pH-Responsive Assembly of Gold Nanoparticles and 鈥淪patiotemporally Concerted鈥?Drug Release for Synergistic Cancer Therapy

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• 作者：Jutaek Nam ; Wan-Geun La ; Sekyu Hwang ; Yeong Su Ha ; Nokyoung Park ; Nayoun Won ; Sungwook Jung ; Suk Ho Bhang ; Yoon-Ji Ma ; Yong-Min Cho ; Min Jin ; Jin Han ; Jung-Youn Shin ; Eun Kyung Wang ; Sang Geol Kim ; So-Hye Cho ; Jeongsoo Yoo ; Byung-Soo Kim ; Sungjee Kim
• 刊名：ACS Nano
• 出版年：2013
• 出版时间：April 23, 2013
• 年：2013
• 卷：7
• 期：4
• 页码：3388-3402
• 全文大小：1136K
• 年卷期：v.7,no.4(April 23, 2013)
• ISSN：1936-086X

文摘

A challenge in using plasmonic nanostructure鈥揹rug conjugates for thermo鈥揷hemo 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.

Keywords:

gold nanoparticle; pH-responsive; drug delivery; photothermal therapy; synergistic effect; tumor targeting