Research Center for Intelligent and Wearable Technology, College of Chemistry and Chemical Engineering, Qingdao University, Qingdao 266071, P. R. China.
Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao 266003, P. R. China.
Theranostics. 2020 Jul 9;10(18):8250-8263. doi: 10.7150/thno.45803. eCollection 2020.
Chemo-gene therapy is an emerging synergetic modality for the treatment of cancers. Herein, we developed pH-responsive multifunctional DNA nanomicelles (DNMs) as delivery vehicles for controllable release of doxorubicin (Dox) and anaplastic lymphoma kinase (ALK)-specific siRNA for the chemo-gene synergetic therapy of anaplastic large cell lymphoma (ALCL). DNMs were synthesized by performing in situ rolling circle amplification (RCA) on the amphiphilic primer-polylactide (PLA) micelles, followed by functionalization of pH-responsive triplex DNA via complementary base pairing. The anticancer drug Dox and ALK-specific siRNA were co-loaded to construct Dox/siRNA/DNMs for chemo-gene synergetic cancer therapy. When exposed to the acidic microenvironment (pH below 5.0), C-G·C triplex structures were formed, leading to the release of Dox and siRNA for gene silencing to enhance the chemosensitivity in ALCL K299 cells. The chemo-gene synergetic anticancer effect of Dox/siRNA/DNMs on ALCL was evaluated and . The pH-responsive DNMs exhibited good monodispersity at different pH values, good biocompatibility, high drug loading capacity, and excellent stability even in the human serum. With the simultaneous release of anticancer drug Dox and ALK-specific siRNA in response to pH in the tumor microenvironment, the Dox/siRNA/DNMs demonstrated significantly higher treatment efficacy for ALCL compared with chemotherapy alone, because the silencing of ALK gene expression mediated by siRNA increased the chemosensitivity of ALCL cells. From the pathological analysis of tumor tissue, the Dox/siRNA/DNMs exhibited the superiority in inhibiting tumor growth, low toxic side effects and good biosafety. DNMs co-loaded with Dox and ALK-specific siRNA exhibited significantly enhanced apoptosis of ALCL K299 cells and effectively inhibited tumor growth without obvious toxicity, providing a potential strategy in the development of nanomedicines for synergetic cancer therapy.
化疗-基因治疗是治疗癌症的一种新兴协同模式。在此，我们开发了 pH 响应型多功能 DNA 纳米胶束（DNM）作为载体，用于可控释放阿霉素（Dox）和间变性淋巴瘤激酶（ALK）特异性 siRNA，用于治疗间变性大细胞淋巴瘤（ALCL）的化疗-基因协同治疗。DNM 通过在两亲性引物-聚乳酸（PLA）胶束上进行原位滚环扩增（RCA）来合成，然后通过互补碱基配对功能化 pH 响应三链 DNA。将抗癌药物 Dox 和 ALK 特异性 siRNA 共装载以构建 Dox/siRNA/DNM 用于化疗-基因协同癌症治疗。当暴露于酸性微环境（pH 低于 5.0）时，形成 C-G·C 三链结构，导致 Dox 和 siRNA 释放以进行基因沉默，从而增强 ALCL K299 细胞的化疗敏感性。评估了 Dox/siRNA/DNM 对 ALCL 的化疗-基因协同抗癌作用，结果表明。pH 响应型 DNM 在不同 pH 值下表现出良好的单分散性、良好的生物相容性、高载药量和优异的稳定性，即使在人血清中也是如此。由于在肿瘤微环境中 pH 响应下同时释放抗癌药物 Dox 和 ALK 特异性 siRNA，与单独化疗相比，Dox/siRNA/DNM 对 ALCL 表现出更高的治疗效果，因为 siRNA 介导的 ALK 基因表达沉默增加了 ALCL 细胞的化疗敏感性。从肿瘤组织的病理分析来看，Dox/siRNA/DNM 在抑制肿瘤生长方面表现出优势，毒性副作用低，生物安全性好。共载有 Dox 和 ALK 特异性 siRNA 的 DNM 显著增强了 ALCL K299 细胞的凋亡，有效抑制了肿瘤生长，且无明显毒性，为协同癌症治疗的纳米药物开发提供了一种潜在策略。
