RESUMO
In biomedical applications, polyethylene glycol (PEG) functionalization has been a major approach to modify nanocarriers such as nano-graphene oxide for particular biological requirements. However, incorporation of a PEG shell poses a significant diffusion barrier that adversely affects the release of the loaded drugs. This study addresses this critical issue by employing a redox-responsive PEG detachment mechanism. A PEGylated nano-graphene oxide (NGO-SS-mPEG) with redox-responsive detachable PEG shell is developed that can rapidly release an encapsulated payload at tumor-relevant glutathione (GSH) levels. The PEG shell grafted onto NGO sheets gives the nanocomposite high physiological solubility and stability in circulation. It can selectively detach from NGO upon intracellular GSH stimulation. The surface-engineered structures are shown to accelerate the release of doxorubicin hydrochloride (DXR) from NGO-SS-mPEG 1.55 times faster than in the absence of GSH. Confocal microscopy shows clear evidence of NGO-SS-mPEG endocytosis in HeLa cells, mainly accumulated in cytoplasm. Furthermore, upon internalization of DXR-loaded NGO with a disulfide-linked PEG shell into HeLa cells, DXR is effectively released in the presence of an elevated GSH reducing environment, as observed in confocal microscopy and flow cytometric experiments. Importantly, inhibition of cell proliferation is directly correlated with increased intracellular GSH concentrations due to rapid DXR release.
Assuntos
Doxorrubicina/administração & dosagem , Doxorrubicina/química , Portadores de Fármacos/química , Grafite/química , Polietilenoglicóis/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Citometria de Fluxo , Glutationa/metabolismo , Células HeLa , Humanos , Microscopia Confocal , Oxirredução/efeitos dos fármacosRESUMO
The specific characteristics of the tumor vascular microenvironment such as microvascular permeability and water diffusion have been demonstrated to play essential roles in the evaluation of infiltration of tumors. However, at present, there are few contrast agents (CAs) for magnetic resonance imaging to enhance the sensitivity for acquiring this vital information. Herein, we develop Gd-doped (CeO2:Gd) nanoparticles as CAs to detect the tumor vascular microenvironment with high sensitivity. The lattice oxygen vacancies on the surface of CeO2:Gd nanoparticles could bind considerable water molecules to improve the r1 value, achieving an excellent dynamic contrast-enhanced perfusion weighted imaging performance for the measurement of microvascular permeability. Diffusion limiting of water molecules by oxygen vacancies of CeO2:Gd nanoparticles further enhances the diffusion-weighted magnetic resonance imaging signal in vitro and in vivo. Excitingly, the strategy is not only essential for obtaining tumor vascular microenvironment information but also offers a way for further research in the design of magnetic resonance CAs.
Assuntos
Cério/química , Gadolínio/química , Neoplasias Pulmonares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Nanopartículas/química , Oxigênio/química , Microambiente Tumoral , Células A549 , Animais , Cério/administração & dosagem , Gadolínio/administração & dosagem , Humanos , Camundongos , Nanopartículas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/químicaRESUMO
Lipid-polymer hybrid nanoparticles (NPs) are advantageous for drug delivery. However, their intracellular trafficking mechanism and relevance for oral drug absorption are poorly understood. In this study, self-assembled core-shell lipid-polymer hybrid NPs made of poly(lactic-co-glycolic acid) (PLGA) and various lipids were developed to study their differing intracellular trafficking in intestinal epithelial cells and their relevance for oral absorption of a model drug saquinavir (SQV). Our results demonstrated that the endocytosis and exocytosis of hybrid NPs could be changed by varying the kind of lipid. A glyceride mixture (hybrid NPs-1) decreased endocytosis but increased exocytosis in Caco-2 cells, whereas the phospholipid (E200) (hybrid NPs-2) decreased endocytosis but exocytosis was unaffected as compared with PLGA nanoparticles. The transport of hybrid NPs-1 in cells involved various pathways, including caveolae/lipid raft-dependent endocytosis, and clathrin-mediated endocytosis and macropinocytosis, which was different from the other groups of NPs that involved only caveolae/lipid raft-dependent endocytosis. Compared with that of the reference formulation (nanoemulsion), the oral absorption of SQV-loaded hybrid NPs in rats was poor, probably due to the limited drug release and transcytosis of NPs across the intestinal epithelium. In conclusion, the intracellular processing of hybrid NPs in intestinal epithelia can be altered by adding lipids to the NP. However, it appears unfavorable to use PLGA-based NPs to improve oral absorption of SQV compared with nanoemulsion. Our findings will be essential in the development of polymer-based NPs for the oral delivery of drugs with the purpose of improving their oral absorption.