State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, China; Biomedical Imaging Laboratory (BIG), Department of Electrical and Computer Engineering, University of Macau, Taipa, Macau SAR, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau SAR, China.
J Control Release. 2023 Aug;360:82-92. doi: 10.1016/j.jconrel.2023.06.015. Epub 2023 Jun 22.
Camptothecin (CPT) and cisplatin (Pt) have shown synergistic effects on a variety of cancers during preclinical and clinical studies. However, the ratio of the two drugs often could not be precisely regulated in different delivery systems, which hinders the desired synergistic effect. In addition, the low delivery efficiency of the two drugs to the tumor further impedes the ideal therapeutic outcomes. Herein, we report that a platelet-mimicking supramolecular nanomedicine (SN) could precisely control of the ratio of CPT and Pt with a high tumor accumulation rate for cascade amplification of synergistic chemotherapy. The SN was fabricated via the host-guest interaction between cucurbit[7]uril conjugated hyaluronic acid (HA-CB[7]) and adamantane (ADA) respectively functionalized CPT- and Pt-based prodrugs. The ratio of CPT and Pt in the SN could be facilely regulated by simply controlling the loading ratio, based on the strong binding affinity between CB[7] and ADA, and SN60 with 60% CPT and 40% Pt showed the highest synergistic effects on 4T1 cells. To improve the tumor accumulation efficiency of SN, 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a tumor vasculature-disruptive agent) was loaded into the optimized SN and then coated with platelet membrane to yield platelet-mimicking supramolecular nanomedicine (D@SN-P). D@SN-P could first passively accumulate in tumors owing to the enhanced permeability and retention (EPR) effect after intravenous administration. The initially release of DMXAA from D@SN-P could induce tumor vascular disruption, and the resultant epithelial collagen exposure around the disrupted tumor vasculature provided a target for further recruitment of platelet-mimicking SN, leading to cascade amplification of tumor accumulation with synergistic chemotherapy. Hence, this platelet-mimicking supramolecular nanomedicine presents a universal supramolecular strategy to finely regulate the ratio of loaded pro-drugs, and improve the accumulation efficiency to amplify chemotherapy via platelet-mimics.
喜树碱（CPT）和顺铂（Pt）在临床前和临床研究中已显示出对多种癌症的协同作用。然而，在不同的给药系统中，两种药物的比例往往无法精确调节，这阻碍了理想的协同作用。此外，两种药物向肿瘤的低递送效率进一步阻碍了理想的治疗效果。在这里，我们报告了一种血小板模拟的超分子纳米药物（SN），可以通过葫芦[7]脲接枝透明质酸（HA-CB[7]）和金刚烷（ADA）分别功能化的 CPT 和基于 Pt 的前药之间的主客体相互作用，精确控制 CPT 和 Pt 的比例，具有高肿瘤积累率，用于协同化疗的级联放大。SN 的比率可以通过简单地控制载药比来轻松调节，这基于 CB[7]和 ADA 之间的强结合亲和力，并且 SN60 具有 60%的 CPT 和 40%的 Pt 对 4T1 细胞显示出最高的协同作用。为了提高 SN 的肿瘤积累效率，将 5,6-二甲基黄嘌呤-4-乙酸（DMXAA，一种肿瘤血管破坏剂）加载到优化的 SN 中，然后用血小板膜包被，得到血小板模拟的超分子纳米药物（D@SN-P）。D@SN-P 可以在静脉注射后首先由于增强的通透性和保留（EPR）效应而被动地在肿瘤中积累。D@SN-P 中最初释放的 DMXAA 可以诱导肿瘤血管破坏，并且破坏的肿瘤血管周围暴露的上皮胶原提供了进一步募集血小板模拟 SN 的靶点，导致肿瘤积累的级联放大和协同化疗。因此，这种血小板模拟的超分子纳米药物提供了一种通用的超分子策略，可以精细调节负载前药的比例，并通过血小板模拟物提高积累效率以放大化疗。
