Abstract
Development of versatile nanoplatforms for cancer theranostics remains a hot topic in the area of nanomedicine. We report here a general approach to create polyethylenimine (PEI)-based hybrid nanogels (NGs) incorporated with ultrasmall iron oxide (Fe3O4) nanoparticles (NPs) and doxorubicin for T1-weighted MR imaging-guided chemotherapy of tumors. In this study, PEI NGs were first prepared using an inverse emulsion approach along with Michael addition reaction to cross-link the NGs, modified with citric acid-stabilized ultrasmall Fe3O4 NPs through 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride (EDC) coupling, and physically loaded with anticancer drug doxorubicin (DOX). The formed hybrid NGs possess good water dispersibility and colloidal stability, excellent DOX loading efficiency (51.4%), pH-dependent release profile of DOX with an accelerated release rate under acidic pH, and much higher r1 relaxivity (2.29 mM-1 s-1) than free ultrasmall Fe3O4 NPs (1.15 mM-1 s-1). In addition, in contrast to the drug-free NGs that possess good cytocompatibility, the DOX-loaded hybrid NGs display appreciable therapeutic activity and can be taken up by cancer cells in vitro. With these properties, the developed hybrid NGs enabled effective inhibition of tumor growth under the guidance of T1-weighted MR imaging. The developed hybrid NGs may be applied as a versatile nanoplatform for MR imaging-guided chemotherapy of tumors.
Highlights
Nanomedicine remains a challenging field for cancer theranostics
Through the inverse mini-emulsion method and BIS-mediated cross-linking,[11] PEI NGs with abundant amines were prepared, surface functionalized with ultrasmall Fe3O4 NPs through ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride (EDC) coupling, and acetylated to neutralize the remaining NG surface amines (Figure 1)
The magnetic resonance (MR) signal intensity of tumor increases first with the time post-injection, and declines at 30 min post-injection. This suggests that free ultrasmall Fe3O4 NPs and the Fe3O4/PEI-Ac NGs/DOX complexes can be enriched in the tumor site with blood circulation after intravenous injection possibly through the passive enhanced permeability and retention (EPR) effect
Summary
Nanomedicine remains a challenging field for cancer theranostics. To realize effective cancer theranostics, it is crucial to develop a variety of different nanoplatforms that can combine both therapeutic and diagnostic elements within the same platform. The MR signal intensity of tumor (as indicated in the white circles) increases first with the time post-injection, and declines at 30 min post-injection This suggests that free ultrasmall Fe3O4 NPs and the Fe3O4/PEI-Ac NGs/DOX complexes can be enriched in the tumor site with blood circulation after intravenous injection possibly through the passive enhanced permeability and retention (EPR) effect. At 30 min post-injection, the Fe3O4/ PEI-Ac NGs/DOX complexes can be gradually metabolized in vivo, leading to gradually decreased Fe concentration in the tumor site These results suggest that the Fe3O4/PEI-Ac NGs/ DOX complexes display an enhanced MR imaging performance than free ultrasmall Fe3O4 NPs. We checked the biodistribution of the Fe3O4/PEI-Ac. NGs/DOX complexes in the major organs and tumor of mice at different time points post-administration to evaluate the metabolic pathway (Figure S4). Our results suggest that the developed Fe3O4/PEI-Ac NGs/DOX complexes do not influence the major organs of mice, having a good biosafety profile
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