Smart Polymersomes Dually Functionalized with cRGD and Fusogenic GALA Peptides Enable Specific and High-Efficiency Cytosolic Delivery of Apoptotic Proteins.
Biomacromolecules
; 20(1): 184-191, 2019 01 14.
Article
em En
| MEDLINE
| ID: mdl-30289705
ABSTRACT
Low cell selectivity and uptake coupled with endosomal entrapment pose critical hurdles for intracellular delivery and clinical translation of therapeutic proteins. Herein, we report that smart polymersomes dually functionalized with cRGD and fusogenic GALA peptides (cRGD/GALA-Ps) enable ανß3-specific and high-efficiency cytosolic delivery of cytochrome C (CC), a model apoptotic protein, to A549 human lung cancer cells. cRGD/GALA-Ps was prepared with 20 mol % cRGD and varying GALA contents from 2 to 4 to 6 mol % via coassembly of PEG- b-poly(trimethylene carbonate- co-dithiolane trimethylene carbonate)-spermine (PEG- b-P(TMC- co-DTC)-spermine), cRGD-PEG- b-P(TMC- co-DTC), and maleimide-PEG- b-P(TMC- co-DTC) and postmodification using GALA-SH (sequence CWEAALAEALAEALAEHLAEALAEALEALAA). cRGD/GALA-Ps loaded with â¼13 wt % CC displayed a small size of about 65 nm and fast glutathione-triggered protein release. Interestingly, cRGD/GALA-Ps maintained a similar targeting ability to cRGD-Ps in ανß3-positive A549 lung cancer cells, while markedly enhanced cytosolic release of FITC-labeled CC, as revealed by confocal microscopy. MTT assays exhibited that CC-loaded cRGD/GALA-Ps was significantly more potent than CC-loaded cRGD-Ps, in which cell viabilities of 76.2, 51.0, 29.6, and 35.5% were discerned for cRGD/GALA-Ps with 0, 2, 4, and 6 mol % GALA, respectively, at 15.4 µM CC. Apoptosis assays corroborated that cRGD/GALA-Ps-CC with 4 mol % GALA induced better apoptosis of A549 cells than cRGD-Ps-CC (cell apoptosis 36.4 vs 14.4%). These results highlight that dual-functionalization of polymersomes with targeting and fusogenic peptides provides an appealing strategy for cytosolic protein delivery.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
/
Peptídeos
/
Apoptose
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Liberação Controlada de Fármacos
/
Polímeros Responsivos a Estímulos
Aspecto:
Implementation_research
Limite:
Humans
Idioma:
En
Revista:
Biomacromolecules
Ano de publicação:
2019
Tipo de documento:
Article