DR5 mAb-conjugated, DTIC-loaded immuno-nanoparticles effectively and specifically kill malignant melanoma cells in vivo.
DR5 mAb-conjugated, DTIC-loaded immuno-nanoparticles effectively and specifically kill malignant melanoma cells in vivo.
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DR5 mAb 缀合、DTIC 负载的免疫纳米颗粒可有效、特异性地杀死体内恶性黑色素瘤细胞
DOI：
10.18632/oncotarget.11014
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发表时间：
2016-08-30
期刊：
影响因子：
--
通讯作者：
Gao S
中科院分区：
文献类型：
--
作者：
Ding B;Zhang W;Wu X;Wang J;Xie C;Huang X;Zhan S;Zheng Y;Huang Y;Xu N;Ding X;Gao S
我们通过构建由死亡受体5单克隆抗体（DR5 mAb）偶联纳米颗粒（DTIC-NPs-DR5 mAb）负载达卡巴嗪（DTIC-NPs-DR5 mAb）组成的双重治疗功能免疫纳米颗粒（NPs），将化学和免疫疗法结合起来。我们通过实时成像系统评估DTIC-NPs-DR5单抗在荷瘤裸鼠中的分布，确定其体内靶向特异性。根据对肿瘤体积、生存时间、组织形态学、微血管密度（MVD）和凋亡指数（AI）的影响来评估治疗效果。通过测量白细胞（WBC）计数、丙氨酸转氨酶（ALT）水平和肌酐清除率（CR）来评估全身毒性。体内和离体成像表明，DR5 mAb修饰增强了异种移植物肿瘤内NPs的积累。DTIC- nps -DR5 mAb比单独使用DTIC或DR5 mAb更有效地抑制肿瘤生长，说明通过制药工程将DTIC与DR5 mAb联合使用达到了更好的治疗效果。此外，DTIC- nps -DR5 mAb的毒性远低于DTIC，这意味着DR5 mAb靶向减少了DTIC进入正常组织的非特异性摄取，从而减少了毒副作用。这些结果表明，DTIC-NPs-DR5单抗是一种安全有效的纳米颗粒制剂，有可能提高黑色素瘤治疗的疗效和特异性。
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.