Institute for Bioscience and Biotechnology Research (IBBR) and Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742-4450, USA.
Institute for Bioengineering of Catalonia (IBEC) of the Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain.
J Control Release. 2020 Aug 10;324:181-193. doi: 10.1016/j.jconrel.2020.05.009. Epub 2020 May 7.
The interaction of drug delivery systems with tissues is key for their application. An example is drug carriers targeted to endothelial barriers, which can be transported to intra-endothelial compartments (lysosomes) or transcellularly released at the tissue side (transcytosis). Although carrier targeting valency influences this process, the mechanism is unknown. We studied this using polymer nanocarriers (NCs) targeted to intercellular adhesion molecule-1 (ICAM-1), an endothelial-surface glycoprotein whose expression is increased in pathologies characterized by inflammation. A bell-shaped relationship was found between NC targeting valency and the rate of transcytosis, where high and low NC valencies rendered less efficient transcytosis rates than an intermediate valency formulation. In contrast, an inverted bell-shape relationship was found for NC valency and lysosomal trafficking rates. Data suggested a model where NC valency plays an opposing role in the two sub-processes involved in transcytosis: NC binding-uptake depended directly on valency and exocytosis-detachment was inversely related to this parameter. This is because the greater the avidity of the NC-receptor interaction the more efficient uptake becomes, but NC-receptor detachment post-transport is more compromised. Cleavage of the receptor at the basolateral side of endothelial cells facilitated NC transcytosis, likely by helping NC detachment post-transport. Since transcytosis encompasses both sets of events, the full process finds an optimum at the intersection of these inverted relationships, explaining the bell-shaped behavior. NCs also trafficked to lysosomes from the apical side and, additionally, from the basolateral side in the case of high valency NCs which are slower at detaching from the receptor. This explains the opposite behavior of NC valency for transcytosis vs. lysosomal transport. Anti-ICAM NCs were verified to traffic into the brain after intravenous injection in mice, and both cellular and in vivo data showed that intermediate valency NCs resulted in higher delivery of a therapeutic enzyme, acid sphingomyelinase, required for types A and B Niemann-Pick disease.
药物递送系统与组织的相互作用是其应用的关键。例如，靶向内皮屏障的药物载体可以被转运到内皮细胞内区室（溶酶体）或通过细胞转运在组织侧释放（转胞吞作用）。尽管载体靶向效价会影响这个过程，但机制尚不清楚。我们使用靶向细胞间黏附分子-1（ICAM-1）的聚合物纳米载体（NCs）研究了这个问题，ICAM-1 是一种内皮表面糖蛋白，其表达在以炎症为特征的病理中增加。发现 NC 靶向效价与转胞吞作用速率之间存在钟形关系，其中高和低 NC 效价比中间效价制剂产生的转胞吞作用速率效率更低。相比之下，NC 效价与溶酶体转运速率之间存在倒钟形关系。数据表明，NC 效价在转胞吞作用涉及的两个子过程中发挥相反的作用：NC 结合摄取直接依赖于效价，而胞吐作用-脱附则与此参数相反。这是因为 NC-受体相互作用的亲合力越大，摄取越有效，但 NC 受体在运输后脱离的效率越低。内皮细胞基底外侧侧受体的切割促进了 NC 的转胞吞作用，可能是通过帮助 NC 在运输后脱离。由于转胞吞作用包含这两组事件，完整的过程在这些倒置关系的交点处找到最佳值，解释了钟形行为。NC 也从顶侧和基底外侧侧运输到溶酶体，并且在高效价 NC 的情况下，由于它们从受体上脱离较慢，也从基底外侧侧运输到溶酶体。这解释了 NC 效价对转胞吞作用与溶酶体运输的相反行为。静脉注射到小鼠体内后，抗 ICAM NC 被证实可进入大脑，细胞和体内数据均表明，中间效价 NC 可使治疗酶酸性鞘磷脂酶的递送增加，该酶在 A 型和 B 型尼曼-匹克病中是必需的。
