title: pH-responsive assembly of gold nanoparticles and "spatiotemporally concerted" drug release for synergistic cancer therapy.
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.
authors.affiliation: Department of Chemistry, Pohang University of Science & Technology, San 31, Hyojadong, Namgu, Pohang 790-784, South Korea.
authors.forename: Jutaek
authors.initials: J
authors.lastname: Nam
authors.forename: Wan-Geun
authors.initials: WG
authors.lastname: La
authors.forename: Sekyu
authors.initials: S
authors.lastname: Hwang
authors.forename: Yeong Su
authors.initials: YS
authors.lastname: Ha
authors.forename: Nokyoung
authors.initials: N
authors.lastname: Park
authors.forename: Nayoun
authors.initials: N
authors.lastname: Won
authors.forename: Sungwook
authors.initials: S
authors.lastname: Jung
authors.forename: Suk Ho
authors.initials: SH
authors.lastname: Bhang
authors.forename: Yoon-Ji
authors.initials: YJ
authors.lastname: Ma
authors.forename: Yong-Min
authors.initials: YM
authors.lastname: Cho
authors.forename: Min
authors.initials: M
authors.lastname: Jin
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Jung-Youn
authors.initials: JY
authors.lastname: Shin
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Wang
authors.forename: Sang Geol
authors.initials: SG
authors.lastname: Kim
authors.forename: So-Hye
authors.initials: SH
authors.lastname: Cho
authors.forename: Jeongsoo
authors.initials: J
authors.lastname: Yoo
authors.forename: Byung-Soo
authors.initials: BS
authors.lastname: Kim
authors.forename: Sungjee
authors.initials: S
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003692:Delayed-Action Preparations / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage*; D006046:Gold / Q000627:therapeutic use*; D006863:Hydrogen-Ion Concentration; D006979:Hyperthermia, Induced / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D020349:Surface Plasmon Resonance / Q000379:methods; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D006046:Gold; D004317:Doxorubicin