Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai.
Int J Nanomedicine. 2011;6:1991-2005. doi: 10.2147/IJN.S24094. Epub 2011 Sep 15.
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.
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.
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.
The DTIC-NPs-DR5 mAb described in this paper might be a potential formulation for targeting chemotherapy and immunotherapy to DR5-overexpressing metastatic melanoma.
近几十年来，恶性黑色素瘤的发病率不断上升，其死亡率高，且对治疗的反应明显，这给治疗带来了巨大的挑战。因此，迫切需要新的治疗策略，如免疫治疗和靶向治疗，来治疗黑色素瘤。在本研究中，构建了一种新的主动靶向药物传递系统，将化学疗法和主动特异性免疫疗法结合起来。
以诱导细胞通过内在途径发生凋亡的化学治疗药物——达卡巴嗪（DTIC）为模型药物，制备负载 DTIC 的聚乳酸（PLA）纳米粒（DTIC-NPs），通过共价键将其与高特异性的靶向功能 TRAIL 受体 2（DR5）单克隆抗体（mAb）结合，该 mAb 可以通过外在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-DR5 mAb 纳米粒（DTIC-NPs-DR5 mAb）是一种主动靶向药物传递系统，能够特异性地靶向 DR5 过表达的恶性黑色素瘤细胞，并被有效地内化。最显著的是，与传统的 DTIC-NPs 相比，DTIC-NPs-DR5 mAb 对 DR5 阳性恶性黑色素瘤细胞表现出显著增强的细胞毒性和增加的细胞凋亡。
本文所述的 DTIC-NPs-DR5 mAb 可能是一种针对 DR5 过表达转移性黑色素瘤的靶向化疗和免疫治疗的潜在制剂。
