Enhancing subcutaneous injection and target tissue accumulation of nanoparticles via co-administration with macropinocytosis inhibitory nanoparticles (MiNP),Nanoscale Horizons

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Enhancing subcutaneous injection and target tissue accumulation of nanoparticles via co-administration with macropinocytosis inhibitory nanoparticles (MiNP)
Nanoscale Horizons ( IF 8.0 ) Pub Date : 2021-4-13 , DOI: 10.1039/d0nh00679c
Trevor Stack ₁ , Yugang Liu ₁ , Molly Frey ₁ , Sharan Bobbala ₁ , Michael Vincent ₁ , Evan Scott ₁

Affiliation

A significant barrier to the application of nanoparticles for precision medicine is the mononuclear phagocyte system (MPS), a diverse population of phagocytic cells primarily located within the liver, spleen and lymph nodes. The majority of nanoparticles are indiscriminately cleared by the MPS via macropinocytosis before reaching their intended targets, resulting in side effects and decreased efficacy. Here, we demonstrate that the biodistribution and desired tissue accumulation of targeted nanoparticles can be significantly enhanced by co-injection with polymeric micelles containing the actin depolymerizing agent latrunculin A. These macropinocytosis inhibitory nanoparticles (MiNP) were found to selectively inhibit non-specific uptake of a second “effector” nanoparticle in vitro without impeding receptor-mediated endocytosis. In tumor bearing mice, co-injection with MiNP in a single multi-nanoparticle formulation significantly increased the accumulation of folate-receptor targeted nanoparticles within tumors. Furthermore, subcutaneous co-administration with MiNP allowed effector nanoparticles to achieve serum levels that rivaled a standard intravenous injection. This effect was only observed if the effector nanoparticles were injected within 24 h following MiNP administration, indicating a temporary avoidance of MPS cells. Co-injection with MiNP therefore allows reversible evasion of the MPS for targeted nanoparticles and presents a previously unexplored method of modulating and improving nanoparticle biodistribution following subcutaneous administration.

中文翻译：

通过与巨胞饮抑制纳米颗粒 (MiNP) 共同给药，增强纳米颗粒的皮下注射和靶组织积累

纳米颗粒在精准医疗中应用的一个重大障碍是单核吞噬细胞系统（MPS），这是一种主要位于肝脏、脾脏和淋巴结内的多样化吞噬细胞群。大多数纳米颗粒在达到预期目标之前都会被 MPS通过巨胞饮作用无差别地清除，从而导致副作用和功效降低。在这里，我们证明，通过与含有肌动蛋白解聚剂 latrunculin A 的聚合物胶束共注射，可以显着增强靶向纳米颗粒的生物分布和所需的组织积累。这些巨胞饮抑制纳米颗粒 (MiNP) 被发现可以选择性抑制非特异性摄取体外的第二个“效应器”纳米颗粒不会阻碍受体介导的内吞作用。在荷瘤小鼠中，在单一多纳米颗粒制剂中与 MiNP 共注射显着增加了肿瘤内叶酸受体靶向纳米颗粒的积累。此外，与 MiNP 皮下联合给药使效应纳米颗粒达到可与标准静脉注射相媲美的血清水平。只有在 MiNP 给药后 24 小时内注射效应纳米颗粒时才能观察到这种效应，表明暂时避免了 MPS 细胞。因此，与 MiNP 共注射可以可逆地逃避靶向纳米颗粒的 MPS，并提供了一种以前未探索过的调节和改善皮下给药后纳米颗粒生物分布的方法。

更新日期：2021-04-22

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