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pH-Responsive Assembly of Gold Nanoparticles and “Spatiotemporally Concerted” Drug Release for Synergistic Cancer Therapy

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 ‡△*, and Sungjee Kim †∥*

Department of Chemistry, Pohang University of Science & Technology, San 31, Hyojadong, Namgu, Pohang 790-784, South Korea
School of Chemical and Biological Engineering, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul 151-742, South Korea
§ Department of Molecular Medicine, School of Medicine, Kyungpook National University, Dongin-dong, Joong-gu, Daegu 700-422, South Korea
Frontier Research Laboratory, Samsung Advanced Institute of Technology, Samsung Electronics, Yongin, Kyunggi-do 446-712, South Korea
School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science & Technology, San 31, Hyojadong, Namgu, Pohang 790-784, South Korea
Department of Surgery, School of Medicine, Kyungpook National University, Dongin-dong, Joong-gu, Daegu 700-422, South Korea
# Nano-Materials Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, South Korea
Bio-MAX Institute, Institute of Chemical Processes, Engineering Research Institute, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul 151-742, South Korea

*Correspondence to Byung-Soo Kim, Sungjee Kim

Abstract
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.

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

논문정보
- 형식: Research article
- 게재일: 2013년 03월 (BRIC 등록일 2013-04-09)
- 연구진: 국내연구진태극기
광유전학의 과거, 현재와 미래[Neuron]
김윤석
발표: 김윤석 (Stanford University)
일자: 2020년 7월 30일 (목) 오후 02시 (한국시간)
언어: 한국어
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