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1.
Biomacromolecules ; 21(12): 5093-5103, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33151670

RESUMO

Enzyme-responsive polypeptide vesicles have attracted considerable attention for precision theranostics because of their biocompatibility, biodegradability, and unique secondary conformation transition triggered by the catalytic actions of enzymes. These promising potentials of polypeptide vesicles could be limited in a drug delivery system by the very slow enzyme diffusion rate into vesicles that could reduce the efficacy of the drug. On the other hand, stimuli-responsive polymeric vesicles that respond to stimuli can undergo microstructure destruction for the burst release of drugs, which would penetrate through the membrane of dead cells and the tumor extracellular matrix, inducing acute toxicity to neighboring cells. Here, we designed amphiphilic PEG-polypeptide copolymers containing esterase-labile carbamate-caged primary amines. It was found that the diblock can self-assemble into vesicular structures. Esterase-triggered self-immolative decaging reactions could quickly release the primary amine moiety of monomers that can undergo an amidation reaction for transition of the bilayer of vesicles from hydrophobic to partially hydrophilic. This esterase-responsive process retains the nanostructure of vesicles but permeabilizes the vesicle membrane, which can afford the sustained release of encapsulating drugs. These esterase-responsive polypeptide vesicles mediate selective cytotoxicity in cancer cells with high esterase expression over normal fibroblasts with low esterase, enabling the potent anticancer chemotherapy with minimized side effects.


Assuntos
Sistemas de Liberação de Medicamentos , Esterases , Animais , Linhagem Celular , Preparações de Ação Retardada , Portadores de Fármacos , Fibroblastos , Humanos , Camundongos , Peptídeos
2.
Mater Sci Eng C Mater Biol Appl ; 106: 110294, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753340

RESUMO

Controlled release strategies of DNA vaccine hold promise for the design of in vivo vaccination platforms, yet the formulation and sustained delivery still pose a substantial challenge. In this study, we developed a novel hybrid dual-particulate delivery system, nanoparticle-in-microsphere (NIM), to integrate the advantages of nano-sized polymer/DNA polyplex with the sustained-release microsphere for DNA vaccine delivery. The nano-sized cores, consisting of polyethylene glycol-graft-polyethylenimine (PEG-g-PEI)/DNA polyplexes, were formulated into PLGA microspheres using a solid-in-oil-in-water (S/O/W) emulsion. The PEG block was used as stabilizing excipient to make DNA soluble and stable in organic solvent to prevent the inactivation of DNA at aqueous-organic interface during encapsulation. The fashion of DNA in dry solid state greatly increased the encapsulation efficiency of DNA in NIMs. This new formulation exhibited a burst release less than 15% and then sustain release close to zero-order kinetics in physiological environment. In addition, the microspheres showed pH-sensitivity and degraded faster in lysosomal compartments, which contributed to the accelerated intracellular release kinetics of DNA. Finally, intramuscular injection of NIMs encoding HIV proteins elicited distinct humoral and cellular immune response in mice at low dose. These results thus may aid NIM-based vaccination towards more extensive clinical evaluations.


Assuntos
Microesferas , Nanopartículas/química , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Vacinas de DNA/imunologia , Animais , Células COS , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , HIV/genética , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Plasmídeos/química , Plasmídeos/metabolismo , Polietilenoimina/química , Células RAW 264.7 , Transfecção , Vacinas de DNA/química , Vacinas de DNA/metabolismo , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/metabolismo
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