Low molecular weight heparin-based reduction-sensitive nanoparticles for antitumor and anti-metastasis of orthotopic breast cancer

摘要

Tumor metastasis has become a major obstacle for the clinical treatment of malignant breast cancer. Thus, a delivery system capable of both antitumor and anti-metastasis efficacy is desired. In this work, a low molecular weight heparin (LMWH)-based reduction-sensitive delivery system was developed, aiming to combine the properties of both the antitumor drug and active excipients to achieve a synergistic antitumor and anti-metastatic efficiency as well as resolving the potential adverse effects of both doxorubicin and LMWH. That is, the efficiency of DOX could be enhanced and its toxicity could be lowered. Meanwhile, the biological properties of LMWH could be strengthened and its bleeding risk could also be alleviated. Briefly, drug-loaded crosslinked nanoparticles (DOX/cLLHC(2)) had a longer blood circulation time and exhibited a rapid reduction-triggered release of DOX. The in vitro assays revealed that DOX/cLLHC(2) exhibited a higher cellular uptake and cytotoxicity compared to free DOX. Meanwhile, for the existence of LMWH, DOX/cLLHC(2) inhibited cell migration and invasion, as well as effectively inhibited the tube-like formation of human umbilical vein endothelial cells. DOX/cLLHC(2) possessed a superior tumor accumulation compared to lipoic acid unmodified nanoparticles and free DOX. Also, DOX/cLLHC(2) exhibited encouraging antitumor and anti-metastasis efficiency in an orthotopic breast cancer model. Overall, DOX/cLLHC(2) could exert antitumor, anti-metastasis, and anti-angiogenesis efficacy simultaneously as well as having lower systemic toxicity, which makes it suitable for the therapy of metastatic breast carcinoma.