Ott_a_259428 8055..8067

Department of Oncology, The Eighth People’s Hospital of Shanghai, Shanghai 200233, People’s Republic of China Introduction: The failure of chemotherapy in osteosarcoma results in drug resistance and acute side effects in the body. Methods: In this study, we have prepared a novel folate receptor-targeted doxorubicin (DOX) and edelfosine (EDL)-loaded lipid–polymer hybrid nanoparticle (DE-FPLN) to enhance the anticancer efficacy in osteosarcoma. The nanoparticles were thoroughly characterized for in vitro biological assays followed by detailed antitumor efficacy analysis and toxicity analysis in a xenograft model. Results: The dual drug-loaded nanoparticles showed a nanosized morphology and physiological stability. The targeted nanoparticles showed enhanced cellular internalization and subcellular distribution in MG63 cancer cells compared to that of non-targeted nanoparticles. Among many ratios of DOX and EDL, 1:1 ratiometric combinations of drugs were observed to be highly synergistic in killing the cancer cells. MTT assay and caspase-3/7 activity assay clearly showed the superior anticancer efficacy of DE-FPLN formulations in inducing the cancer cell death. In vitro results indicate that the co-administration of two drugs in a folic acid-targeted nanoparticle could potentially induce the apoptosis and cell death. In vivo results displayed the potency of tumor cell killing and significant suppression of tumor growth without any detectable side effects. Conclusion: The lipid–polymer hybrid nanocarriers with multiple properties of high drug loading, sequential and ratiometric drug release, improved physiological stability, prolonged blood circulation, and tumor-specific targeting are promising for the delivery of multiple drugs in the treatment of osteosarcoma.