Department of Pharmacology, Institute for Digital Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Department of Surgery, Immunology Program, Cancer Program and Nanomedicine Translational Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Cell Prolif. 2022 Sep;55(9):e13255. doi: 10.1111/cpr.13255. Epub 2022 Jul 18.
Acute Myeloid Leukaemia (AML) is the most common blood cancer in adults. Although 2 out of 3 AML patients go into total remission after chemotherapies and targeted therapies, the disease recurs in 60%-65% of younger adult patients within 3 years after diagnosis with a dramatically decreased survival rate. Therapeutic oligonucleotides are promising treatments under development for AML as they can be designed to silence oncogenes with high specificity and flexibility. However, there are not many well validated approaches for safely and efficiently delivering oligonucleotide drugs. This issue could be resolved by utilizing a new generation of delivery vehicles such as extracellular vesicles (EVs).
In this study, we harness red blood cell-derived EVs (RBCEVs) and engineer them via exogenous drug loading and surface functionalization to develop an efficient drug delivery system for AML. Particularly, EVs are designed to target CD33, a common surface marker with elevated expression in AML cells via the conjugation of a CD33-binding monoclonal antibody onto the EV surface.
The conjugation of RBCEVs with the CD33-binding antibody significantly increases the uptake of RBCEVs by CD33-positive AML cells, but not by CD33-negative cells. We also load CD33-targeting RBCEVs with antisense oligonucleotides (ASOs) targeting FLT3-ITD or miR-125b, 2 common oncogenes in AML, and demonstrate that the engineered EVs improve leukaemia suppression in in vitro and in vivo models of AML.
Targeted RBCEVs represent an innovative, efficient, and versatile delivery platform for therapeutic ASOs and can expedite the clinical translation of oligonucleotide drugs for AML treatments by overcoming current obstacles in oligonucleotide delivery.
急性髓系白血病（AML）是成人中最常见的血液癌。尽管 3 分之 2 的 AML 患者在化疗和靶向治疗后进入完全缓解，但在诊断后 3 年内，60%-65%的年轻成年患者疾病复发，生存率急剧下降。治疗性寡核苷酸是 AML 中正在开发的有前途的治疗方法，因为它们可以设计为高度特异性和灵活性地沉默致癌基因。然而，安全有效地输送寡核苷酸药物的方法并不多。这个问题可以通过利用新一代的输送载体来解决，如细胞外囊泡（EVs）。
在这项研究中，我们利用红细胞衍生的 EVs（RBCEVs），通过外源性药物负载和表面功能化对其进行工程改造，开发用于 AML 的高效药物输送系统。特别是，通过将 CD33 结合单克隆抗体连接到 EV 表面，设计 EV 来靶向 AML 细胞中表达升高的常见表面标志物 CD33。
RBCEVs 与 CD33 结合抗体的缀合显著增加了 CD33 阳性 AML 细胞对 RBCEVs 的摄取，但对 CD33 阴性细胞没有影响。我们还将 CD33 靶向 RBCEVs 装载针对 AML 中两种常见致癌基因 FLT3-ITD 或 miR-125b 的反义寡核苷酸（ASOs），并证明工程化 EVs 改善了 AML 体外和体内模型中的白血病抑制作用。
靶向 RBCEVs 代表了一种创新、高效且多功能的治疗性 ASO 输送平台，可以通过克服寡核苷酸输送中的当前障碍，加速 AML 治疗用寡核苷酸药物的临床转化。
