Donghua Di

Dual-stimuli responsive hyaluronic acid-conjugated mesoporous silica for targeted delivery to CD44-overexpressing cancer cells.

In this paper, a redox and enzyme dual-stimuli responsive delivery system (MSN-SS-HA) based on mesoporous silica nanoparticles (MSN) for targeted drug delivery has been developed, in which hyaluronic acid (HA) was conjugated on the surface of silica by cleavable disulfide (SS) bonds. HA possesses many attractive features, including acting as a targeting ligand and simultaneously a capping agent to achieve targeted and controlled drug release, prolonging the blood circulation time, and increasing the physiological stability and biocompatibility of MSN. The anticancer drug doxorubicin (DOX) was chosen as a model drug. In vitro drug release profiles showed that the release of DOX was markedly restricted in pH 7.4 and pH 5.0 phosphate buffer solution (PBS), while it was significantly accelerated upon the addition of glutathione (GSH)/hyaluronidases (HAase). In addition, the release was further accelerated in the presence of both GSH and HAase. Confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS) showed that MSN-SS-HA exhibited a higher cellular uptake via cluster of differentiation antigen-44 (CD44) receptor-mediated endocytosis compared with thiol (SH)-functionalized MSN (MSN-SH) in CD44 receptor over-expressed in human HCT-116 cells. The DOX-loaded MSN-SS-HA was more cytotoxic against HCT-116 cells than NIH-3T3 (CD44 receptor-negative) cells due to the enhanced cellular uptake of MSN-SS-HA. This paper describes the development of an effective method for using a single substance as multi-functional material for MSN to simultaneously regulate drug release and achieve targeted delivery.

Redox and pH dual-responsive PEG and chitosan-conjugated hollow mesoporous silica for controlled drug release

In this paper, a hollow mesoporous silica nanoparticles (HMSN) was used as the drug vehicle to develop the redox and pH dual stimuli-responsive delivery system, in which the chitosan (CS), a biodegradable cationic polymer, was grafted on the surface of HMSN via the cleavable disulfide bonds. CS was chosen as the gatekeeper mainly due to its appropriate molecular weight as well as possessing abundant amino groups which could be protonated in the acidic condition to achieve pH-responsive drug release. In addition, the PEG was further grafted on the surface of CS to increase the stability and biocompatibility under physiological conditions. The DOX loaded DOX/HMSN-SS-CS@PEG had a relatively high drug loading efficiency up to 32.8%. In vitro release results indicated that DOX was dramatically blocked within the mesopores of HMSN-SS-CS@PEG in pH 7.4 PBS without addition of GSH. However, the release rate of DOX was markedly increased after the addition of 10mM GSH or in pH5.0 release medium. Moreover, the release of DOX was further improved in pH5.0 PBS with 10mM GSH. The HMSN-SS-CS@PEG could markedly decrease the hemolysis percent and protein adsorption, and increase the biocompatibility and stability of HMSN compared with the HMSN-SS-CS and bare HMSN. This work suggested an exploration about HMSN based stimuli-responsive drug delivery and these results demonstrated that HMSN-SS-CS@PEG exhibited dual-responsive drug release property and could be used as a promising carrier for cancer therapy.

Fluorescent carbon dot modified mesoporous silica nanocarriers for redox-responsive controlled drug delivery and bioimaging.

In this paper, a smart nanocarrier (MSNs-SS-CDPAA) is developed for redox-responsive controlled drug delivery and in vivo bioimaging by grafting fluorescent carbon dots to the surface of mesoporous silica nanoparticles (MSNs) via disulfide bonds. The polyanion polymer poly(acrylic acid) (PAA) was used to prepare the carboxyl-abundant carbon dots (CDPAA) by hydrothermal polymerization. The negatively charged CDPAA were anchored to the openings of MSNs containing the disulfide bonds through amidation and were used as gatekeepers for trapping the drugs within the pores. The in vitro release results indicated that the prepared MSNs-SS-CDPAA/DOX showed highly redox-responsive drug release in pH 7.4 and pH 5.0 PBS. In addition, the redox-responsive release mechanism was studied by measurement of the Zeta potential and fluorescence spectrophotometry. The prepared MSNs-SS-CDPAA exhibited excellent biocompatibility and fluorescence properties. Confocal laser scanning microscopy (CLSM) showed that MSNs-SS-CDPAA could emit blue, green and red fluorescence at an excitation wavelength of 408, 488 and 561nm, respectively. In addition, MSNs-SS-CDPAA/DOX exhibited a high cellular uptake as shown by CDPAA imaging and a therapeutic effect on cancer cells by MTT assay. This study describes a novel strategy for simultaneously controlled drug delivery and real-time imaging to track the behavior of nanoparticles during tumor therapy.

Solvent-shift strategy to identify suitable polymers to inhibit humidity-induced solid-state crystallization of lacidipine amorphous solid dispersions.

The solvent-shift strategy was used to identify appropriate polymers that inhibit humidity-induced solid-state crystallization of amorphous solid dispersions (ASDs). Lacidipine with the polymers, PVP-K30, HPMC-E5 or Soluplus, were combined to form amorphous solid dispersions prepared by solvent evaporation. The formulations were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier-transform infrared spectroscopy (FT-IR) and were subjected to in vitro dissolution testing. The moisture had a significant impact on the amount dissolved for the solid dispersions. Molecular docking studies established that hydrogen bonding was critical for the stabilization of the solid dispersions. The rank order of the binding energy of the drug-polymer association was Soluplus (-6.21 kcal/mol)>HPMC-E5 (-3.21 kcal/mol)>PVP-K30 (-2.31 kcal/mol). PVP-K30 had the highest water uptake among the polymers, as did ASD system of lacidipine-PVP-K30 ASDs. In the Soluplus ASDs, with its strong drug-polymer interactions and low water uptake, moisture-induced solid-state crystallization was not observed.

Core-matched encapsulation of an oleate prodrug into nanostructured lipid carriers with high drug loading capability to facilitate the oral delivery of docetaxel.

Nanostructured lipid carriers (NLC) have been considered as promising vehicles for oral delivery of taxanes, such as docetaxel (DTX). However, the low drug loading capability (∼5%, w/w) has greatly limited their clinical application. In response to this challenge, a novel lipophilic oleate prodrug of DTX (DTX-OA) was synthesized and efficiently encapsulated in NLC using core-match technology, in which liquid lipid (OA) was used as core matrix to enhance compatibility with DTX-OA. DTX-OA-NLC showed uniform particle size of about 100nm with markedly high drug loading capability (∼23% of DTX, w/w) compared with DTX-NLC (∼5%, w/w). Besides, DTX-OA-NLC showed better colloidal stability and slower drug release property compared with DTX-NLC. The prepared NLC could be accumulated more easily in MDCK cells than drug solution, and clathrin-mediated endocytosis was the main endocytosis pathway. In situ single-pass intestinal perfusion (SPIP) and intestinal biodistribution studies demonstrated the improved membrane permeability and intestinal wall bioadhesion of NLCs. The bioavailability of DTX-OA-NLC showed 4.04-fold and 2.06-fold higher than DTX solution and DTX-NLC, respectively. These results suggest that the core-matched prodrug-NLC is a promising platform to facilitate the oral delivery of DTX.

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.

Targeted delivery of epirubicin to tumor-associated macrophages by sialic acid-cholesterol conjugate modified liposomes with improved antitumor activity

With the knowledge that the receptors of sialic acid are overexpressed on the surface of tumor-associated macrophages (TAMs), which play a crucial role in the tumors progression and metastasis, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SAL) to improve the delivery of EPI to the TAMs. The liposomes were developed using remote loading technology via a pH gradient. The liposomes were evaluated for particle size, encapsulation efficiency, in vitro release, stability, in vitro cytotoxicity and pharmacokinetics. And the in vitro and in vivo cellular uptake studies demonstrated EPI-SAL achieved enhanced accumulation of EPI into TAMs. The antitumor studies indicated that EPI-SAL provided the strongest antitumor activity compared with the other formulations (EPI-S, EPI-CL and EPI-PL represent EPI solution, conventional liposomal EPI, PEGylated liposomal EPI, respectively), and the survival percent of tumor-bearing mice was 83.3%. The superior antitumor efficacy was probably attributed to the killing of TAMs by EPI-SAL, and modulating the tumor microenvironment with the depletion of TAMs. These findings suggested that SA-CH decorated EPI-loaded liposomes may present an effective strategy to eradicate TAMs, which may be a promising approach for cancer therapy.

Fluorescent carbon dot-gated multifunctional mesoporous silica nanocarriers for redox/enzyme dual-responsive targeted and controlled drug delivery and real-time bioimaging

Graphical abstract Figure. No caption available. ABSTRACT A distinctive and personalized nanocarrier is described here for controlled and targeted antitumor drug delivery and real‐time bioimaging by combining a redox/enzyme dual‐responsive disulfide‐conjugated carbon dot with mesoporous silica nanoparticles (MSN‐SS‐CDHA). The carbon dot with controlling and targeting abilities was prepared through a polymerizing reaction by applying citric acid and HA as starting materials (named CDHA). The as‐prepared MSN‐SS‐CDHA exhibited not only superior photostability and excellent biocompatibility, but also the ability to target A549 cells with overexpression of CD44 receptors. Upon loading the antitumor drug, doxorubicin (DOX), into the mesoporous channels of MSN nanoparticles, CDHA with a diameter size of 3 nm completely blocked the pore entrance of DOX‐encapsulated MSN nanoparticles with a pore size of about 3 nm, thus preventing the premature leakage of DOX and increasing the antitumor activity until being triggered by specific stimuli in the tumor environment. The results of the cell imaging and cytotoxicity studies demonstrated that the redox/enzyme dual‐responsive DOX‐encapsulated MSN‐SS‐CDHA nanoparticles can selectively deliver and control the release of DOX into tumor cells. Ex vivo fluorescence images showed a much stronger fluorescence of MSN‐SS‐CDHA‐DOX in the tumor site than in normal tissues, greatly facilitating the accumulation of DOX in the target tissue. However, its counterpart, MSN‐SH‐DOX exhibited no or much lower tumor cytotoxicity and drug accumulation in tumor tissue. In addition, MSN‐SS‐CD was also used as a control to investigate the ability of MSN‐SS‐CDHA to target A549 cells. The results obtained indicated that MSN‐SS‐CDHA possessed a higher cellular uptake through the CD44 receptor‐mediated endocytosis compared with MSN‐SS‐CD in the A549 cells. Such specific redox/enzyme dual‐responsive targeted nanocarriers are a useful strategy achieving selective controlled and targeted delivery of therapeutic reagents with real‐time bioimaging, and may also facilitate the development of drug delivery systems for a number of clinical applications.

Hollow mesoporous carbon as a near-infrared absorbing carrier compared with mesoporous carbon nanoparticles for chemo-photothermal therapy

In this study, hollow mesoporous carbon nanoparticles (HMCN) and mesoporous carbon nanoparticles (MCN) were used as near-infrared region (NIR) nanomaterials and drug nanocarriers were prepared using different methods. A comparison between HMCN and MCN was performed with regard to the NIR-induced photothermal effect and drug loading efficiency. The results of NIR-induced photothermal effect test demonstrated that HMCN-COOH had a better photothermal conversion efficacy than MCN-COOH. Given the prominent photothermal effect of HMCN-COOH in vitro, the chemotherapeutic drug DOX was chosen as a model drug to further evaluate the drug loading efficiencies and NIR-triggered drug release behaviors of the nanocarriers. The drug loading efficiency of DOX/HMCN-COOH was found to be up to 76.9%, which was higher than that of DOX/MCN-COOH. In addition, the use of an 808nm NIR laser markedly increased the release of DOX from both carbon carriers in pH 5.0 PBS and pH 7.4 PBS. Cellular photothermal tests involving A549 cells demonstrated that HMCN-COOH had a much higher photothermal efficacy than MCN-COOH. Cell viability experiments and flow cytometry were performed to evaluate the therapeutic effect of DOX/HMCN-COOH and the results obtained demonstrated that DOX/HMCN-COOH had a synergistic therapeutic effect in cancer treatment involving a combination of chemotherapy and photothermal therapy.

Dry state microcrystals stabilized by an HPMC film to improve the bioavailability of andrographolide

OBJECTIVE The main purpose of this study was to improve the in-vitro dissolution and the in-vivo bioavailability of a poorly water-soluble drug, andrographolide (ADG). METHODS A wet-milled suspension was prepared using a Lab basket mill in the presence of a hydrophilic carrier solution and then it was layered on to MCC beads with a fluidized bed coater to obtain solidified pellets. Optical microscopy, particle size distribution investigation, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were used to characterize the wet-milled suspension. In addition, the ADG pellets were subjected to investigations involving scanning electron microscopy (SEM), as well as dissolution, accelerated stability and bioavailability measurements. RESULTS The particle size was significantly reduced (from 31.6 μm to 2.17 μm), however, the ADG in suspension retained its crystallinity as shown by the results of the DSC and PXRD investigations. The dissolution of the new pellets and commercial dripping pills was 95.6% and 48%, respectively, in pure water over 60 min. After a 6 month accelerated test (40°C and RH 75%), although the initial dissolution rate declined slightly, the overall dissolution of the new pellets within 60 min was almost as high as the freshly prepared pellets. In the in-vivo evaluation, the Cmax (87.54 ± 54.82 μg/L) and AUC(0-t) of the new pellets (495.86 ± 281.05 μg/Lh) were clearly higher than those of the dripping pills (30.88 ± 12.02 μg/L, 301.07 ± 133.85 μg/Lh), while the Tmax of the test preparation was shorter than that of the reference (1.38 h vs 3.29 h). CONCLUSION These results showed that the new core-shell structured pellets consisting of ADG microcrystalline particles and stabilized by HPMC alone, markedly improved the dissolution and bioavailability of andrographolide.