DR5 mAb-conjugated, DTIC-loaded immuno-nanoparticles effectively and specifically kill malignant melanoma cells in vivo
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Baoyue Ding1,2,3,*, Wei Zhang4,*, Xin Wu5,*, Jeffrey Wang3, Chen Xie3, Xuan Huang1, Shuyu Zhan1, Yongxia Zheng1, Yueyan Huang1, Ningyin Xu1, Xueying Ding5, Shen Gao2
1Department of Pharmaceutics, Medical College of Jiaxing University, Jiaxing, PR China
2Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, PR China
3Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, USA
4Department of Pharmaceutics, Shanghai Pulmonary Hospital, Tongji University, Shanghai, PR China
5Department of Pharmaceutics, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, PR China
*These authors have contributed equally to this work
Shen Gao, email: email@example.com
Xueying Ding, email: firstname.lastname@example.org
Baoyue Ding, email: email@example.com
Keywords: malignant melanoma, DR5 monoclonal antibodies, dacarbazine, chemoimmunotherapy, active targeting nanoparticles
Received: April 25, 2016 Accepted: July 19, 2016 Published: August 2, 2016
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.
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