Shim Man Kyu, Moon Yujeong, Yang Suah, Kim Jinseong, Cho Hanhee, Lim Seungho, Yoon Hong Yeol, Seong Joon-Kyung, Kim Kwangmeyung
Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Department of Bioengineering, Korea University, Seoul, 02841, Republic of Korea.
Biomaterials. 2020 Dec;261:120347. doi: 10.1016/j.biomaterials.2020.120347. Epub 2020 Aug 26.
Chemotherapy has shown remarkable therapeutic efficacy for various types of cancer. However, drug resistance reduces the effectiveness and sensitivity of chemotherapy, leading treatment failure and cancer relapse in many clinical indications. Herein, we propose cancer-specific drug-drug nanoparticles (DD-NPs) that improve the therapeutic efficacy of chemotherapy against drug-resistant cancer. Cancer-specific and pro-apoptotic drug-drug conjugate was prepared by conjugating the pro-apoptotic peptide drug (SMAC; Ala-Val-Pro-Ile-Ala-Gln, AVPIAQ) and cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly, FRRG) to a doxorubicin (DOX), resulting in SMAC-FRRG-DOX that allows self-assembled into nanoparticles. The resulting DD-NPs were specifically cleaved to pro-apoptotic SMAC and cytotoxic DOX only in cathepsin B-overexpressing cancer cells, inducing a synergy of the pro-apoptotic activity with the chemotherapy. In MCF-7 breast tumor-bearing mice, intravenously injected DD-NPs highly accumulated at targeted tumor tissues via enhanced permeability and retention (EPR) effect, releasing SMAC and DOX, which showed a synergetic pro-apoptotic/chemotherapy. Furthermore, DD-NPs greatly suppressed tumor growth and improved overall survival in a metastatic lung cancer model. Collectively, these cancer-specific drug-drug nanoparticles may be a promising strategy to treat drug-resistant cancers with high cancer cell-specificity.
化疗已显示出对各种类型癌症具有显著的治疗效果。然而，耐药性会降低化疗的有效性和敏感性，导致在许多临床适应症中治疗失败和癌症复发。在此，我们提出了癌症特异性药物-药物纳米颗粒（DD-NPs），其可提高化疗对耐药性癌症的治疗效果。通过将促凋亡肽药物（SMAC；丙氨酸-缬氨酸-脯氨酸-异亮氨酸-丙氨酸-谷氨酰胺，AVPIAQ）和组织蛋白酶B可裂解肽（苯丙氨酸-精氨酸-精氨酸-甘氨酸，FRRG）与阿霉素（DOX）偶联，制备了癌症特异性且具有促凋亡作用的药物-药物偶联物，得到SMAC-FRRG-DOX，其可自组装成纳米颗粒。所得的DD-NPs仅在组织蛋白酶B过表达的癌细胞中特异性裂解为促凋亡的SMAC和具有细胞毒性的DOX，从而诱导促凋亡活性与化疗的协同作用。在携带MCF-7乳腺肿瘤的小鼠中，静脉注射的DD-NPs通过增强的渗透和滞留（EPR）效应在靶向肿瘤组织中高度蓄积，释放出SMAC和DOX，表现出协同的促凋亡/化疗作用。此外，在转移性肺癌模型中，DD-NPs极大地抑制了肿瘤生长并改善了总体生存率。总体而言，这些癌症特异性药物-药物纳米颗粒可能是一种具有高癌细胞特异性来治疗耐药性癌症的有前景的策略。
