DR5 mAb-conjugated, DTIC-loaded immuno-nanoparticles effectively and specifically kill malignant melanoma cells<i>in vivo</i>

Abstract

// Baoyue Ding 1, 2, 3, * , Wei Zhang 4, * , Xin Wu 5, * , Jeffrey Wang 3 , Chen Xie 3 , Xuan Huang 1 , Shuyu Zhan 1 , Yongxia Zheng 1 , Yueyan Huang 1 , Ningyin Xu 1 , Xueying Ding 5 , Shen Gao 2 1 Department of Pharmaceutics, Medical College of Jiaxing University, Jiaxing, PR China 2 Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, PR China 3 Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, USA 4 Department of Pharmaceutics, Shanghai Pulmonary Hospital, Tongji University, Shanghai, PR China 5 Department of Pharmaceutics, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, PR China * These authors have contributed equally to this work Correspondence to: Shen Gao, email: liullk@126.com Xueying Ding, email: dingxueying@126.com Baoyue Ding, email: lena_310@163.com Keywords: malignant melanoma, DR5 monoclonal antibodies, dacarbazine, chemoimmunotherapy, active targeting nanoparticles Received: April 25, 2016&emsp;&emsp;&emsp;&emsp; Accepted: July 19, 2016&emsp;&emsp;&emsp;&emsp; Published: August 2, 2016 ABSTRACT We combined chemo- and immunotherapies by constructing dual therapeutic function immuno-nanoparticles (NPs) consisting of death receptor 5 monoclonal antibody (DR5 mAb)-conjugated nanoparticles loaded with dacarbazine (DTIC) (DTIC-NPs-DR5 mAb). We determined the in vivo targeting specificity of DTIC-NPs-DR5 mAb by evaluating distribution in tumor-bearing nude mice using a real-time imaging system. Therapeutic efficacy was assessed in terms of its effect on tumor volume, survival time, histomorphology, microvessel density (MVD), and apoptotic index (AI). Systemic toxicity was evaluated by measuring white blood cells (WBC) counts, alanine aminotransferase (ALT) levels, and creatinine clearance (CR). In vivo and ex vivo imaging indicates that DR5 mAb modification enhanced the accumulation of NPs within the xenograft tumor. DTIC-NPs-DR5 mAb inhibited tumor growth more effectively than DTIC or DR5 mAb alone, indicating that combining DTIC and DR5 mAb through pharmaceutical engineering achieves a better therapeutic effect. Moreover, the toxicity of DTIC-NPs-DR5 mAb was much lower than that of DTIC, implying that DR5 mAb targeting reduces nonspecific uptake of DTIC into normal tissue and thus decreases toxic side effects. These results demonstrate that DTIC-NPs-DR5 mAb is a safe and effective nanoparticle formulation with the potential to improve the efficacy and specificity of melanoma treatment.