Shan Zhao

Modeling and optimization of membrane preparation conditions of the alginate‐based microcapsules with response surface methodology

Microencapsulation has been a promising approach for drug delivery, cell implantation, cell-based gene therapy and large-scale cell culture. To make use of microcapsules more effectively, it is important to accurately construct the microcapsule membranes with desired properties including a certain thickness, strength, and so forth. To date single factor experiments have been widely used, however, they are time-consuming to obtain the desired membrane preparation conditions. Response surface methodology (RSM) is a mathematical and statistical technique for building empirical models that gained importance for optimizing reacting conditions. In this study, three signifficant effect factors that affect alginate-based microcapsule membrane properties, including membrane thickness, swelling degree, and mechanical stability, were determined with Plackett-Burman method, and then three empirical models were built to optimize the preparation conditions of the microcapsule membranes according to the responses of these three signifficant effect factors respectively with RSM. These models can be used to predict the characteristics of microcapsules under different membrane preparation conditions, which provide a guide for optimizing the microencapsulation technology.

Role of three‐dimensional matrix stiffness in regulating the chemoresistance of hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) was the most common primary liver cancer, and its resistance to anti‐tumor drugs often caused the death of patients suffering with HCC. Matrix stiffness was reported to be closely related to tumor chemoresistance; however, the relationship between HCC drug resistance and three‐dimensional (3D) matrix stiffness is still unclear at present. In this study, alginate gel (ALG) beads with controllable matrix stiffness were used to mimic tumor tissue rigidity, and the role of 3D matrix stiffness in regulating the chemoresistance of HCC cells was investigated by using these ALG beads. It was found that HCC cells in ALG beads with 105 kPa stiffness had highest resistance to paclitaxel, 5‐FU, and cisplatin. Although the mechanism was still uncovered, ABC transporters and endoplasmic reticulum stress‐related molecules were highly expressed in ALG bead‐encapsulated HCC cells compared with two‐dimensional‐cultured cells, which suggested a very complex mechanism underlying HCC drug resistance in 3D culture conditions. In addition, to mimic the specific stiffness of HCC tumor tissue, or other tumor tissues in vivo, response surface methodology (RSM) was used to build up a prediction mathematical model so that ALG beads with desired matrix stiffness could be prepared by simply changing three factors: molecular weight, G content, and alginate concentration.

Influence of Microemulsion–Mucin Interaction on the Fate of Microemulsions Diffusing through Pig Gastric Mucin Solutions

Mucus layer, a selective diffusion barrier, has an important effect on the fate of drug delivery systems in the gastrointestinal tract. To study the fate of microemulsions in the mucus layer, four microemulsion formulations with different particle sizes and lipid compositions were prepared. The microemulsion-mucin interaction was demonstrated by the fluorescence resonance energy transfer (FRET) method. Moreover, the microemulsions were observed aggregated into micron-sized emulsions by laser confocal microscopy. We concluded the microemulsion-mucin interaction not only led to microemulsions closely adhered to mucins but also destroyed the structure of microemulsions. At last, the diffusion of blank microemulsions and microemulsion-carried drugs (resveratrol and hymecromone) through mucin solutions was determined by the fluorescence recovery after photobleaching (FRAP) method and the Franz diffusion cell method. The results demonstrated the diffusion of microemulsions was significantly hindered by mucin solutions. The particle size of microemulsions had a negligible effect on the diffusion coefficients. However, the type of lipid played an important role, which could form hydrophobic interactions with mucins. Interestingly, microemulsion-carried drugs with different core/shell locations seemed to suffer different fates in the mucin solutions. The drug incorporated in the oil core of microemulsions, resveratrol, was transported through the mucus layer by the carriers, while the drug incorporated in the surfactant shell of microemulsions, hymecromone, was separated from the carriers and diffused toward the epithelium in the form of free molecules.

Effect of Lipolysis on Drug Release from Self-microemulsifying Drug Delivery Systems (SMEDDS) with Different Core/Shell Drug Location

The objective of this study is to investigate the effect of lipolysis on the release of poorly water-soluble drug from SMEDDS in the perspective of drug core/shell location. For this purpose, four SMEDDS formulations with various core/shell properties were developed based on long-chain lipid or medium-chain lipid as well as different surfactant/oil ratios. Poorly water-soluble drugs, hymecromone and resveratrol, were significantly solubilized in all SMEDDS formulations and the diluted microemulsions. Fluorescence spectra analysis indicated that hymecromone was mainly located in the shell of microemulsions, while resveratrol was located in the core. The effect of lipolysis on the release rates of drugs with different core/shell locations were investigated by a modified in vitro drug release model. For the drug located in the shell, hymecromone, the release profiles were not affected during the lipolysis process and no significant differences were observed among four formulations. For the drug located in the core, resveratrol, the release rates were increased to various degrees depending on the extent of digestion. In conclusion, the drug core/shell location plays an important role for determining the effect of lipolysis on drug release from SMEDDS formulation.

Evaluate the ability of PVP to inhibit crystallization of amorphous solid dispersions by density functional theory and experimental verify.

&NA; In this study, we used density functional theory (DFT) to predict polymer‐drug interactions, and then evaluated the ability of poly (vinyl pyrrolidone) (PVP) to inhibit crystallization of amorphous solid dispersions by experimental‐verification. Solid dispersions of PVP/resveratrol (Res) and PVP/griseofulvin (Gri) were adopted for evaluating the ability of PVP to inhibit crystallization. The density functional theory (DFT) with the B3LYP was used to calculate polymer‐drug and drug‐drug interactions. Fourier transform infrared spectroscopy (FTIR) was used to confirm hydrogen bonding interactions. Polymer‐drug miscibility and drug crystallinity were characterized by the modulated differential scanning calorimetry (MDSC) and X‐ray powder diffraction (XRD). The release profiles were studied to investigate the dissolution advantage. DFT results indicated that EPVP‐Res > ERes‐Res (E: represents hydrogen bonding energy). A strong interaction was formed between PVP and Res. In addition, Fourier transform infrared spectroscopy (FTIR) analysis showed hydrogen bonding formed between PVP and Res, but not between PVP and Gri. MDSC and XRD results suggested that 70–90 wt% PVP/Res and PVP/Gri solid dispersions formed amorphous solid dispersions (ASDs). Under the accelerated testing condition, PVP/Res dispersions with higher miscibility quantified as 90/10 wt% were more stable than PVP/Gri dispersions. The cumulative dissolution rate of 90 wt% PVP/Res dispersions still kept high after 90 days storage due to the strong interaction. However, the cumulative dissolution rate of PVP/Gri solid dispersions significantly dropped because of the recrystallization of Gri. Graphical abstract Figure. No caption available.

Effect of plasma components on the stability and permeability of microcapsule

Immobilization of hepatocytes in microcapsules has been a potentially alternative methodology for bioartificial livers (BALs). Moreover, the stability and permeability are the key parameters of these microcapsules. However, these alginate-based microcapsules are unstable if the surrounding medium disrupts the ionic interactions between alginate and the polycation. As hundreds of components are included in human plasma, the stability and permeability in plasma of microcapsules need to be sufficiently investigated. In the present study, the stability of three kinds of alginate-based microcapsules was evaluated when they were immersed in plasma. Our results showed that stability of alginate-α-poly (L-lysine)-alginate (α-APA) microcapsules was well maintained, better than those of alginate-ε-poly (L-lysine)-alginate (ε-APA) and alginate-chitosan-alginate (ACA) microcapsules. Also, factors affecting the stability of microcapsules in plasma were analyzed and it showed that heparin was the key factor that affected the stability of α-APA microcapsules, whereas heparin and low molecular electrolytes such as HCO3(-) and H2 PO4(-)/HPO4(2-) were the factors to ε-APA and ACA microcapsules. In addition, the permeability evaluation showed no decrease in permeability of microcapsules after incubation in plasma. Our study might provide a foundation for the selection and modification of materials for microcapsule-based BAL devices.

Gastroretentive drug delivery systems for the treatment of Helicobacter pylori

Helicobacter pylori (H. pylori) is one of the most common pathogenic bacterial infections and is found in the stomachs of approximately half of the worlds population. It is the primary known cause of gastritis, gastroduodenal ulcer disease and gastric cancer. However, combined drug therapy as the general treatment in the clinic, the rise of antibiotic-resistant bacteria, adverse reactions and poor patient compliance are major obstacles to the eradication of H. pylori. Oral site-specific drug delivery systems that could increase the longevity of the treatment agent at the target site might improve the therapeutic effect and avoid side effects. Gastroretentive drug delivery systems potentially prolong the gastric retention time and controlled/sustained release of a drug, thereby increasing the concentration of the drug at the application site, potentially improving its bioavailability and reducing the necessary dosage. Recommended gastroretentive drug delivery systems for enhancing local drug delivery include floating systems, bioadhesive systems and expandable systems. In this review, we summarize the important physiological parameters of the gastrointestinal tract that affect the gastric residence time. We then focus on various aspects useful in the development of gastroretentive drug delivery systems, including current trends and the progress of novel forms, especially with respect to their application for the treatment of H. pylori infections.

Natural Anionic Polymer Acts as Highly Efficient Trypsin Inhibitor Based on an Electrostatic Interaction Mechanism

Sodium alginate (SA), acting as a trypsin inhibitor by means of electrostatic interaction, is studied. The half-maximal inhibitory concentration (IC50 = 0.05 μg mL(-1) ) of this natural anionic polymer is about 400 times lower than that of commercial soybean trypsin inhibitor (STI). Unlike the Ca(2+) -deprivation mechanisms, its inhibition may be attributed to preventing the trypsin active site (TAS) from accessing the macromolecular substrates instead of denaturing it. SA is an efficient, innocuous, and cost-effective inhibitory excipient that can be conveniently used in many peptide and protein dosage formulations.

The relationship between the inflammatory response and cell adhesion on alginate–chitosan–alginate microcapsules after transplantation

Cell microencapsulation technology is a potential alternative therapy, but cell overgrowth and adhesion on the microcapsules after transplantation shortens their time of therapeutic efficacy. Inflammatory cells were the main cells that adhered to the microcapsules, so understanding the bodys inflammatory processes would help to better identify the mechanisms of cell adhesion to the outer surface of the microcapsules. Our study measured the inflammatory cells and the cytokines and characterized the associated changes in the alginate-chitosan-alginate (ACA) microcapsules 1, 7, 14, and 28 days after implantation in the peritoneal cavity. Then the relationship between the inflammatory response and cell adhesion on the microcapsules was evaluated by multiple regression analysis. The results showed that the microcapsules did not evoke a systemic inflammatory response, but initiated a local inflammatory response in the peritoneal cavity. Furthermore, the correlation analysis showed that the level of cell adhesion on the microcapsules was related to the number of lymphocytes and macrophages, and the amount of IL-6, IL-10, and MCP-1 in the peritoneal cavity. Our results may provide a foundation for reducing the immune response to these microcapsules, prolonging graft survival and improving the efficacy of these treatments.

Study of chemical characteristics, gelation properties and biological application of calcium pectate prepared using apple or citrus pectin

The most notable and unique property of pectin is the ability to form gel; thus, many biological applications of pectin are based on its gelation properties. Pectin isolated from different plant cell walls may differ in molecular structure and distribution pattern, which may result in different gelling and function properties. In this work, we investigated the chemical characteristics, gelation properties, and biological application of calcium pectate (CaP) prepared using apple (AP) or citrus pectin (CP). These two types of pectins exhibited similar molecular parameters and glycosidic bone structure; however, there was a difference in the composition proportion of single monosaccharide. In addition, it was found that it was relatively easier to form CaP beads with CP compared with AP. Moreover, CP exhibited a higher binding capability with Ca2+. The morphological study suggests that CP-CaP beads have a rough wrinkle structure on the surface, which might benefit mass transfer and cell proliferation. Moreover, although there are some differences in the viability and proliferation of cells encapsulated in the AP-CaP and CP-CaP beads, both can be used for cell encapsulation.