Yikun Gao

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.

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.

RVG-peptide-linked trimethylated chitosan for delivery of siRNA to the brain.

In this work, a peptide derived from the rabies virus glycoprotein (RVG) was linked to siRNA/trimethylated chitosan (TMC) complexes through bifunctional PEG for efficient brain-targeted delivery of siRNA. The physiochemical properties of the complexes, such as siRNA complexing ability, size and ζ potential, morphology, serum stability, and cytotoxicity, were investigated prior to studying the cellular uptake, in vitro gene silencing efficiency, and in vivo biodistribution. The RVG-peptide-linked siRNA/TMC-PEG complexes showed increased serum stability, negligible cytotoxicity, and higher cellular uptake than the unmodified siRNA/TMC-mPEG complexes in acetylcholine receptor positive Neuro2a cells. The potent knockdown of BACE1, a therapeutic target in Alzheimers disease, demonstrated the gene silencing efficiency. In vivo imaging analysis showed significant accumulation of Cy5-siRNA in the isolated brain of mice injected with RVG-peptide-linked complexes. Therefore, the RVG-peptide-linked TMC-PEG developed in this study can be used as a potential carrier for delivery of siRNA to the brain.

Exploitation of 3D face-centered cubic mesoporous silica as a carrier for a poorly water soluble drug: Influence of pore size on release rate

The purposes of the present work were to explore the potential application of 3D face-centered cubic mesoporous silica (FMS) with pore size of 16.0nm as a delivery system for poorly soluble drugs and investigate the effect of pore size on the dissolution rate. FMS with different pore sizes (16.0, 6.9 and 3.7nm) was successfully synthesized by using Pluronic block co-polymer F127 as a template and adjusting the reaction temperatures. Celecoxib (CEL), which is a BCS class II drug, was used as a model drug and loaded into FMS with different pore sizes by the solvent deposition method at a drug-silica ratio of 1:4. Characterization using scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transformation infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), nitrogen adsorption, X-ray diffraction (XRD), and differential scanning calorimetry (DSC) was used to systematically investigate the drug loading process. The results obtained showed that CEL was in a non-crystalline state after incorporation of CEL into the pores of FMS-15 with pore size of 16.0nm. In vitro dissolution was carried out to demonstrate the effects of FMS with different pore sizes on the release of CEL. The results obtained indicated that the dissolution rate of CEL from FMS-15 was significantly enhanced compared with pure CEL. This could be explained by supposing that CEL encountered less diffusion resistance and its crystallinity decreased due to the large pore size of 16.0nm and the nanopore channels of FMS-15. Moreover, drug loading and pore size both play an important role in enhancing the dissolution properties for the poorly water-soluble drugs. As the pore size between 3.7 and 16.0nm increased, the dissolution rate of CEL from FMS gradually increased.

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.

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.

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.

Preparation of novel porous starch microsphere foam for loading and release of poorly water soluble drug

Abstract Background: Organic porous material is a promising carrier for enhancing the dissolution of poorly water soluble drug. The aim of the present study was to enhance dissolution and oral bioavailability of lovastatin (LV) by preparing a porous starch microsphere foam (PSM) using a novel method, meanwhile, looking into the mechanism of improving dissolution of LV. Methods: PSM was prepared by the W/O emulsion – freeze thawing method. The porous structure of PSM was characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis. The adsorption role of nanopores on the drug dissolution and physical state of LV was systematically studied by instrumental analysis, and in vitro and in vivo drug dissolution studies. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate carrier cytotoxicity. Results: The SEM images of PSM showed nanometer-sized pores. Physical state characterization indicated that porous structure effectively limited the degree of crystallinity of LV. The results of in vitro and in vivo tests testified that PSM accelerated the release of LV and enhanced its oral bioavailability in comparison with crude LV and commercial capsules. The loaded PSM powder indicated a good physical stability under storage for 12 months. MTT assay shows PSM has no toxicity for Caco-2 cell. Conclusion: The preparation was a promising method to produce small and uniform PSM with markedly enhanced dissolution rate and oral bioavailability due to the spatial confinement effect of porous structure. The present work demonstrates the significant potential for the use of PSM as a novel delivery system for poorly water soluble drugs.

Mechanism study on pH-responsive cyclodextrin capped mesoporous silica: effect of different stalk densities and the type of cyclodextrin

Cyclodextrin (CD)-capped mesoporous silica nanoparticles (MSN) with pH-responsive properties were synthesized, but little research has been carried out to evaluate the impact of critical factors such as the stalk density and the type of CD on the pH-responsive release behavior. Here, the effect of different stalk densities on the pH-responsive release behavior was investigated. Either too low or too high density of the grafted p-anisidine stalk could result in poor cargo release, and the optimum stalk density for MSN was measured by thermal analysis, and found to be approximately 8.7 stalks nm(-2). To achieve effective release control, the CD capes, α-CD and β-CD, were also investigated. Isothermal titration calorimetry (ITC) analysis was employed to determine the formation constants (Kf) of the two CD with p-anisidine at different pH values. The results obtained showed that the complex of β-CD with p-anisidine had excellent pH-responsive behavior as it exhibited the largest changed formation constant (ΔKf) in different pH media. Furthermore, the pH-responsive mechanism between CD and p-anisidine molecules was investigated through ITC and a molecular modeling study. The release of antitumor drug DOX presents a significant prospect toward the development of pH-responsive nanoparticles as a drug delivery vehicle.

A comparison between sphere and rod nanoparticles regarding their in vivo biological behavior and pharmacokinetics

In recent years, spherical nanoparticles has been studied extensively on biomedical applications including bioimaging and biosensing, diagnostics and theranostics, but the effect of the shape of nanoparticles has received little attention. In the present study, we designed three different shaped fluorescent mesoporous silica nanoparticles (MSNs), long rod nanoparticles (NLR), short rod nanoparticles (NSR), and spherical nanoparticles (NS) to systematically examine their behavior in vivo after oral administration. The results of the ex vivo optical imaging study in mice indicated that rod nanoparticles had a longer residence time in the gastrointestinal compared with spherical nanoparticles. The in vivo biodistribution showed that all the orally administered MSNs were mainly taken up by the liver, and kidney. NLR had a great capacity to overcoming rapid clearance by the RES and exhibited a longer circulation in the blood than NSR and NS. During renal excretion, the spherical nanoparticles were cleared faster than rod nanoparticles. In addition, it was also found that MSNs can be degraded in vivo and NSR were degraded faster than NLR and NS probably owing to their higher specific surface area. The pharmacokinetic results demonstrated that nifedipine(NI)-loaded NLR had a higher bioavailability than NI-loaded NSR and NS.