Max Planck Institute for Polymer Research, Mainz, Germany.
Department of Dermatology, University Hospital Münster, University of Münster, Münster, Germany.
Nanoscale Horiz. 2024 Oct 21;9(11):1978-1989. doi: 10.1039/d4nh00161c.
In order to achieve a therapeutic effect, many drugs have to reach specific cellular compartments. Nanoscale drug delivery systems extend the circulation time, reduce adverse effects and thus improve tolerability compared to systemic administration. We have developed two types of albumin-coated nanocarriers equipped with built-in dyes to track their cellular uptake and intracellular enzymatic opening. Using the approved antiprotozoal drug and STAT3 inhibitor Atovaquone (Ato) as prototype for a hydrophobic small molecule, we show that Ato-loaded ovalbumin-coated nanocapsules (Ato-nCap) preferentially enter human myeloid cells. In contrast, Ato nanocrystals coated with human serum albumin (Ato-nCry) distribute their cargo in all different immune cell types, including T and B cells. By measuring the effect of Ato nanocarriers on induced STAT3 phosphorylation in IL-10-primed human dendritic cells and constitutive STAT3 phosphorylation in human melanoma cells, we demonstrate that the intracellular Ato release is particularly effective from Ato nanocrystals and less toxic than equal doses of free drug. These new nanocarriers thus represent effective systems for intracellular drug delivery.
为了达到治疗效果，许多药物必须到达特定的细胞区室。与全身给药相比，纳米尺度的药物递送系统可延长循环时间，减少副作用，从而提高耐受性。我们开发了两种带内置染料的白蛋白包覆纳米载体，以跟踪其细胞摄取和细胞内酶促开启。我们以已批准的抗原虫药物和 STAT3 抑制剂阿托伐醌（Ato）作为疏水小分子的原型药物，证明负载 Ato 的卵清蛋白包覆纳米胶囊（Ato-nCap）优先进入人髓样细胞。相比之下，用人血清白蛋白包覆的 Ato 纳米晶体（Ato-nCry）将其货物分布在所有不同的免疫细胞类型中，包括 T 和 B 细胞。通过测量 Ato 纳米载体对 IL-10 预刺激的人树突状细胞中诱导的 STAT3 磷酸化和人黑素瘤细胞中组成性 STAT3 磷酸化的影响，我们证明 Ato 纳米晶体的细胞内 Ato 释放特别有效，且毒性低于同等剂量的游离药物。因此，这些新型纳米载体代表了有效的细胞内药物递送系统。
