Rodell Christopher B, Baldwin Paige, Fernandez Bianca, Weissleder Ralph, Sridhar Srinivas, Dubach J Matthew
Center for Systems Biology, Massachusetts General Hospital, Boston, MA.
School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA.
Adv Ther (Weinh). 2021 Mar;4(3). doi: 10.1002/adtp.202000125. Epub 2020 Dec 16.
Nanoencapsulated drug delivery to solid tumors is a promising approach to overcome pharmacokinetic limitations of therapeutic drugs. However, encapsulation leads to complex drug biodistribution and delivery making analysis of delivery efficacy challenging. As proxies, nanocarrier accumulation or total tumor drug uptake in the tumor are used to evaluate delivery. Yet, these measurements fail to assess delivery of active, released drug to the target, and thus it commonly remains unknown if drug-target occupancy has been achieved. Here, we develop an approach to evaluate the delivery of encapsulated drug to the target, where residual drug target vacancy is measured using a fluorescent drug analog. measurements reveal that burst release governs drug delivery independent of nanoparticle uptake, and highlight limitations of evaluating nanoencapsulated drug delivery in these models. , however, our approach captures successful nanoencapsulated delivery, finding that tumor stromal cells drive nanoparticle accumulation and mediate drug delivery to adjacent cancer cells. These results, and generalizable approach, provide a critical advance to evaluate delivery of encapsulated drug to the drug target - the central objective of nanotherapeutics.
纳米封装药物递送至实体瘤是克服治疗药物药代动力学限制的一种有前景的方法。然而，封装导致药物生物分布和递送复杂，使得分析递送效果具有挑战性。作为替代指标，纳米载体在肿瘤中的积累或肿瘤中药物的总摄取量被用于评估递送。然而，这些测量方法无法评估活性释放药物向靶标的递送，因此通常仍不清楚是否实现了药物与靶标的结合。在此，我们开发了一种评估封装药物向靶标递送的方法，其中使用荧光药物类似物测量残留药物靶标空位。测量结果表明，突释决定药物递送，与纳米颗粒摄取无关，并突出了在这些模型中评估纳米封装药物递送的局限性。然而，我们的方法捕捉到了成功的纳米封装递送，发现肿瘤基质细胞驱动纳米颗粒积累并介导药物递送至相邻癌细胞。这些结果以及通用方法为评估封装药物向药物靶标的递送提供了关键进展，这是纳米治疗的核心目标。
