Preparation and characterization of TAM-loaded HPMC/PAN composite fibers for improving drug-release profiles

The present paper reports the preparation and characterization of composite hydroxypropyl methylcellulose/polyacrylonitrile (HPMC/PAN)-medicated fibers via a wet spinning technique. Tamoxifen (TAM) was selected as a model drug. Numerous analyses were conducted to characterize the mechanical, structure and morphology properties of the composite fibers. The drug content and in vitro dissolution behavior were also investigated. SEM images showed that the TAM-loaded HPMC/PAN composite fibers had a finger-like outer skin and a porous structure. FT-IR spectra demonstrated that there was a good compatibility between polymer and drug. Results from X-ray diffraction and DSC suggested that most of the incorporated TAM was evenly distributed in the fiber matrix in an amorphous state, except for a minority that aggregated on the surface of fibers. The drug content in the fibers was lower than that in the spinning solution and about 10% of TAM was lost during spinning process. In vitro dissolution results indicated that, compared to TAM-PAN fibers, HPMC/PAN composite systems had weaker initial burst release effects and more drug-loading. The combination of hydrophilic polymer HPMC with PAN could improve the performance of polymer matrix composite fibers in regulating the drug-release profiles.     

Artemisinin–Polyvinylpyrrolidone Composites Prepared by Evaporative Precipitation of Nanosuspension for Dissolution Enhancement

Nanoparticles of a poorly water-soluble anti-malarial drug, artemisinin (ART), and its composite particles with a hydrophilic polymer, polyvinylpyrrolidone (PVP), were synthesized using a nanofabrication method called the evaporative precipitation of nanosuspension (EPN). ART nanoparticles and ART/PVP composite particles containing ART nanoparticles coated with PVP were successfully prepared with the aim of improving the dissolution rate of ART. The effect of polymer concentration on the physical and morphological properties, and dissolution rate of the EPN-prepared ART/PVP composite particles was investigated. The crystallinity of ART nanoparticles decreased with increasing polymer concentration, as suggested by the differential scanning calorimetry and X-ray diffraction studies. The phase solubility studies revealed an A_L-type of curve, indicating a linear increase in the drug solubility with PVP concentration. The dissolution of the ART nanoparticles and ART/PVP composite particles markedly increased as compared to that of the original ART powder due to lower particle size and reduced crystallinity of the drug particles. The percent dissolution efficiency (DE), relative dissolution (RD), t _75% and similarity factor (f ₂) were calculated for the statistical analysis. Various mathematical models, viz., zero-order, first-order, Korsemeyer–Peppas and Higuchi, were applied to fit the experimental drug-dissolution data and diffusion was found to be the drug release mechanism.     

Biodegradable polyhydroxyalkanoate implants for osteomyelitis therapy: in vitro antibiotic release

Various random copolyesters of 3-hydroxybutyrate and 3-hydroxyvalerate (PHBV) and 3-hydroxybutyrate and 4-hydroxybutyrate P(3HB-4HB) were used in the construction of biodegradable, implantable rods for the local delivery of antibiotics (Sulperazone^® and Duocid^®) in chronic osteomyelitis therapy. Drug loading, type of active agent, and additional coating of the implant surface all have significant contributions to the in vitro release profile. The rate and duration of Sulperazone^® release from P(3HB-4HB) rods were controlled by the polymer/drug ratio (drug loading). The rate of drug dissolution was substantially higher than that of polymer degradation. Therefore, the release phenomenon was more dependent on drug dissolution rather than on polymer degradation or diffusion. Coating rods with the same type of polymer substantially reduced the initial burst effect observed with the uncoated rods, and significantly decreased the release rate so that the release kinetics became almost zero order. Antibiotic release from coated rods was sustained for over a period of 2 weeks at a constant rate, whereas uncoated rods released their contents in less than a week. Impregnation of Duocid^® into the hydrophobic polymer matrix yielded a rod with a smoother surface topography. The release from these rods was significantly higher than for rods loaded with Sulperazone^® and a zero order release could not be obtained with these samples.     

Preparation and characterization of bioadhesive controlled-release gels of cidofovir for vaginal delivery

The aim of this study was to develop mucoadhesive and thermosensitive gels for vaginal delivery that would be able to provide a controlled release of the model drug, cidofovir. The study also monitored the drug’s potential antiviral properties. Cidofovir was put into the form of a vaginal gel, using mucoadhesive and thermosensitive polymers such as chitosan, Carbopol 974P, HPMC, and poloxamer 407. The physicopharmaceutical properties and stability of the vaginal gel formulations were evaluated. The gel formulation which was prepared with HPMC K100M exhibited the highest viscosity, as well as maximum adhesiveness, cohesiveness, and mucoadhesion values. The results of antiviral activity studies, which used the bovine herpes virus type 1 virus infection in vitro model using Vero cells, demonstrated the antiherpetic effect of the cidofovir gel containing HPMC K100M, at least under in vitro conditions. The study found that a mucoadhesive vaginal gel containing cidofovir can be a promising and innovative alternative therapeutic system for the treatment of genital herpes simplex virus and human papilloma virus induced infections in women.     

Orthogonal experimental preparation of Sanguis Draconis- Polyvinylpyrrolidone microfibers by electrospinning

How to improve the bioavailability of the Sanguis Draconis (SD) is an important problem in the potential clinical applications. The aim of this study was to develop a drug delivery system to achieve high bioavailability of SD, a drug with poor water solubility. It will promote the research about new formulations of the SD and the other insoluble drugs. In this study, a highly biocompatible hydrophilic polymer, polyvinylpyrrolidone (PVP), was selected as a carrier, mixed with different proportions of SD to produce SD-PVP microfibers by solution electrospinning. By orthogonal experiments, the optimal spinning conditions of the preparation of SD-PVP fibers were investigated. The morphology of different proportions of SD-PVP microfibers was observed by scanning electron microscopy, and the phase characteristics were characterized by Fourier transform infrared spectrometry, X-ray diffraction, and differential scanning calorimetry. The hydrophilic properties of SD-PVP fiber membranes with different SD content were analyzed by the water contact angle assay. In vitro dissolution experiments were carried out to observe the dissolution of drugs in SD-PVP fiber membranes. The results showed that the diameter of SD-PVP fibers increased with the enlargement of SD content. A eutectic mixture was formed after blending PVP and SD, and the hydrogen bonds were formed between the SD and PVP with no chemical reaction occurred. The dispersion of SD in the fiber decreased with the increase of SD content. The higher the content of SD in the fiber, the more hydrophobic the fiber membrane. In vitro dissolution studies revealed that the dissolution content of SD from SD-PVP microfibers was significantly higher than that of the pure or original drug SD. However, as the SD content increased from 15% to 30%, the dissolution of the drug in the SD-PVP fibers decreased. The SD-PVP fiber prepared in this study showed much higher solubility than the original drug in vitro, which has great significance for the development of new dosage forms for the clinical application of SD, and it has a useful reference for the study of similar bioavailability of poorly soluble drugs.     

琥珀酸美托洛尔HPMC骨架片释放影响因素研究

以羟丙基甲基纤维素（HPMC）为骨架材料，乙基纤维素（EC）为阻滞剂，采用湿颗粒压片法制备琥珀酸美托洛尔亲水凝胶骨架片，考察HPMC用量、HPMC黏度、EC用量、制备方法、压片压力、释放介质及转速对琥珀酸美托洛尔（MS）骨架片体外释药的影响。结果表明，MS骨架片体外释药符合Higuchi方程，药物释放机制是骨架溶蚀和药物扩散的综合效应；HPMC用量与黏度、阻滞剂用量、制备方法、压片压力对释放速率均有显著性影响；释放介质的pH值及转速对释放速率无显著性影响。     

Properties of Antibacterial Polypropylene/Nanometal Composite Fibers

Melt spinning of polypropylene fibers containing silver and zinc nanoparticles was investigated. The nanometals were generally uniformly dispersed in polypropylene, but aggregation of these materials was observed on fiber surface and in fiber cross-sections. The mechanical properties of the resulted composite fibers with low concentration of nanometal were comparable to those for the control PP yarns. Extruded composite fibers that contained 0.72% silver and 0.60% zinc nanoparticles had outstanding antibacterial efficacy as documented by the percentage count reduction growth of Escherichia coli and Staphylococcus aureus. Fibers containing silver particles had improved antistatic properties.     

Three-dimensional prostate tumor model based on a hyaluronic acid-alginate hydrogel for evaluation of anti-cancer drug efficacy

In vitro cell-based assays are widely applied to evaluate anti-cancer drug efficacy. However, the conventional approaches are mostly based on two-dimensional (2D) culture systems, making it difficult to recapitulate the in vivo tumor scenario because of spatial limitations. Here, we develop an in vitro three-dimensional (3D) prostate tumor model based on a hyaluronic acid (HA)-alginate hybrid hydrogel to bridge the gap between in vitro and in vivo anticancer drug evaluations. In situ encapsulation of PCa cells was achieved by mixing HA and alginate aqueous solutions in the presence of cells and then crosslinking with calcium ions. Unlike in 2D culture, cells were found to aggregate into spheroids in a 3D matrix. The expression of epithelial to mesenchyme transition (EMT) biomarkers was found to be largely enhanced, indicating an increased invasion and metastasis potential in the hydrogel matrix. A significant up-regulation of proangiogenic growth factors (IL-8, VEGF) and matrix metalloproteinases (MMPs) was observed in 3D-cultured PCa cells. The results of anti-cancer drug evaluation suggested a higher drug tolerance within the 3D tumor model compared to conventional 2D-cultured cells. Finally, we found that the drug effect within the in vitro 3D cancer model based on HA-alginate matrix exhibited better predictability for in vivo drug efficacy.     

Preparation of Budesonide-Loaded Polycaprolactone Nanobeads by Electrospraying for Controlled Drug Release

Corticosteroids such as budesonide are the drugs of choice for the treatment of inflammatory disorders with an inherent limitation, viz., rapid elimination. To overcome this constraint and attain sustained release, budesonide was encapsulated in a biodegradable polymer, polycaprolactone (PCL), by DC electrospraying. By varying the experimental parameters involved in electrospraying such as applied voltage, flow rate, viscosity as well as conductivity of the polymer solution, the dimensionality of nanostructures was tuned from 1-D nanofibers to spherical nanoparticles. By adopting this rapid and viable method of DC electrospraying, we successfully prepared aqueous suspensions of nearly monodispersed, nano-sized drug encapsulated PCL. Drug encapsulation efficiency, in vitro drug release as well as biocompatibility studies of budesonide-loaded PCL nanobeads were carried out. The cytocompatible nanobeads prepared by electrospraying exhibited good encapsulation efficiency (approx. 75%), with controlled drug release enabled by the dissolution of the polymer. Our results demonstrate the potential of this novel technique of electrospraying in developing efficient drug encapsulated polymeric nanocarriers possessing sustained drug release profile.     

Matrix Modifications Modulate Ophthalmic Drug Delivery From Photo-Cross-Linked Poly(propylene Fumarate)-Based Networks

In this work, different modifications of photo-cross-linked poly(propylene fumarate)/poly(N-vinyl pyrrolidone) (PPF/PNVP) matrices were studied for their effect on the release kinetics of two ophthalmic drugs. The hydrophilicity of solid PPF/PNVP matrices loaded with acetazolamide (AZ) or timolol maleate (TM) was increased by adding various amounts of poly(ethylene glycol) (PEG) or by increasing the amount of N-vinyl pyrrolidone (NVP) in the polymer mixture prior to cross-linking. The in vitro release studies that utilized high-performance liquid chromatography for quantification revealed highly accelerated drug release from the matrices with increasing contents of the hydrophilic modifier. AZ was released from matrices containing 5% PEG in 56 days, which equals approximately 25% of the release period found for the unmodified matrices. A comparable acceleration in drug release was found for TM-loaded samples modified with 5% PEG. These studies further revealed that 1% PEG is sufficient to shorten the TM release duration by one-third. A significant acceleration in drug release was also found for the samples that were fabricated from a PPF–NVP mixture with increased NVP content. Matrix water content and erosion were assessed gravimetrically. Micro-computed tomography was used to image structural changes of the release systems and shed light on the drug-release mechanism. This study showed that hydrophilic matrix modifications of PPF/PNVP matrices accelerate the drug release of two ophthalmic drugs and represent a suitable tool to adjust drug-release rates from PPF-based matrices for different therapeutic needs.     

Fabrication of Nano-fibrous PLLA Scaffold Reinforced with Chitosan Fibers

In this study, a nano-fibrous PLLA scaffold reinforced by micro-scale chitosan fibers was fabricated using thermally-induced phase separation (TIPS). The morphology, porosity, mechanical performance and pH changes in in vitro degradation of the scaffold were also investigated. Results showed that the mechanical properties of the scaffold increased with the amount of chitosan fibers embedded, and the pH in in vitro degradation of the scaffold changed more slowly than that of the pure nano-fibrous PLLA scaffold without chitosan fibers. The new composite scaffold might be a very promising scaffold for tissue engineering.     

A strategy for controlling degradation in vitro of carbon fiber-reinforced polylactic acid composites (by combining fiber modification and pulsed electromagnetic fields)

Abstract

Carbon fiber-reinforced polylactic acid (C/PLA) composites are a human bone-fixation material, but control of the material’s degradation remains a major factor hindering its widespread use. In this study, a combined method for controlling the degradation performance in vitro of C/PLA composites was designed. In this strategy, carbon fibers for C/PLA composite reinforcement were prepared in both modified and unmodified forms. A pulsed electromagnetic field (PEF) was then selectively applied during the subsequent degradation process. Results and analysis showed that the interfacial ester bonding between modified carbon fibers and PLA matrices significantly affected degradation in vitro of C/PLA composite. However, PEF affected the degradation performance of C/PLA composites and, after PEF treatment, the material's water absorption, mass retention, and bending and shearing strengths were changed to varying degrees. This method, by combining fiber modification and pulsed electromagnetic fields (abbreviated as CMP) provided a new strategy for the controlled degradation of C/PLA composites in human skeletal fixation.     

In vitro and in vivo degradation of non-woven materials made of poly(ε-caprolactone) nanofibers prepared by electrospinning under different conditions

The aim of this study was to prepare non-woven materials from a biodegradable polymer, poly(ε-caprolactone) (PCL) by electrospinning. PCL was synthesized by ring-opening polymerization of ε-caprolactone in bulk using stannous octoate as the catalyst under nitrogen atmosphere. PCL was then processed into non-woven matrices composed of nanofibers by electrospinning of the polymer from its solution using a high voltage power supply. The effects of PCL concentration, composition of the solvent (a mixture of chloroform and DMF with different DMF content), applied voltage and tip–collector distance on fiber diameter and morphology were investigated. The diameter of fibers increased with the increase in the polymer concentration and decrease in the DMF content significantly. Applied voltage and tip–collector distance were found critical to control 'bead' formation. Elongation-at-break, ultimate strength and Young's modulus were obtained from the mechanical tests, which were all increased by increasing fiber diameter. The fiber diameter significantly influenced both in vitro degradation (performed in Ringer solution) and in vivo biodegradation (conducted in rats) rates. In vivo degradation was found to be faster than in vitro. Electrospun membranes were more hydrophobic than PCL solvent-casted ones; therefore, their degradation was a much slower process.     

Polyethylene‐Assisted Exfoliation of Hexagonal Boron Nitride in Composite Fibers: A Combined Experimental and Computational Study

A joint experimental and computational approach is used to explore the exfoliation mechanism for hexagonal boron nitride (h‐BN) in polyethylene (PE)/h‐BN composite fibers during hot‐drawing. A shear‐flow gel‐spinning apparatus is utilized to fabricate PE/h‐BN composite fibers with 11 wt% h‐BN loading. Different exfoliation states of the h‐BN platelets before and after hot‐drawing are experimentally examined using wide‐angle X‐ray diffraction and Raman spectroscopy. Compared with the undrawn (as‐spun) fibers, both analyses show that the intensity of the major h‐BN peaks attributed to interlayer interaction significantly decreased for the drawn fibers, suggesting exfoliation of the h‐BN. A full atomistic steered molecular dynamics approach is used to obtain baseline force and work required for h‐BN layer separation, as well as to simulate the h‐BN exfoliation behavior as a result of the PE matrix shearing effect in the composite. Computational results indicate that a large interactive area between the polymer and the fillers is required to induce enough stress transfer to exceed the h‐BN exfoliation force/energy threshold. Once this threshold is achieved, complete exfoliation of the platelets to monolayer h‐BN is demonstrated. By understanding the relationship between interfacial area and interaction strength between polymer matrix and fillers, this work provides new insight toward use of polymers for producing mono‐ and few‐layered h‐BN.

     

M2 polarization of tumor-associated macrophages is dependent on integrin β3 via peroxisome proliferator-activated receptor-γ up-regulation in breast cancer

Macrophages are particularly abundant and play an important role throughout the tumor progression process, namely, tumor-associated macrophages (TAM) in the tumor microenvironment. TAM can be polarized to disparate functional phenotypes, the M1 and M2 macrophages. M1-like type macrophages are defined as pro-inflammatory cells involved in killing cancer cells, while M2-like type cells can specially promote tumor growth and metastasis, tissue remodeling and immunosuppression. In this study, we first found that integrin β3 was highly expressed on the surface of TAM, both in vivo and in vitro, that displayed the M2-like characteristics. Under intervention of CYC or triptolide, the integrin β3 inhibitors, the M2 polarization of TAM could be inhibited. Moreover, in the cell model of M2 polarization, either blockade or knockout/knockdown of integrin β3 could also suppress macrophage M2 polarization, which suggested that the M2 polarization was dependent on integrin β3. Using knockdown of peroxisome proliferator-activated receptor-γ (PPARγ), an M2 regulator, we found that expression and activation of PPARγ participated in M2 polarization that was mediated by integrin β3. Finally, to verify the activity of integrin β3 inhibitors on TAM in vivo, 4T1 tumor-bearing mice were treated with CYC or triptolide; in response, the M1/M2 ratio of TAM was up-regulated, while the infiltration of total lymphocytes into tumor tissue was not altered. In general, our study found a connection between integrin β3 and macrophage polarization, which provides a strategy for facilitating M2 to M1 repolarization and reconstructing the tumor immune microenvironment.     

Biodegradable poly(vinyl alcohol)/polyoxalate electrospun nanofibers for hydrogen peroxide-triggered drug release

Release of drugs in a controlled and sustainable manner is of great interest for treating some inflammatory diseases, drug delivery, and cosmetics. In this work, we demonstrated the control release of a drug from composite nanofibers mediated by hydrogen peroxide. Composite nanofibers of polyvinyl alcohol (PVA)/polyoxalate (PVA/POX NFs) blended at various weight ratios were successfully prepared by electrospinning. Rhodamine B (RB) was used as a model of drug and was initially loaded into the POX portion. The morphology of NFs was characterized using scanning electron microscopy (SEM). The functional groups presented in the NFs were characterized using IR spectroscopy. In vitro release behavior and cell toxicity of nanofibers were also investigated using the MTT assay. The results indicated that POX content had a significant effect on the size and release profiles of nanofibers. Microstructure analysis revealed that sizes of PVA/POX NFs increased with increasing POX content, ranging from 214 to 422 nm. Release profiles of RB at 37 °C were non-linear and showed different release mechanisms. The mechanism of drug release depended on the chemical composition of the NFs. RB release from the NFs with highest POX content was caused by the degradation of the nanofiber matrix, whereas the RB release in lower POX content NFs was caused by diffusion. The NFs with POX showed a loss of structural integrity in the presence of hydrogen peroxide as seen using SEM. The MTT assay showed that composite nanofibers had minimal cytotoxicity. We anticipate that nanofibrous PVA/POX can potentially be used to target numerous inflammatory diseases that overproduce hydrogen peroxide and may become a potential candidate for use as a local drug delivery vehicle.     

Degradation of P(3HB) and P(3HB-co-3HV) in biological media

The biodegradability of oriented fibers made of polyhydroxybutyrate (P(3HB)) and its co-polymer with β-hydroxyvalerate (P(3HB-co-3HV)) was investigated in buffer solutions and in biological media in vitro and in vivo. The fibers of both polymer types demonstrated resistance to hydrolytic degradation in buffer solutions at 38°C and pH from 4.5 to 7.0 (for up to 180 days). It has been found that the biodegradation of the fibers in vitro in blood and serum and in vivo is accompanied by weight losses and minor changes in the microstructure with no significant losses in the tensile strength over a long time (up to 180 days). The biodegradation rate of the less crystalline co-polymer P(3HB-co-3HV) fibers was 1.4–2.0-times higher than that of the homopolymer P(3HB). It has also been shown that the degradation of the fibers in vivo is influenced both by tissue fluid enzymes and cells (macrophages and foreign-body giant cells). The fibers were eroded on the surface only with no gross defects and no dramatic effects on their mechanical performance.     

Biocompatibility evaluation of dicalcium phosphate/calcium sulfate/poly (amino acid) composite for orthopedic tissue engineering in vitro and in vivo

In vitro cytocompatibility of ternary biocomposite of dicalcium phosphate (DCP) and calcium sulfate (CS) containing 40 wt% poly (amino acid) (PAA) was evaluated using L929 ?broblasts and MG-63 osteoblast-like cells. Thereafter, the biocompatibility of biocomposite in vivo was investigated using an implantation in muscle and bone model. In vitro L929 and MG-63 cell culture experiments showed that the composite and PAA polymer were noncytotoxic and allowed cells to adhere and proliferate. The scanning electron microscope (SEM) confirmed that two kinds of cells maintained their phenotype on all of samples surfaces. Moreover, the DCP/CS/PAA composite showed higher cellular viability than that of PAA; meanwhile, the cell proliferation and ALP activity were much higher when DCP/CS had added into PAA. After implanted in muscle of rabbits for 12 weeks, the histological evaluation indicated that the composite exhibited excellent biocompatibility and no inflammatory responses were found. When implanted into bone defects of femoral condyle of rabbits, the composite was combined directly with the host bone tissue without fibrous capsule tissue, which shown good biocompatibility and osteoconductivity. Thus, this novel composite may have potential application in the clinical setting.     

Dual-Drug Encapsulation and Release from Core–Shell Nanofibers

The purpose of this work was to develop a type of tissue-engineering scaffold or drug-delivery carrier with the capability of encapsulation and controlled release of dual drugs. In this study, Rhodamine B and bovine serum albumin (BSA) were successfully incorporated into nanofibers by means of blending or coaxial electrospinning. The morphology of composite nanofibers was studied by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The composite nanofibrous mats made from coaxial electrospinning were characterized by X-ray diffraction. In vitro dual-drug release behaviors from composite nanofibrous mats were investigated. From the drug-release profiles, it shows that the location where the drug or protein is put into (into the core or shell of the nanofibers) can affect the drug-release profile in the coaxially electrospun fibers. The results imply that the drug- and/or protein-release profile in composite fibrous mats made from electrospinning can be controlled by altering the coaxial electrospinning process and has significant implications for a wide range of applications such as tissue regeneration, combined therapies or even cancer treatments.     

Synthesis,Characterization and Cytocompatibility of a Poly(diol-tricarballylate) Visible Light Photo-Cross-Linked Biodegradable Elastomer

The synthesis, characterization and in vitro cytocompatibility of a new family of photo-cross-linked amorphous poly(diol-tricarballylate) (PDT) biodegradable elastomeric polyesters are reported. The synthesis was based on the polycondensation reaction between tricarballylic acid and alkylene diols, followed by acrylation. The prepared and acrylated poly(diol-tricarballylate) (APDT) was characterized by means of FT-IR, ¹H-NMR, GPC and DSC. Liquid-to-solid photo-curing was carried out by exposing the APDT to visible light in the presence of camphorquinone as a photoinitiator. The thermal properties, mechanical characteristics, sol content, long-term in vitro degradation and cytocompatibility of the prepared PDT elastomers were also reported. The mechanical and degradation properties of this new photocurable elastomer can be precisely controlled by varying the density of acrylate moieties in the matrix of the polymer, and through changes in the pre-polymer chain length. The use of visible light cross-linking, possibility of solventless drug loading, controllable mechanical properties and cytocompatibility of these new elastomers make them excellent candidates for use in controlled implantable drug-delivery systems of protein drugs and other biomedical applications.