长效纳米制剂多拉韦林的研制。

Creation of a long-acting nanoformulated dolutegravir.

机构信息

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.

出版信息

Nat Commun. 2018 Feb 6;9(1):443. doi: 10.1038/s41467-018-02885-x.

Potent antiretroviral activities and a barrier to viral resistance characterize the human immunodeficiency virus type one (HIV-1) integrase strand transfer inhibitor dolutegravir (DTG). Herein, a long-acting parenteral DTG was created through chemical modification to improve treatment outcomes. A hydrophobic and lipophilic modified DTG prodrug is encapsulated into poloxamer nanoformulations (NMDTG) and characterized by size, shape, polydispersity, and stability. Retained intracytoplasmic NMDTG particles release drug from macrophages and attenuate viral replication and spread of virus to CD4+ T cells. Pharmacokinetic tests in Balb/cJ mice show blood DTG levels at, or above, its inhibitory concentration of 64 ng/mL for 56 days, and tissue DTG levels for 28 days. NMDTG protects humanized mice from parenteral challenge of the HIV-1 strain for two weeks. These results are a first step towards producing a long-acting DTG for human use by affecting drug apparent half-life, cell and tissue drug penetration, and antiretroviral potency.

高效的抗逆转录病毒活性和对病毒耐药性的屏障特征是人类免疫缺陷病毒 1 型（HIV-1）整合酶链转移抑制剂多替拉韦（DTG）。在此，通过化学修饰创造了一种长效的注射用 DTG，以改善治疗效果。一种疏水性和亲脂性修饰的 DTG 前药被包裹在泊洛沙姆纳米制剂（NMDTG）中，并通过大小、形状、多分散性和稳定性进行了表征。保留在细胞质内的 NMDTG 颗粒从巨噬细胞中释放药物，从而减弱病毒复制和病毒向 CD4+T 细胞的传播。在 Balb/cJ 小鼠中的药代动力学测试显示，血液中的 DTG 水平在 56 天内达到或超过其 64ng/mL 的抑制浓度，组织中的 DTG 水平在 28 天内达到。NMDTG 可保护人源化小鼠免受 HIV-1 株两周的注射挑战。这些结果是通过影响药物表观半衰期、细胞和组织药物渗透以及抗逆转录病毒效力，生产长效 DTG 供人类使用的第一步。