The investigation on polyion complex micelles composed of diammonium glycyrrhizinate/poly(ethylene glycol)-glycidyltrimethylammonium chloride-grafted polyasparthydrazide.

To prepare stable polyion complex (PIC) micelles, polyasparthydrazide (PAHy) modified with glycidyltrimethylammonium groups and methoxy poly(ethylene glycol) (mPEG) (mPEG-g-PAHy-GTA) was synthesized. The cytotoxicity of the polymer was evaluated by the methyl tetrazolium assay. The polymer entrapped the diammonium glycyrrhizinate (DG) and formed polyion complexes. The effect of pH value, grafting degree of mPEG, copolymer and drug concentration on the micelle formation was investigated by means of measuring entrapment efficiency and micelle size. In vitro DG release from the PIC micelles was detected by dialysis in various media of different ionic strengths. To examine the pharmacokinetic behavior of micelles in vivo, the time course of the drug in plasma was evaluated. The cytotoxicity of the polymer was very low. The results showed that entrapment efficiency can reach about 93%, and the mean particle size was almost 50 nm. The drug release rate decreased with a decrease in ionic strength of the release medium or an increase in the PEG grafting degree. Compared with DG solution, the AUC of DG micelles had a twofold increase. The smaller clearance and longer mean residence time of the DG micelles group compared with DG solution group showed that the DG loaded in PIC micelles can reduce drug elimination and prolong the drug residence time in the blood circulation. The results indicated that PIC micelles composed of mPEG-g-PAHy-GTA would be prospective as a drug carrier to the drugs which can be ionized in solution.

Polydopamine-coated mesoporous silica nanoparticles for multi-responsive drug delivery and combined chemo-photothermal therapy.

Synergistic therapy of chemotherapy and photothermal therapy exhibits great potential to improve the therapeutic efficiency for cancer therapy. In this study, a new biocompatible multiple sensitive drug delivery system (DDS) was synthesized by covering a polydopamine (PDA) layer on doxorubicin (DOX)-loaded mesoporous silica nanoparticle (MSN) via disulfide bonds (MSN-SS-PDA/DOX). PDA worked as a photothermal therapy (PTT) agent and also a gate keeper to control drug release, which was highly sensitive to pH and could prolong the residence time, simultaneously increase water solubility and biocompatibility of the nanoparticles. The DDS exhibited excellent monodispersity, redox/pH/NIR-multi-dependent release characteristics, remarkable photothermal conversion property (photothermal conversion efficiency η = 40.21%) and outstanding tumor cell synergistic killing efficiency of chemotherapy and photothermal therapy (combination index CI = 0.175). The biodistribution and pharmacodynamics experiments of MSN-SS-PDA/DOX in 4T1 tumor models indicated that MSN-SS-PDA made more DOX accumulate in tumor tissue than free DOX, extend circulation time of DOX in the body, and exhibit a significant synergistic antitumor efficacy. Meanwhile, the tumor growth was remarkably inhibited, which was much more obvious than any monotherapy effect. Thus, the novel nanoplatform presents a promising future as a drug delivery system for combination therapy.

Polyion complex micelles composed of pegylated polyasparthydrazide derivatives for siRNA delivery to the brain.

In order to achieve efficient siRNA delivery to the brain, we designed a novel polyion complex (PIC) micelles composed of rabies virus glycoprotein (RVG) peptide tagged PEGylated polyasparthydrazide (PAHy) derivatives. The synthesized derivatives were characterized using (1)H NMR. The PIC micelles were formed by electrostatic attraction between the polymer and siRNA. Then the micelles were decorated with RVG using PEG as a linker. The physiochemical properties of micelles, such as gel retardation assay, zeta potential, particle size, morphology and serum stability, were investigated. Moreover, the cytotoxicity, cellular uptake, gene silencing efficiency and in vivo distribution of micelles were also evaluated systematically. Compared with unmodified micelles, RVG-modified micelles can be more easily internalized by the neuro2a cells and efficiently silence gene expression. In vivo animal experiments further confirmed that RVG modified micelles had brain targeting ability. These results demonstrated that RVG-modified micelles were promising carriers for siRNA delivery to the brain.

Investigation of 3D ordered macroporous carbon with different polymer coatings and their application as an oral vaccine carrier.

3-D ordered macroporous carbon with different polymer coatings were developed as new oral vaccine immunological systems. Poly dimethyl diallyl ammonium (PDDA), polyethyleneimine (PEI) and chitosan (CTS), three different polymers with electropositive or adsorption-promoting properties, were chosen as the coating materials to endow the vaccine delivery systems with different surface properties. The bovine serum albumin (BSA) was used as a model vaccine. The three different polymer coated systems exhibited similar release rate which minimized the influence of release rate. The measured value of immunoglobulin G (IgG) titers suggested that the sustained release rate of BSA from polymer coated systems exhibited no strengthened effect on the immune response but could delay the appearance of the peak of the IgG titers compared with uncoated system. The electrostatic attraction between the mucosal and positively charged carrier would be useful during the whole immune experiment. In addition, using the coating material with the ability of enhancing mucosal adsorption was important in the mid-late period of immune. The immunoglobulin A (IgA) titers induced by the polymer coated systems were significantly higher than that induced by the oral BSA solution or i.m. BSA with Freund's complete adjuvant (FCA) which suggested the successful mucosal immune response of the three different coated systems. Overall, this work provides valuable information for the development of oral vaccine delivery system.

Hybrid lipid-capped mesoporous silica for stimuli-responsive drug release and overcoming multidrug resistance.

Multidrug resistance (MDR) is known to be a great obstruction to successful chemotherapy, and considerable efforts have been devoted to reverse MDR including designing various functional drug delivery systems. In this study, hybrid lipid-capped mesoporous silica nanoparticles (LTMSNs), aimed toward achieving stimuli-responsive drug release to circumvent MDR, were specially designated for drug delivery. After modifying MSNs with hydrophobic chains through disulfide bond on the surface, lipid molecules composing polymer d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) with molar ratio of 5:1 were subsequently added to self-assemble into a surrounded lipid layer via hydrophobic interaction acting as smart valves to block the pore channels of carrier. The obtained LTMSNs had a narrow size distribution of ca. 190 nm and can be stably dispersed in body fluids, which may ensure a long circulating time and ideal enhanced permeability and retention effect. Doxorubicin (DOX) was chosen as a model drug to be encapsulated into LTMSNs. Results showed that this hybrid lipid-capped mesoporous silica drug delivery system can achieve redox and pH-responsive release of DOX, thereby avoiding the premature leakage of drug before reaching the specific site and releasing DOX within the cancerous cells. Owing to the presence of TPGS-containing lipid layer, LTMSNs-DOX exhibited higher uptake efficiency, cytotoxicity, and increased intracellular accumulation in resistant MCF-7/Adr cells compared with DOX solution, proving to be a promising vehicle to realize intracellular drug release and inhibit drug efflux.

Hyaluronic acid oligosaccharide modified redox-responsive mesoporous silica nanoparticles for targeted drug delivery.

A redox-responsive delivery system based on colloidal mesoporous silica (CMS) has been developed, in which 6-mercaptopurine (6-MP) was conjugated to vehicles by cleavable disulfide bonds. The oligosaccharide of hyaluronic acid (oHA) was modified on the surface of CMS by disulfide bonds as a targeting ligand and was able to increase the stability and biocompatibility of CMS under physiological conditions. In vitro release studies indicated that the cumulative release of 6-MP was less than 3% in the absence of glutathione (GSH), and reached nearly 80% within 2 h in the presence of 3 mM GSH. Confocal microscopy and fluorescence-activated cell sorter (FACS) methods were used to evaluate the cellular uptake performance of fluorescein isothiocyanate (FITC) labeled CMS, with and without oHA modification. The CMS-SS-oHA exhibited a higher cellular uptake performance via CD44 receptor-mediated endocytosis in HCT-116 (CD44 receptor-positive) cells than in NIH-3T3 (CD44 receptor-negative) cells. 6-MP loaded CMS-SS-oHA exhibited greater cytotoxicity against HCT-116 cells than NIH-3T3 cells due to the enhanced cell uptake behavior of CMS-SS-oHA. This study provides a novel strategy to covalently link bioactive drug and targeting ligand to the interiors and exteriors of mesoporous silica to construct a stimulus-responsive targeted drug delivery system.

Poly dimethyl diallyl ammonium coated CMK-5 for sustained oral drug release.

A new oral sustained drug delivery system (DDS) involving a combination of inorganic mesoporous material (CMK-5) and organic polymer poly dimethyl diallyl ammonium (PDDA) was established to determine its general suitability for use with poorly water soluble drugs. Nimodipine, carvedilol and fenofibrate, three different drugs with acidic or alkaline properties, were selected as model drugs and loaded into carriers. The physicochemical properties of the drug carriers were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nitrogen adsorption. The structural body changes of the composites in release medium, with or without additional salts, were also studied using particle sizing systems, nitrogen adsorption and zeta potential measurement in order to investigate the sustained release mechanism of the drugs. The results obtained showed that sustained release of drug from the designed DDS was mainly due to the blockage effect arising from the strong swelling of the coated polymers when in contact with release medium. Additional salts, when they reached a certain level, allowed a dramatic burst release. We believe that our designed sustained DDS provide a new option for water insoluble drugs and can be considered as fundamental for those more sophisticated DDS increasingly required in modern medical treatments.

PEGylated mesoporous silica as a redox-responsive drug delivery system for loading thiol-containing drugs.

In this paper, we describe the development of a redox-responsive delivery system based on 6-mercaptopurine (6-MP)-conjugated colloidal mesoporous silica (CMS) via disulfide bonds. mPEG was modified on the surface of silica to improve the dispersibility and biocompatiblity of CMS by reducing hemolysis and protein adsorption. The CMS carriers with different amounts of thiol groups were prepared to evaluate the impact of modified thiol on the drug loading efficiency. In vitro release studies demonstrated that the CMS nanoparticles exhibited highly redox-responsive drug release. The cumulative release of 6-MP was less than 3% in absence of GSH, and reached more than 70% within 2h in the presence of 3mM GSH. In addition, by comparing the cumulative release profiles of CMS-SS-MP@mPEG with their counterparts without the grafting of hydrophilic PEG, it was found that mPEG chains did not hinder the drug release due to the cleavable disulfide bonds and the improved dispersibility. Overall, this work provides a new strategy to connect thiol-containing/thiolated drugs and hydrophilic polymers to the interior and exterior of silica via disulfide bonds to obtain redox-responsive release and improve the dispersibility and biocompatibility of silica.