Caulier Benjamin, Stofleth Gaëlle, Hannani Dalil, Guidetti Mélanie, Josserand Véronique, Laurin David, Chroboczek Jadwiga, Mossuz Pascal, Plantaz Dominique
University Grenoble Alpes, CNRS, CHU Grenoble Alpes, Grenoble INP, TIMC-IMAG, 38000 Grenoble, France.
Institute of Biology and Pathology, Laboratory of Cellular Hematology, University Grenoble Alpes Hospital, Grenoble, France.
Mol Ther Methods Clin Dev. 2020 Nov 17;20:181-190. doi: 10.1016/j.omtm.2020.11.009. eCollection 2021 Mar 12.
Intensive systemic chemotherapy is the gold standard of acute myeloid leukemia (AML) treatment and is associated with considerable off-target toxicities. Safer and targeted delivery systems are thus urgently needed. In this study, we evaluated a virus-like particle derived from the human type 3 adenovirus, called the adenoviral dodecahedron (Dd) to target AML cells. The vectorization of leukemic cells was proved very effective at nanomolar concentrations in a time- and dose-dependent manner, without vector toxicity. The internalization involved clathrin-mediated energy-dependent endocytosis and strongly correlated with the expression of αβ integrin. The treatment of healthy donor peripheral blood mononuclear cells showed a preferential targeting of monocytes compared to lymphocytes and granulocytes. Similarly, monocytes but also AML blasts were the best-vectorized populations in patients while acute lymphoid leukemia blasts were less efficiently targeted. Importantly, AML leukemic stem cells (LSCs) could be addressed. Finally, Dd reached peripheral monocytes and bone marrow hematopoietic stem and progenitor cells following intravenous injection in mice, without excessive spreading in other organs. These findings reveal Dd as a promising myeloid vector especially for therapeutic purposes in AML blasts, LSCs, and progenitor cells.
强化全身化疗是急性髓系白血病（AML）治疗的金标准，但会带来相当多的脱靶毒性。因此，迫切需要更安全、靶向性更强的递送系统。在本研究中，我们评估了一种源自人3型腺病毒的病毒样颗粒，称为腺病毒十二面体（Dd），用于靶向AML细胞。在纳摩尔浓度下，白血病细胞的载体化被证明非常有效，呈时间和剂量依赖性，且无载体毒性。内化过程涉及网格蛋白介导的能量依赖性内吞作用，且与αβ整合素的表达密切相关。对健康供者外周血单个核细胞的处理显示，与淋巴细胞和粒细胞相比，单核细胞具有优先靶向性。同样，在患者中，单核细胞以及AML原始细胞是最佳的载体化群体，而急性淋巴细胞白血病原始细胞的靶向效率较低。重要的是，AML白血病干细胞（LSC）也能够被靶向。最后，在小鼠静脉注射后，Dd能够到达外周单核细胞以及骨髓造血干细胞和祖细胞，而不会在其他器官过度扩散。这些发现表明，Dd是一种很有前景的髓系载体，尤其适用于AML原始细胞、LSC和祖细胞的治疗。
