives in Diagnostics and Therapy

“…Gu et al also used triptolide as an anticancer agent but they loaded TPL into exosomes harboring a cRGD peptide, which targeted the αvβ3 integrin receptor overexpressed on melanoma cells. cRGD-Exo-TPL construct significantly inhibited melanoma growth in vivo and prolonged the half-life of TPL [ 169 ]. PEG-coated EVs were shown to deliver doxorubicin to B16-F10 murine melanoma models [ 170 ].…”

Recent Trends in the Use of Small Extracellular Vesicles as Optimal Drug Delivery Vehicles in Oncology

“…Furthermore, the codelivery of oxaliplatin and PGM5AS1 via sEVs improved therapeutic effects in colon cancer by reversing drug resistance . In addition to FDA-approved drugs, other small molecules, peptides, and nanoparticles coupled with sEVs were exploited to treat solid tumor malignancies. ,,, Neutrophil elastase (ELANE) and Hiltonol-loaded sEVs derived from genetically engineered MDA-MB-231 cells were able to induce immunogenic cell death in tumor organoids and orthotopic TNBC mice . This combinational drug delivery system enhanced the immunogenicity-dependent tumor regression by conventional dendric cell (DC) and CD8+ T cell responses, as compared to free Hiltonol.…”