Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Cancer Pathology Laboratory, Houston Methodist Research Institute, 6565 Fannin St., Houston, TX, 77030, USA.
Small. 2018 Jan;14(4). doi: 10.1002/smll.201702103. Epub 2017 Dec 4.
Chemotherapy is the mainstream treatment of anaplastic large cell lymphoma (ALCL). However, chemotherapy can cause severe adverse effects in patients because it is not ALCL-specific. In this study, a multifunctional aptamer-nanomedicine (Apt-NMed) achieving targeted chemotherapy and gene therapy of ALCL is developed. Apt-NMed is formulated by self-assembly of synthetic oligonucleotides containing CD30-specific aptamer and anaplastic lymphoma kinase (ALK)-specific siRNA followed by self-loading of the chemotherapeutic drug doxorubicin (DOX). Apt-NMed exhibits a well-defined nanostructure (diameter 59 mm) and stability in human serum. Under aptamer guidance, Apt-NMed specifically binds and internalizes targeted ALCL cells. Intracellular delivery of Apt-NMed triggers rapid DOX release for targeted ALCL chemotherapy and intracellular delivery of the ALK-specific siRNA induced ALK oncogene silencing, resulting in combined therapeutic effects. Animal model studies reveal that upon systemic administration, Apt-NMed specifically targets and selectively accumulates in ALCL tumor site, but does not react with off-target tumors in the same xenograft mouse. Importantly, Apt-NMed not only induces significantly higher inhibition in ALCL tumor growth, but also causes fewer or no side effects in treated mice compared to free DOX. Moreover, Apt-NMed treatment markedly improves the survival rate of treated mice, opening a new avenue for precision treatment of ALCL.
化疗是间变大细胞淋巴瘤（ALCL）的主流治疗方法。然而，由于化疗不是针对 ALCL 的，因此会给患者带来严重的不良反应。在这项研究中，开发了一种多功能适体-纳米药物（Apt-NMed），可实现 ALCL 的靶向化疗和基因治疗。Apt-NMed 通过自组装含有 CD30 特异性适体和间变性淋巴瘤激酶（ALK）特异性 siRNA 的合成寡核苷酸形成，然后自行装载化疗药物阿霉素（DOX）。Apt-NMed 在人血清中具有明确的纳米结构（直径 59nm）和稳定性。在适体的引导下，Apt-NMed 特异性地结合并内化靶向的 ALCL 细胞。Apt-NMed 的细胞内递送触发靶向 ALCL 化疗的 DOX 快速释放和 ALK 特异性 siRNA 的细胞内递送，诱导 ALK 癌基因沉默，从而产生联合治疗效果。动物模型研究表明，在系统给药后，Apt-NMed 特异性地靶向并选择性地积聚在 ALCL 肿瘤部位，但不会与同种异体移植小鼠中的非靶肿瘤发生反应。重要的是，与游离 DOX 相比，Apt-NMed 不仅在抑制 ALCL 肿瘤生长方面效果更高，而且在治疗小鼠中引起的副作用更少或没有。此外，Apt-NMed 治疗显著提高了治疗小鼠的存活率，为 ALCL 的精准治疗开辟了新途径。
