We have developed a macromolecular prodrug platform based on poly(l-lysine succinylated) (PLS) that targets scavenger receptor A1 (SR-A1), a receptor expressed by myeloid and endothelial cells. We demonstrate the selective uptake of PLS by murine macrophage, RAW 264.7 cells, which was eliminated upon cotreatment with the SR-A inhibitor polyinosinic acid (poly I). Further, we observed no uptake of PLS in an SR-A1-deficient RAW 264.7 cell line, even after 24 h incubation. In mice, PLS distributed to lymphatic organs following i.v. injection, as observed by ex vivo fluorescent imaging, and accumulated in lymph nodes following both i.v. and i.d. administrations, based on immunohistochemical analysis with high-resolution microscopy. As a proof-of-concept, the HIV antiviral emtricitabine (FTC) was conjugated to the polymer’s succinyl groups via ester bonds, with a drug loading of 14.2% (wt/wt). The prodrug (PLS-FTC) demonstrated controlled release properties in vitro with a release half-life of 15 h in human plasma and 29 h in esterase-inhibited plasma, indicating that drug release occurs through both enzymatic and nonenzymatic mechanisms. Upon incubation of PLS-FTC with human peripheral blood mononuclear cells (PBMCs), the released drug was converted to the active metabolite FTC triphosphate. In a pharmacokinetic study in rats, the prodrug achieved ∼7–19-fold higher concentrations in lymphatic tissues compared to those in FTC control, supporting lymphatic-targeted drug delivery. We believe that the SR-A1-targeted macromolecular PLS prodrug platform has extraordinary potential for the treatment of infectious diseases.

中文翻译：

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清道夫受体 A1 靶向聚合物前药平台在 HIV 淋巴药物递送中的应用。

我们开发了一种基于聚（l-赖氨酸琥珀酰化）（PLS）的大分子前药平台，其靶向清道夫受体 A1（SR-A1），这是一种由骨髓细胞和内皮细胞表达的受体。我们证明了鼠巨噬细胞 RAW 264.7 细胞对 PLS 的选择性吸收，在与 SR-A 抑制剂聚肌苷酸 (poly I) 共同处理后被消除。此外，我们观察到在 SR-A1 缺陷的 RAW 264.7 细胞系中没有摄取 PLS，即使在孵育 24 小时后也是如此。在小鼠中，如体外观察到的，静脉注射后 PLS 分布到淋巴器官荧光成像，并在 iv 和 id 给药后在淋巴结中积累，基于高分辨率显微镜的免疫组织化学分析。作为概念验证，HIV 抗病毒药物恩曲他滨 (FTC) 通过酯键与聚合物的琥珀酰基结合，载药量为 14.2% (wt/wt)。前药 (PLS-FTC)在体外表现出控释特性在人血浆中的释放半衰期为 15 小时，在酯酶抑制的血浆中为 29 小时，表明药物释放通过酶促和非酶促机制发生。在将 PLS-FTC 与人外周血单核细胞 (PBMC) 孵育后，释放的药物转化为活性代谢物 FTC 三磷酸。在大鼠的药代动力学研究中，与 FTC 对照相比，前药在淋巴组织中的浓度高出约 7-19 倍，支持淋巴靶向药物递送。我们相信以 SR-A1 为靶点的大分子 PLS 前药平台在治疗传染病方面具有非凡的潜力。