Department of Chemistry, Pohang University of Science & Technology, San 31, Hyojadong, Namgu, Pohang 790-784, South Korea.
ACS Nano. 2013 Apr 23;7(4):3388-402. doi: 10.1021/nn400223a. Epub 2013 Apr 8.
A challenge in using plasmonic nanostructure-drug conjugates for thermo-chemo combination cancer therapy lies in the huge size discrepancy; the size difference can critically differentiate their biodistributions and hamper the synergistic effect. Properly tuning the plasmonic wavelength for photothermal therapy typically results in the nanostructure size reaching ∼100 nm. We report a new combination cancer therapy platform that consists of relatively small 10 nm pH-responsive spherical gold nanoparticles and conjugated doxorubicins. They are designed to form aggregates in mild acidic environment such as in a tumor. The aggregates serve as a photothermal agent that can selectively exploit external light by their collective plasmon modes. Simultaneously, the conjugated doxorubicins are released. The spatiotemporal concertion is confirmed at the subcellular, cellular, and organ levels. Both agents colocalize in the cell nuclei. The conjugates accumulate in cancer cells by the rapid phagocytic actions and effective blockage of exocytosis by the increased aggregate size. They also effectively accumulate in tumors up to 17 times over the control because of the enhanced permeation and retention. The conjugates exhibit a synergistic effect enhanced by nearly an order of magnitude in cellular level. The synergistic effect is demonstrated by the remarkable reductions in both the therapeutically effective drug dosage and the photothermal laser threshold. Using an animal model, effective tumor growth suppression is demonstrated. The conjugates induce apoptosis to tumors without any noticeable damage to other organs. The synergistic effect in vivo is confirmed by qRT-PCR analysis over the thermal stress and drug-induced growth arrest.
在将等离子体纳米结构-药物偶联物用于热化疗联合癌症治疗时，面临的一个挑战在于它们的尺寸差异巨大；这种尺寸差异会严重影响它们的生物分布，从而阻碍协同作用。为光热治疗适当调整等离子体波长通常会导致纳米结构尺寸达到约 100nm。我们报告了一种新的组合癌症治疗平台，它由相对较小的 10nm pH 响应性球形金纳米颗粒和共轭阿霉素组成。它们被设计成在肿瘤等轻度酸性环境中形成聚集体。这些聚集体可以作为光热剂，通过它们的集体等离子体模式选择性地利用外部光。同时，共轭阿霉素也被释放出来。在亚细胞、细胞和器官水平上证实了时空协同作用。两种药物都在细胞核内共定位。通过快速的吞噬作用和增加的聚集体尺寸有效阻止胞吐作用，使药物在癌细胞中积累。由于增强的渗透性和保留，它们在肿瘤中的积累也高达对照的 17 倍。由于协同作用，在细胞水平上增强了近一个数量级。协同作用通过治疗有效药物剂量和光热激光阈值的显著降低得到证实。使用动物模型，有效地抑制了肿瘤生长。该偶联物诱导肿瘤细胞凋亡，而对其他器官没有明显损伤。通过热应激和药物诱导的生长抑制的 qRT-PCR 分析，在体内证实了协同作用。
