Effects of Commonly used Surfactants, Poloxamer 188 and Tween 80, on the Drug Transport Capacity of Intestinal Glucose Transporters.

Some glycoside drugs can be transported through intestinal glucose transporters (IGTs). The surfactants used in oral drug preparations can affect the function of transporter proteins. This study aimed to investigate the effect of commonly used surfactants, Poloxamer 188 and Tween 80, on the drug transport capacity of IGTs. Previous studies have shown that gastrodin is the optimal drug substrate for IGTs. Gastrodin was used as a probe drug to evaluate the effect of these two surfactants on intestinal absorption in SD rats through pharmacokinetic and in situ single-pass intestinal perfusion. Then, the effects of the two surfactants on the expression of glucose transporters and tight-junction proteins were examined using RT-PCR and western blotting. Additionally, the effect of surfactants on intestinal permeability was evaluated through hematoxylin-eosin staining. The results found that all experimental for Poloxamer 188 (0.5%, 2.0% and 8.0%) and Tween 80 (0.1% and 2.0%) were not significantly different from those of the blank group. However, the AUC(0-∞) of gastrodin increased by approximately 32% when 0.5% Tween 80 was used. The changes in IGT expression correlated with the intestinal absorption of gastrodin. A significant increase in the expression of IGTs was observed at 0.5% Tween 80. In conclusion, Poloxamer 188 had minimal effect on the drug transport capacity of IGTs within the recommended limits of use. However, the expression of IGTs increased in response to 0.5% Tween 80, which significantly enhanced the drug transport capacity of IGTs. However, 0.1% and 2.0% Tween 80 had no significant effect.

Metal-Ligand Coordination Nanomaterials for Biomedical Imaging.

Over the past two decades, amorphous nanoscale coordination polymers (NCPs) and crystalline nanoscale metal-organic frameworks (NMOFs) have emerged as attractive nanomaterials in biomedical applications, especially in drug delivery, biomedical imaging, and biosensing. The biodegradability, tunable composition, and feasible functionality of NCPs/NMOFs make them excellent contrast agents or nanocarriers for biomedical imaging, including magnetic resonance (MR) imaging, positron emission tomography (PET), computed tomography (CT), optical imaging, and photoacoustic (PA) imaging. In this Topical Review, we will summarize the recent advances of NCPs/NMOFs in biomedical imaging with emphasis on research over the past three years. A variety of imaging technologies based on NCPs/NMOFs will be discussed, followed by the introduction of the application of NCPs/NMOFs in multimodal imaging where optical/MR imaging is highlighted. In the final part, we will make concluding remarks and point out the challenges and prospects for the further development in this area of research.

A novel macrophage-mediated biomimetic delivery system with NIR-triggered release for prostate cancer therapy.

BACKGROUND: Macrophages with tumor-tropic migratory properties can serve as a cellular carrier to enhance the efficacy of anti neoplastic agents. However, limited drug loading (DL) and insufficient drug release at the tumor site remain the main obstacles in developing macrophage-based delivery systems. In this study, we constructed a biomimetic delivery system (BDS) by loading doxorubicin (DOX)-loaded reduced graphene oxide (rGO) into a mouse macrophage-like cell line (RAW264.7), hoping that the newly constructed BDS could perfectly combine the tumor-tropic ability of macrophages and the photothermal property of rGO. RESULTS: At the same DOX concentration, the macrophages could absorb more DOX/PEG-BPEI-rGO than free DOX. The tumor-tropic capacity of RAW264.7 cells towards RM-1 mouse prostate cancer cells did not undergo significant change after drug loading in vitro and in vivo. PEG-BPEI-rGO encapsulated in the macrophages could effectively convert the absorbed near-infrared light into heat energy, causing rapid release of DOX. The BDS showed excellent anti-tumor efficacy in vivo. CONCLUSIONS: The BDS that we developed in this study had the following characteristic features: active targeting of tumor cells, stimuli-release triggered by near-infrared laser (NIR), and effective combination of chemotherapy and photothermotherapy. Using the photothermal effect produced by PEG-BPEI-rGO and DOX released from the macrophages upon NIR irradiation, MAs-DOX/PEG-BPEI-rGO exhibited a significant inhibitory effect on tumor growth.

Dummy molecularly imprinted polymers as the coating of stir bar for sorptive extraction of bisphenol A in tap water.

A unique stir bar coated with dummy molecularly imprinted polymers for bisphenol A was prepared by sol-gel technique. The scanning electron microscopic image of the coating presented a homogeneous surface with a thickness of about 57 ± 2.5 µm. The Fourier transform infrared spectrum of the coating proved the incorporating of dummy molecularly imprinted polymers with the sol-gel network. When used to extract bisphenol A from aqueous solution containing bisphenol A and its three analogs (4-tert-butylphenol, 4,4'-dihydroxybiphenyl, and 3,3',5,5'-tetrabromo-bisphenol A). Dummy molecularly imprinted polymers-coated stir bar showed better selectivity than the bars coated with polydimethylsiloxane or non-imprinted polymers. The extraction conditions including stirring speed, pH, and extraction time were optimized. After back extraction with methanol, the extracts were analyzed by high-performance liquid chromatography-fluorescence detection. The linear range was 0.0228-0.456 ng/mL with correlation coefficient of 0.9994 and the detection limit was about 5.70 × 10(-3) ng/mL based on three times ratio of signal-to-noise. The method was applied to the determination of trace bisphenol A in tap water.

Highly selective stir bar coated with dummy molecularly imprinted polymers for trace analysis of bisphenol A in milk.

A water compatible molecularly imprinted polymers (MIPs) coated stir bar for bisphenol A(BPA) was prepared with 3,3',5,5'-tetrabromobisphenol A as the dummy template molecule in this study. The dummy molecularly imprinted polymers coated stir bar (DMIPs-SB) showed better selectivity than the bars coated with polydimethylsiloxane or non-imprinted polymers when used to extract BPA and its three analogues. The saturated adsorption amount of the DMIPs coating was 3.0 times over that of the non-imprinted polymers coating. To achieve the optimum extraction performance, several parameters, including extraction and desorption time, pH value, adsorption temperature and stirring speed were investigated. The high-performance liquid chromatography combined with the DMIPs-SB was employed in the analysis of BPA in aqueous solution. The linear range of BPA concentration in aqueous medium was 0.0228-2.28 ng/mL with correlation coefficient of 0.9994 and the detection limit was about 6.84 × 10(-3) ng/mL based on three times ratio of signal to noise. This method was directly applied to the determination of trace BPA in milk with satisfactory results.

Versatile cationic liposomes for RIP3 overexpression in colon cancer therapy and RIP3 downregulation in acute pancreatitis therapy.

Because the induction of strong host antitumor responses plays a very important role in antitumor therapy, identifying effective approaches to elicit immunogenic cell death could have important implications. RIP3-dependent necroptotic cancer cells have been reported to release damage-associated molecular patterns and enhance antitumor immunity. In this study, hyaluronic acid-conjugated cationic liposomes (DOTAP/DOPE/PEG-DSPE/CHOL) (HA-P-LP) were prepared as a vector for mRIP3-pDNA overexpression in tumours. Compared with standard cationic liposomes, this vector markedly increased cellular gene internalisation in vitro, enhanced the tumour-targeting effect in vivo and exhibited a significant antitumor effect in combination with adjuvant chloroquine. Considering the dramatic increase in RIP3 under the pathological condition of pancreatitis and the correlation between pancreatitis and necroptosis, non-HA-conjugated liposomes with the same formulation loaded with shRNA mRIP3-pDNA effectively controlled the disease by decreasing the serum amylase concentration and inflammatory cell infiltration. The versatile cationic liposomes loaded with plasmids with opposing functions in this study provide a new concept and method for both tumour therapy and pancreatitis therapy.

Recent Advance in Polymer Based Microspheric Systems for Controlled Protein and Peptide Delivery.

Sustained-release systems made by biodegradable polymers for protein and peptide drug delivery have received considerable attention by academic researchers and major pharmaceutical companies around the world. Various types of biodegradable materials, including natural and synthetic polymers, have been applied to form protein and peptide drug carriers. Among these material candidates, poly lactic acid (PLA) and poly lactic-co-glycolic acid (PLGA) are the most commonly used biodegradable materials in the development of protein and peptide microspheres. In addition, many microsphere preparation technologies, including spray drying, coacervation, multiple emulsion solvent evaporation method and microporous membrane emulsification have been developed for microspheres preparation. In this review, we particularly summarize and briefly introduce the materials and methods that are used to fabricate microspheres as protein delivery systems. The existing opportunities and challenges for successful protein delivery are also discussed.

Dual agents loaded PLGA nanoparticles: systematic study of particle size and drug entrapment efficiency.

PLGA nanoparticles simultaneously loaded with vincristine sulfate (VCR) and quercetin (QC) were prepared via O/W emulsion solvent evaporation. Six independent processing parameters and PLGA characteristics were assessed systematically to enhance the incorporation of the dual agents with different properties (VCR and QC, hydrophilic and hydrophobic molecule, respectively) into PLGA nanoparticles and control particle size. Approaches investigated for the enhancement of drug entrapment efficiencies and the controlling of particle size included the influence of the molecular weight (MW) of PLGA and the lactide-to-glycolide (L:G) ratio of PLGA, PLGA concentration, PVA concentration, initial QC content, acetone-to-dichloromethane (A/D) volume ratio, aqueous phase pH and aqueous to organic phase (W/O) volume ratio. The nanoparticles produced by optimal formulation were submicron size (139.5+/-4.3 nm, n=3) with low polydispersity index (0.095+/-0.031, n=3). Nanoparticles observed by transmission electron microscopy (TEM) showed extremely spherical shape. The entrapment efficiencies determined by high performance liquid chromatography (HPLC) by ultracentrifuge method were 92.84+/-3.37% for VCR and 32.66+/-2.92% for QC (n=3). The drug loadings were 0.0037+/-0.0001% for VCR and 1.36+/-0.12% for QC (n=3).

PLGA nanoparticles simultaneously loaded with vincristine sulfate and verapamil hydrochloride: systematic study of particle size and drug entrapment efficiency.

PLGA nanoparticles simultaneously loaded with vincristine sulfate (VCR) and verapamil hydrochloride (VRP) were prepared via combining O/W emulsion solvent evaporation and salting-out method. Ten independent processing parameters and two materials characteristics were assessed systematically to enhance the incorporation of the two hydrophilic low molecular weight drugs into PLGA nanoparticles and minimize nanoparticles size. Approaches investigated for the enhancement of drug entrapment efficiencies and the minimization of particle size included the influence of the molecular weight (MW) of PLGA and the lactide to glycolide (L:G) ratio of PLGA, PLGA concentration, the degrees of hydrolyzation and polymerization of PVA, PVA concentration, initial VCR and VRP content, acetone to dichloromethane volume ratio, aqueous phase pH, salt concentration of aqueous phase, aqueous to organic phase volume ratio, sonication time, sonication energy and removal rate of organic solvents. The nanoparticles produced by optimal formulation were submicron size (111.4+/-2.35nm, n=3) and of low polydispersity (0.062+/-0.023, n=3). Nanoparticles observed by transmission electron microscopy (TEM) showed extremely spherical shape. The entrapment efficiencies determined with high performance liquid chromatogram (HPLC) by ultracentrifuge method were 55.35+/-4.22% for VCR and 69.47+/-5.34% for VRP, respectively (n=3).

Novel two-step release system for the traditional Chinese medicine compound Danshen.

A novel two-step release system for the traditional Chinese medicine compound Danshen was developed by combining an effervescent osmotic pump tablet (EOPT) and a pulsed-released tablet (PT) of compound Danshen into one hard capsule. The EOPT of Danshen was prepared with sodium chloride, mannitol, hydroxypropylmethylcellulose (HPMC), and sodium bicarbonate as osmotic agents. The osmotic pressure from EOPT was greatly enhanced by carbon dioxide generated from the reaction between sodium bicarbonate and acidic components from Danshen. It was shown that the tested Danshen components could be completely released from the prepared EOPT following a zero-order release for up to 12 h. The PT of compound Danshen was a three-layer coated tablet composed of organic acid and osmotic agents. Eudragit RL, HPMC and the mixture of EC and Eudragit RS, RL were the major constituents of the separation layer, swelling layer and controlling release membrane, respectively. The swelling test of the PT indicated that swelling is a prerequisite for drug release from this PT device. In addition, the swelling behavior further suggested the drug release mechanism of PT involves diffusion, the osmotic pumping effect, and organic acid-induced effect, among which the osmotic pumping effect was the most important. Moreover, there was no significant difference among the five active constituents in their release profiles from the final combined two-step release system of compound Danshen.

Receptor-mediated gene delivery by folate-poly(ethylene glycol)-grafted-trimethyl chitosan in vitro.

Folate-poly(ethylene glycol)-grafted-trimethyl chitosan (F-PEG-g-TMC) and methoxypolyethylene glycol-grafted-trimethyl chitosan (mPEG-g-TMC)/pDNA complexes were prepared and characterized concerning physicochemical properties including cytotoxicity, condensation efficiency, particle size, and zeta potential. Furthermore, cellular uptake and transfection efficiency of the complexes were evaluated in vitro and compared with that of folate-trimethyl chitosan (folate-TMC) synthesized by our group to elucidate the effect of PEGylation. The cellular uptake of the F-PEG-g-TMC/pDNA with a copolymer nitrogen-to-DNA phosphate ratio (N/P ratio) of 20 in KB cells was specifically increased up to 1.68-fold compared with that of the mPEG-g-TMC/pDNA (N/P ratio 20) resulting in 1.5-fold and 1.4-fold increased transfection efficiency in KB cells and SKOV3 cells (folate receptor-overexpressing cell lines), respectively. The intracellular uptake and transfection efficiency of the F-PEG-g-TMC/pDNA were significantly enhanced relative to the folate-TMC/pDNA in folate receptor-overexpressing cells due to stabilizing effect of PEGylation. Subcellular localization of the complexes in the process of intracellular transportation was observed by confocal laser scanning microscopy suggesting quicker association of the F-PEG-g-TMC/pDNA. In conclusion, the F-PEG-g-TMC/pDNA complexes are potential vehicles for improving the transfection efficiency and specificity of gene.

Preparation of dummy template imprinted polymers at surface of silica microparticles for the selective extraction of trace bisphenol A from water samples.

Molecularly imprinted polymers for bisphenol A (BPA) were prepared by using surface molecular imprinting technique. Analogues of BPA, namely 4,4'-dihydroxybiphenyl and 3,3',5,5'-tetrabromobisphenol A, were used as the dummy templates instead of BPA, to avoid the leakage of a trace amount of the target analyte (BPA). The resulting dummy molecularly imprinted polymers (DMIPs) showed the large sorption capacity, high recognition ability and fast binding kinetics for BPA. The maximal sorption capacity was up to 958 micromol g(-1), and it only took 40 min for DMIPs to achieve the sorption equilibrium. The DMIPs were successfully applied to the solid-phase extraction coupled with HPLC/UV for the determination of BPA in water samples. The calibration graph of the analytical method was linear with a correlation coefficient more than 0.999 in the concentration range of 0.0760-0.912 ng mL(-1) of BPA. The limit of detection was 15.2 pg mL(-1) (S/N=3). Recoveries were in the range of 92.9-102% with relative standard deviation (RSD) less than 11%. The trace amounts of BPA in tap water, drinking water, rain and leachate of one-off tableware were determined by the method built, and the satisfactory results were obtained.

Preparation and characterization of folate-poly(ethylene glycol)-grafted-trimethylchitosan for intracellular transport of protein through folate receptor-mediated endocytosis.

To develop a receptor-mediated intracellular delivery system that can transport therapeutic proteins to specific tumor cells, folate-poly(ethylene glycol)-grafted-trimethylchitosan (folate-PEG-g-TMC) was synthesized. Nano-scaled spherical polyelectrolyte complexes between the folate-PEG-g-TMC and fluorescein isothiocyanate conjugated bovine serum albumin (FITC-BSA) were prepared under suitable weight ratio of copolymer to FITC-BSA by ionic interaction between the positively charged copolymers and the negatively charged FITC-BSA. Intracellular uptake of FITC-BSA was specifically enhanced in SKOV3 cells (folate receptor over-expressing cell line) through folate receptor-mediated endocytosis compared with A549 cells (folate receptor deficient cell line). Folate-PEG-g-TMC shows promise for intracellular transport of negatively charged therapeutic proteins into folate receptor over-expressing tumor cells.

Reversion of multidrug resistance by co-encapsulation of vincristine and verapamil in PLGA nanoparticles.

Multidrug resistant (MDR) cancer may be treated using combinations of encapsulated cytotoxic drugs and chemosensitizers. To optimize the effectiveness of this combinational approach, poly(d,l-lactide-co-glycolide acid) (PLGA) nanoparticles formulations capable of delivering a cytotoxic drug, vincristine, a chemosensitizer, verapamil, or their combination were prepared via combining O/W emulsion solvent evaporation and salting-out method. Moreover, this work evaluated a number of approaches for the administration of chemosensitizer-cytotoxic drug combinations in a systematic fashion. The results showed that the administration sequence of anticancer drug and chemosensitizer was critical for maximal therapeutic efficacy and the simultaneous administration of vincristine and verapamil could achieve the highest reversal efficacy. In addition, PLGA nanoparticles (PLGANPs) showed moderate MDR reversal activity on MCF-7/ADR cells resistant to vincristine. The dual-agent loaded PLGA nanoparticles system resulted in the similar cytotoxicity to one free drug/another agent loaded PLGANPs combination and co-administration of two single-agent loaded PLGANPs, which was slightly higher than that of the free vincristine/verapamil combination. Co-encapsulation of anticancer drug and chemosensitizer might cause lower normal tissue drug toxicity and fewer drug-drug interactions. Therefore, we speculate that PLGANPs simultaneously loaded with anticancer drug and chemosensitizer might be the most potential formulation in the treatment of drug resistant cancers in vivo.