Xue Shen

Folate-Functionalized Magnetic-Mesoporous Silica Nanoparticles for Drug/Gene Codelivery To Potentiate the Antitumor Efficacy

An appropriate codelivery system for chemotherapeutic agents and nucleic acid drugs will provide a more efficacious approach for the treatment of cancer. Combining gene therapy with chemotherapeutics in a single delivery system is more effective than individual delivery systems carrying either gene or drug. In this work, we developed folate (FA) receptor targeted magnetic-mesoporous silica nanoparticles for the codelivery of VEGF shRNA and doxorubicin (DOX) (denoted as M-MSN(DOX)/PEI-FA/VEGF shRNA). Our data showed that M-MSN(DOX)/PEI-FA could strongly condense VEGF shRNA at weight ratios of 30:1, and possesses higher stability against DNase I digestion and sodium heparin. In vitro antitumor activity assays revealed that HeLa cell growth was significantly inhibited. The intracellular accumulation of DOX by confocal microscopy and fluorescence spectrophotometry showed that M-MSN(DOX)/PEI-FA were more easily taken up than nontargeted M-MSN(DOX). Quantitative PCR and ELISA data revealed that M-MSN/PEI-FA/VEGF shRNA induced a significant decrease in VEGF expression as compared to cells treated with either the control or other complexes. The invasion and migration phenotypes of the HUVECs were significantly decrease after coculture with MSN/PEI-FA/VEGF shRNA nanocomplexes-treated HeLa cells. The approach provides a potential strategy to treat cancer by a singular nanoparticle delivery system.

Polyetherimide-grafted Fe3O4@SiO2 nanoparticles as theranostic agents for simultaneous VEGF siRNA delivery and magnetic resonance cell imaging

Engineering a safe and high-efficiency delivery system for efficient RNA interference is critical for successful gene therapy. In this study, we designed a novel nanocarrier system of polyethyleneimine (PEI)-modified Fe3O4@SiO2, which allows high efficient loading of VEGF small hairpin (sh)RNA to form Fe3O4@SiO2/PEI/VEGF shRNA nanocomposites for VEGF gene silencing as well as magnetic resonance (MR) imaging. The size, morphology, particle stability, magnetic properties, and gene-binding capacity and protection were determined. Low cytotoxicity and hemolyticity against human red blood cells showed the excellent biocompatibility of the multifunctional nanocomposites, and also no significant coagulation was observed. The nanocomposites maintain their superparamagnetic property at room temperature and no appreciable change in magnetism, even after PEI modification. The qualitative and quantitative analysis of cellular internalization into MCF-7 human breast cancer cells by Prussian blue staining and inductively coupled plasma atomic emission spectroscopy analysis, respectively, demonstrated that the Fe3O4@SiO2/PEI/VEGF shRNA nanocomposites could be easily internalized by MCF-7 cells, and they exhibited significant inhibition of VEGF gene expression. Furthermore, the MR cellular images showed that the superparamagnetic iron oxide core of our Fe3O4@SiO2/PEI/VEGF shRNA nanocomposites could also act as a T2-weighted contrast agent for cancer MR imaging. Our data highlight multifunctional Fe3O4@SiO2/PEI/VEGF shRNA nanocomposites as a potential platform for simultaneous gene delivery and MR cell imaging, which are promising as theranostic agents for cancer treatment and diagnosis in the future.

Luminescent/magnetic PLGA-based hybrid nanocomposites: a smart nanocarrier system for targeted codelivery and dual-modality imaging in cancer theranostics

Cancer diagnosis and treatment represent an urgent medical need given the rising cancer incidence over the past few decades. Cancer theranostics, namely, the combination of diagnostics and therapeutics within a single agent, are being developed using various anticancer drug-, siRNA-, or inorganic materials-loaded nanocarriers. Herein, we demonstrate a strategy of encapsulating quantum dots, superparamagnetic Fe3O4 nanocrystals, and doxorubicin (DOX) into biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) polymeric nanocomposites using the double emulsion solvent evaporation method, followed by coupling to the amine group of polyethyleneimine premodified with polyethylene glycol-folic acid (PEI-PEG-FA [PPF]) segments and adsorption of vascular endothelial growth factor (VEGF)-targeted small hairpin RNA (shRNA). VEGF is important for tumor growth, progression, and metastasis. These drug-loaded luminescent/magnetic PLGA-based hybrid nanocomposites (LDM-PLGA/PPF/VEGF shRNA) were fabricated for tumor-specific targeting, drug/gene delivery, and cancer imaging. The data showed that LDM-PLGA/PPF/VEGF shRNA nanocomposites can codeliver DOX and VEGF shRNA into tumor cells and effectively suppress VEGF expression, exhibiting remarkable synergistic antitumor effects both in vitro and in vivo. The cell viability waŝ14% when treated with LDM-PLGA/PPF/VEGF shRNA nanocomposites ([DOX] =25 μg/mL), and in vivo tumor growth data showed that the tumor volume decreased by 81% compared with the saline group at 21 days postinjection. Magnetic resonance and fluorescence imaging data revealed that the luminescent/magnetic hybrid nanocomposites may also be used as an efficient nanoprobe for enhanced T2-weighted magnetic resonance and fluorescence imaging in vitro and in vivo. The present work validates the great potential of the developed multifunctional LDM-PLGA/PPF/VEGF shRNA nanocomposites as effective theranostic agents through the codelivery of drugs/genes and dual-modality imaging in cancer treatment.

Chitosan hybrid nanoparticles as a theranostic platform for targeted doxorubicin/VEGF shRNA co-delivery and dual-modality fluorescence imaging

The current strategies for drug/gene and multimodal imaging probes integrated into a single nanoparticle have some limitations still. Here, multifunctional chitosan hybrid nanoparticles (denoted as FA–CS–FITC(DOX/C-dots)/VEGF shRNA) containing folic acid (FA), fluorescein isothiocyanate (FITC) and doxorubicin (DOX)/carbon quantum dots (C-dots)/VEGF shRNA were fabricated as a targeted drug/gene co-delivery nanovector for potential cancer therapy and fluorescence imaging. The self-assembled FA–CS–FITC(DOX/C-dots)/VEGF shRNA nanocomplexes exhibited a desirable and homogenous particle size (154 ± 24 nm), moderate positive charges (23.2 ± 1.8 mV) and superior stability. The nanocomplexes without noteworthy cytotoxicity are capable of delivering VEGF shRNA into human cervical cancer HeLa cells with high efficiency while effectively protecting shRNA from degradation by exogenous DNase I and nucleases. The release behavior of DOX exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous release at both pH 7.4 and pH 4.5, and also presented a pH-triggered release profile. Confocal microscopy analysis confirmed that both FA-targeted function and FA-enhanced buffering capacity induced high transfection, specific cellular uptake and efficient intracellular delivery of FA–CS–FITC(DOX/C-dots)/VEGF shRNA nanocomplexes in folate receptor-overexpressed HeLa cells. Transfected HeLa cells exhibited significantly decreased VEGF expression, inhibited cell proliferation, and increased cell apoptosis, which led to synergistic antitumor activities. Furthermore, the nanocomplexes demonstrated excellent dual fluorescence cellular imaging at a modest concentration. This work indicates that the integrated theranostic design of FA–CS–FITC(DOX/C-dots)/VEGF shRNA nanocomplexes potentially allows for the image-guided and target-specific treatment of cancer.