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Dual-Targeted Cascade-Responsive Prodrug Micelle System for Tumor Therapy in Vivo
journal contribution
posted on 2017-08-11, 17:51 authored by Liangliang Dai, Ruisi Cai, Menghuan Li, Zhong Luo, Yonglin Yu, Weizhen Chen, Xinkun Shen, Yuxia Pei, Xiaojing Zhao, Kaiyong CaiThis
study reports a cascade-responsive disassemble micellar drug
delivery system with dual-targeting potential (cell and mitochondria
targeting), which optimizes the distribution of antitumor drugs on
systemic, local, and subcellular levels to enhance antitumor efficacy.
A new cationic porphyrin derivative 5-(3-hydroxy-p-(4-trimethylammonium)butoxyphenyl)-10,15,20-triphenylporphyrin chlorine
(MTPP) is synthesized as a mitochondria-targeting photosensitizer.
After accumulating at a tumor site, the micellar nanosystem is endocytosed
by tumor cells facilitated by the folate receptor-mediated pathway.
Then, the hydrophobic PDEA block would be protonated in intracellular
acidic endo-/lysosomes and promote the escape of prodrug micelles
from endo-/lysosome to cytoplasm, resulting in the first-stage destabilization
of micelles. Subsequently, the CPT is released in response to high
concentration of GSH in cytoplasm, which would greatly increase the
hydrophilicity of the BOH block and initiate the complete disassembly
of the polymer micelles owing to the damage of the hydrophilic–hydrophobic
balance. Additionally, the released MTPP is selectively accumulated
in mitochondria and activates mitochondria apoptotic pathway upon
light irradiation as a result of ROS generation. Both in vitro and in vivo studies indicate that the polymeric
micelle not only effectively improves the targeted delivery efficiency
but also dramatically enhances the combinational antitumor efficacy
while reducing the side effects associated with the laser irradiation
and mitochondria-targeted tumor therapy.
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polymer micellesTumor Therapyfirst-stage destabilizationcationic porphyrinGSHCPTstudy reportsdelivery efficiencyside effectsactivates mitochondria apoptotic pathwaylight irradiationmitochondria-targeting photosensitizerantitumor drugstumor siteendoPDEA blocktumor cellsprodrug micellessubcellular levelsvivo studiesmicellar nanosystemmicellar drug delivery systemcombinational antitumor efficacymitochondria-targeted tumor therapycytoplasmantitumor efficacyfolate receptor-mediated pathwayDual-Targeted Cascade-Responsive Prodrug Micelle Systemlaser irradiationMTPPROS generationBOH block
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