Journal
BIOMATERIALS
Volume 34, Issue 27, Pages 6454-6463Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2013.05.017
Keywords
Cancer-cell specific photoactivity; Switchable photoactivity; Pheophorbide a; Glycol chitosan nanoparticles; Photodynamic therapy
Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Fusion Technology Project through the National Research Foundation of Korea (NRF) [2010-50201]
- Ministry of Education, Science and Technology [2012005029]
- Fundamental R&D Program for Core Technology of Materials
- Ministry of Knowledge Economy
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We designed a cancer-cell specific photosensitizer nano-carrier by synthesizing pheophorbide a (PheoA) conjugated glycol chitosan (GC) with reducible disulfide bonds (PheoA-ss-GC). The amphiphilic PheoA-ss-GC conjugates self-assembled in aqueous condition to form core-shell structured nanoparticles (PheoA-ss-CNPs) with good colloidal stability and switchable photoactivity. The photoactivity of PheoA-ss-CNPs in an aqueous environment was greatly suppressed by the self-quenching effect, which enabled the PheoA-ss-CNPs to remain photo-inactive and in a quenched state. However, after the cancer cell-specific uptake, the nanoparticular structure instantaneously dissociated by reductive cleavage of the disulfide linkers, followed by an efficient dequenching process. Compared to non-reducible PheoA-conjugated GC-NPs with stable amide linkages (PheoA-CNPs), PheoA-ss-CNPs rapidly restored their photoactivity in response to intracellular reductive conditions, thus presenting higher cytotoxicity with light treatment. In addition, the PheoA-ss-CNPs presented prolonged blood circulation in vivo compared to free PheoA, demonstrating enhanced tumor specific targeting behavior through the enhanced permeation and retention (EPR) effect. The enhanced tumor accumulation of PheoA-ss-CNPs enabled tumor therapeutic efficacy that was more efficient than free PheoA in tumor-bearing mice. Based on the enhanced intracellular release for cytosolic high dose and switchable photoactivity mechanism for reduced side effects, these results suggest that PheoA-ss-CNPs have good potential for photodynamic therapy (PDT) in cancer treatment. (C) 2013 Elsevier Ltd. All rights reserved.
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