Anti-DR5 monoclonal antibody-mediated DTIC-loaded nanoparticles combining chemotherapy and immunotherapy for malignant melanoma: target formulation development and in vitro anticancer activity

Abstract

Baoyue Ding1,2, Xin Wu1, Wei Fan1,3, Zhaoyong Wu4, Jing Gao5, Wei Zhang1, Lulu Ma5, Wang Xiang1, Quangang Zhu1, Jiyong Liu1, Xueying Ding5, Shen Gao11Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, 2Department of Pharmaceutics, Medical College of Jiaxing University, Jiaxing, 3The 425th Hospital of PLA, Department of Pharmacy, Sanya, 4Department of Pharmaceutics, Jiaxing Maternal and Childcare Hospital, Jiaxing, 5Department of Pharmaceutics, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China The first three authors contributed equally to this work. Background: The increased incidence of malignant melanoma in recent decades, along with its high mortality rate and pronounced resistance to therapy pose an enormous challenge. Novel therapeutic strategies, such as immunotherapy and targeted therapy, are urgently needed for melanoma. In this study, a new active targeting drug delivery system was constructed to combine chemotherapy and active specifc immunotherapy. Methods: The chemotherapeutic drug, dacarbazine (DTIC), that induces apoptosis through the intrinsic pathway which typically responds to severe DNA damage, was used as a model drug to prepare DTIC-loaded polylactic acid (PLA) nanoparticles (DTIC-NPs), which were covalently conjugated to a highly specific targeting functional TRAIL-receptor 2 (DR5) monoclonal antibody (mAb) that can contribute directly to cancer cell apoptosis or growth inhibition through the extrinsic pathway. Results: Our in vitro experiments demonstrated that DTIC-PLA-DR5 mAb nanoparticles (DTIC-NPs-DR5 mAb) are an active targeting drug delivery system which can specifcally target DR5-overexpressing malignant melanoma cells and become efficiently internalized. Most strikingly, compared with conventional DTIC-NPs, DTIC-NPs-DR5 mAb showed significantly enhanced cytotoxicity and increased cell apoptosis in DR5-positive malignant melanoma cells. Conclusion: The DTIC-NPs-DR5 mAb described in this paper might be a potential formulation for targeting chemotherapy and immunotherapy to DR5-overexpressing metastatic melanoma.Keywords: malignant melanoma, DR5 monoclonal antibodies, dacarbazine, apoptosis, chemoimmunotherapy, active targeting nanoparticles