Long-acting and extended-release implant and nanoformulations with a synergistic antiretroviral two-drug combination controls HIV-1 infection in a humanized mouse model,Bioengineering & Translational Medicine

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Long-acting and extended-release implant and nanoformulations with a synergistic antiretroviral two-drug combination controls HIV-1 infection in a humanized mouse model
Bioengineering & Translational Medicine ( IF 6.1 ) Pub Date : 2021-06-09 , DOI: 10.1002/btm2.10237
Jagadish Beloor ₁ , Shalley N Kudalkar _{2,

3} , Gina Buzzelli ₄ , Fan Yang ₄ , Hanna K Mandl ₄ , Jyothi K Rajashekar ₁ , Krasimir A Spasov _{2,

3} , William L Jorgensen ₅ , W Mark Saltzman ₄ , Karen S Anderson _{2,

3} , Priti Kumar ₁

Affiliation

The HIV pandemic has affected over 38 million people worldwide with close to 26 million currently accessing antiretroviral therapy (ART). A major challenge in the long-term treatment of HIV-1 infection is nonadherence to ART. Long-acting antiretroviral (LA-ARV) formulations, that reduce dosing frequency to less than once a day, are an urgent need that could tackle the adherence issue. Here, we have developed two LA-ART interventions, one an injectable nanoformulation, and the other, a removable implant, for the delivery of a synergistic two-drug ARV combination comprising a pre-clinical nonnucleoside reverse transcriptase inhibitor (NNRTI), Compound I, and the nucleoside reverse transcriptase inhibitor (NRTI), 4′-ethynyl-2-fluoro-2′-deoxyadenosine. The nanoformulation is poly(lactide-co-glycolide)-based and the implant is a copolymer of ω-pentadecalactone and p-dioxanone, poly(PDL-co-DO), a novel class of biocompatible, biodegradable materials. Both the interventions, packaged independently with each ARV, released sustained levels of the drugs, maintaining plasma therapeutic indices for over a month, and suppressed viremia in HIV-1-infected humanized mice for up to 42 days with maintenance of CD4⁺ T cells. These data suggest promise in the use of these new drugs as LA-ART formulations in subdermal implant and injectable mode.

中文翻译：

长效缓释植入物和纳米制剂与协同抗逆转录病毒两种药物组合可控制人源化小鼠模型中的 HIV-1 感染

HIV 大流行已影响到全球超过 3800 万人，其中近 2600 万人目前正在接受抗逆转录病毒治疗 (ART)。 HIV-1 感染长期治疗的一个主要挑战是不坚持 ART。长效抗逆转录病毒（LA-ARV）制剂可以将给药频率减少到每天一次以下，这是解决依从性问题的迫切需要。在这里，我们开发了两种 LA-ART 干预措施，一种是可注射的纳米制剂，另一种是可移动植入物，用于递送协同的两种药物 ARV 组合，包括临床前非核苷逆转录酶抑制剂 (NNRTI)、化合物 I ，以及核苷逆转录酶抑制剂（NRTI），4'-乙炔基-2-氟-2'-脱氧腺苷。该纳米制剂基于聚(丙交酯-共-乙交酯)，植入物是ω-十五内酯和对二氧环己酮的共聚物，即聚(PDL-共-DO)，是一类新型的生物相容性、可生物降解材料。这两种干预措施均与每种抗逆转录病毒药物独立包装，释放持续水平的药物，维持血浆治疗指数超过一个月，并在维持 CD4 ⁺ T 细胞的情况下，抑制 HIV-1 感染的人源化小鼠的病毒血症长达 42 天。这些数据表明这些新药作为 LA-ART 制剂在皮下植入和注射模式中的应用前景广阔。

更新日期：2021-06-09

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