Co-loaded aspirin and doxorubicin by chondroitin sulphate nanoparticles inhibited metastasis of breast cancer by squelching circulating tumor microemboli.

Platelets (PLTs) play a critical role in proliferation and migration of cancers, combination therapy based on chemotherapeutical and anti-PLT agents could inhibit tumor development. In this study, chondroitin sulphate (CS) was conjugated with doxorubicin (DOX) to synthesize CS-DOX through hydrazone bond, and aspirin (ASP) was encapsulated into CS-DOX to prepare a pH-responsive nanoparticle (ASP/CS-DOX). After being characterized, the anti-tumor effects of ASP/CS-DOX were pursued further. To mimic tumor environment, "MCF-7+PLT" co-cultured cell model was established in vitro, and ASP/CS-DOX displayed higher cytotoxicity on "MCF-7+PLT" cell model compared to CS-DOX. In a breast cancer cell line and fibroblast assembled xenograft mice model, tumor inhibition rate of ASP/CS-DOX was 83 %, in addition, ASP/CS-DOX mainly enriched in tumor region; in the tail vein model, a lung metastasis nodules decreased by 90.9 %. ASP/CS-DOX effectively decreased activation of PLT and angiogenesis as confirmed by decreased P-selection and CD31 in tumor tissue. ASP/CS-DOX remolded extracellular matrix via inhibiting activation of CAFs as demonstrated by reduced α-SMA and less deposition of collagen. Moreover, ASP/CS-DOX significantly inhibited tumor metastasis in the breast cancer metastasis model. In brief, the integrated treatment based on ASP/CS-DOX nanoparticles is a potential approach for the therapy of breast cancer.