Anti-DR5 monoclonal antibody-mediated DTIC-loaded nanoparticles combining chemotherapy and immunotherapy for malignant melanoma: target formulation development and in vitro anticancer activity
Anti-DR5 monoclonal antibody-mediated DTIC-loaded nanoparticles combining chemotherapy and immunotherapy for malignant melanoma: target formulation development and in vitro anticancer activity
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抗DR5单克隆抗体介导的DTIC负载纳米粒子联合化疗和免疫治疗恶性黑色素瘤：靶向制剂开发和体外抗癌活性
DOI：
10.2147/ijn.s24094
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发表时间：
2011-01-01
影响因子：
8
通讯作者：
Gao, Shen
中科院分区：
文献类型：
--
作者：
Ding, Baoyue;Wu, Xin;Gao, Shen
背景资料：恶性黑色素瘤的发病率在近几十年来增加，沿着其高死亡率和对治疗的明显抗性构成了巨大的挑战。新的治疗策略，如免疫治疗和靶向治疗，是黑色素瘤的迫切需要。本研究构建了一种新的主动靶向给药系统，将联合收割机化疗与主动特异性免疫治疗相结合。以化疗药物达卡巴嗪（dacarbazine，DTIC）为模型药物，制备载DTIC的聚乳酸（PLA）纳米粒（DTIC-NPs），其与高度特异性靶向功能性TRAIL-受体2（DR 5）单克隆抗体（mAb）共价缀合，所述单克隆抗体可通过外源性途径直接促进癌细胞凋亡或生长抑制。我们的体外实验表明，DTIC-PLA-DR 5 mAb纳米粒（DTIC-NPs-DR 5 mAb）是一种主动靶向药物递送系统，可特异性靶向DR 5过表达的恶性黑色素瘤细胞并有效内化。结论：DTIC-NPs-DR 5单抗有望成为一种新的靶向治疗DR 5高表达转移性黑色素瘤的药物。
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 specific 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 specifically 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.