Microrough cobalt-chromium alloy surfaces for Paclitaxel delivery: preparation, characterization, and in vitro drug release studies

Cobalt-chromium (Co-Cr) alloys have extensive biomedical applications including drug-eluting stents (DES). This study investigates the use of eight different microrough Co-Cr alloy surfaces for delivering paclitaxel (PAT) for potential use in DES. The eight different surfaces include four bare microrough and four self-assembled monolayer (SAM) coated microrough surfaces. The bare microrough surfaces were prepared by grit blasting Co-Cr with glass beads (50 and 100 μm in size) and Al(2)O(3) (50 and 110 μm). The SAM coated surfaces were prepared by depositing a -COOH terminated phosphonic acid monolayer on the different microrough surfaces. PAT was then deposited on all the bare and SAM coated microrough surfaces. The surfaces were characterized using scanning electron microscopy (SEM), 3D optical profilometry, and Fourier transform infrared spectroscopy (FTIR). SEM showed the different morphologies of microrough surfaces without and with PAT coating. An optical profiler showed the 3D topography of the different surfaces and the changes in surface roughness and surface area after SAM and PAT deposition. FTIR showed ordered SAMs were formed on glass bead grit blasted surfaces, while the molecules were disordered on Al(2)O(3) grit blasted surfaces. Also, FTIR showed the successful deposition of PAT on these surfaces. The PAT release was investigated for up to two weeks using high performance liquid chromatography. Al(2)O(3) grit blasted bare microrough surfaces showed sustained release profiles, while the glass bead grit blasted surfaces showed burst release profiles. All SAM coated surfaces showed biphasic drug release profiles, which is an initial burst release followed by a slow and sustained release. SAM coated Al(2)O(3) grit blasted surfaces prolonged the sustained release of PAT in a significant amount during the second week of drug elution studies, while this behavior was not observed for any other surfaces used in this study. Thus, this study demonstrates the use of different microrough Co-Cr alloy surfaces for delivering PAT for potential applications in DES and other medical devices.     

pH响应性聚合物胶束的制备、表征及对阿霉素的控制释放研究

以主链含腙键的聚乙二醇大分子(PEG-NH-N=CH-OH)为引发剂,通过开环聚合己内酯(ε-CL),制备了一种具有pH响应性的两亲性嵌段共聚物PEG-NH-N=CH-PCL.运用核磁共振(~1H NMR)、透射电镜(TEM)和动态光散射(DLS)等对聚合物的结构、胶束的形貌及粒径进行表征.结果表明,聚合物胶束呈规整球形且分布均匀,平均粒径约98nm,pH 5.0时胶束粒径显著增加.负载阿霉素(DOX)的聚合物胶束的载药量为16.4%,包封率为57.4%.体外释放研究表明,pH 5.0时药物释放速率比pH 7.4时快,48h后累计释放率达91.1%.因此,该pH响应性聚合物胶束作为抗癌药物载体具有潜在的应用价值.     

Preparation and characterization of temperature- and pH-sensitive hemicellulose-containing hydrogels

In this work, a hemicellulose-containing hydrogel was synthesized. As the first step, a temperature- and pH-sensitive copolymer was synthesized from itaconic acid and N-isopropylacrylamide (NIPAAm). Then the hydrogel was prepared by reacting the copolymer with acylated hemicellulose and polyvinyl alcohol. The morphology, compressive strength, thermal stability, swelling/deswelling behavior, drug-release behavior performances of the hydrogels were investigated. The lower critical solution temperature of the hydrogels varied in 34–44°C when the NIPAAm and itaconic acid mass ratios ranged in 100/0–90/10. Both temperature and pH had a significant influence on equilibrium swelling ratio of hydrogels. The equilibrium swelling ratio increased with pH, but decreased with temperature. Cytocompatibility assay demonstrated that this hemicellulose-containing hydrogel was biocompatible. The release process of salicylic acid suggested that this hydrogel had a potential use in controlled drug release.     

Frontal polymerization synthesis and characterization of temperature- and pH-sensitive hydrogels

The temperature- and pH-sensitive hydrogels, poly(N-isopropylacrylamide-co-acrylic acid) (P(NIPAM-co-AAc)), were synthesized via frontal polymerization (FP). The reaction components have been varied in order to find their influences on frontal parameters and copolymer features. The results showed that front velocity and front temperature were dependent on the initiator concentration, reactant dilution, and NIPMA/AAc molar ratio. In addition, the morphology and sensitive behavior of the FP hydrogels were mainly affected by monomers’ ratio. Namely, the pore size, swelling abilities, LCST, and response kinetics of copolymer hydrogels obviously increased with the increasing acrylic acid concentration; however, they slightly changed with varying of amounts of initiator and solvent. Finally, in comparison with the hydrogels prepared by conventional batch polymerization, the ones synthesized by frontal polymerization exhibited more homogeneous chain composition and improved microstructure and response ability.     

Methotrexate-loaded biodegradable polymeric micelles: preparation, physicochemical properties and in vitro drug release

Polymeric micelles based on amphiphilic diblock copolymers methoxy poly(ethylene glycol)-polylactide with various hydrophobic lengths were designed as carriers of poorly water-soluble anticancer drug methotrexate (MTX). Relationship between physicochemical characteristics of micelles and release behavior was explored. The critical micelle concentration was determined by fluorescence spectroscopy using 9-chloromethyl anthracene as fluorescence probe. Core-shell type polymeric micelles were prepared by free-surfactant dialysis technique. The mean size of micelles loaded with MTX was 50-200 nm with narrow polydispersity. Physicochemical properties of drug-loaded micelles were evaluated. In vitro release behavior of MTX was also investigated. MTX was continuously released from micelles and less than 50% MTX was released in 5 days. Release rate was dependent on chemical structures of micelles and enhanced by decreasing polylactide lengths.     

Novel multiresponsive microgels: synthesis and characterization studies

The dispersion polymerization of 2-(N-morpholino)ethyl methacrylate (MEMA) in the presence of ethylene glycol dimethylacrylate (EGDMA) cross-linker and diblock copolymer stabilizer in n-hexane afforded sterically stabilized multiresponsive PMEMA microgels. By changing the reaction parameters, a wide range of particle sizes (120-720 nm) was obtained. Both dynamic light scattering and electron microscopy studies confirmed monodisperse spherical morphologies. These microgels had a response to the solution pH, temperature, and ionic strength. As expected, PMEMA microgels acquired cationic character at low pH because of the protonation of all morpholino groups. Although PMEMA microgels are in a swollen state in both acidic media and at low temperatures, they are in a deswollen state in basic media at high temperatures and in the presence of electrolytes above pH 6. In addition to these multiresponsive behaviors, PMEMA microgels have the ability to swell in various organic solvents. They also interact very well with magnetic particles and gain responsiveness to the magnetic field. Multiresponsive behaviors of PMEMA microgels were investigated by using DLS, UV-vis spectrophotometry, and zeta potentiometry.     

Tamoxifen-loaded polymeric micelles: preparation, physico-chemical characterization and in vitro evaluation studies

Several samples of polymeric micelles, formed by amphiphilic derivatives of PHEA, obtained by grafting into polymeric backbone of PEGs and/or hexadecylamine groups (PHEA-PEG-C(16) and PHEA-C(16)) and containing different amount of Tamoxifen, were prepared. All Tamoxifen-loaded polymeric micelles showed to increase drug water solubility. TEM studies provided evidence of the formation of supramolecular core/shell architectures containing drug, in the nanoscopic range and with spherical shape. Samples with different amount of encapsulated Tamoxifen were subjected to in vitro cytotoxic studies in order to evaluate the effect of Tamoxifen micellization on cell growth inhibition. All samples of Tamoxifen-loaded polymeric micelles showed a significantly higher antiproliferative activity in comparison with free drug, probably attributable to fluidification of cellular membranes, caused by amphiphilic copolymers, that allows a higher penetration of the drug into tumoral cells. To gain preliminary information about the potential use of prepared micelles as Tamoxifen drug delivery systems, studies evaluating drug release ability of micelle systems in media mimicking biological fluids (buffer solutions at pH 7.4 and 5.5) and in human plasma were carried out. These studies, performed evaluating the amount of Tamoxifen that remains in solution as a function of time, showed that at pH 7.4, as well as in plasma, PHEA-C(16) polymeric micelles were able to release lower drug amounts than PHEA-PEG(5000)-C(16) ones, while at pH 5.5, the behavior difference between two kind of micelles was less pronounced.     

Towards site-specific nanoparticles for drug delivery application: preparation,characterization and release performance

Due to the uncontrollable drug release, traditional chemotherapies could cause great side-effects and are detrimental to normal tissue or organs. Therefore, to avoid those side-effects, drug delivery system (DDS) which is capable of releasing drug molecules at target area with controllable rate according to the development of the disease or to certain functions of the organism/biological rhythm, has attracted especially focus in recent years. In this research, we devoted our efforts in constructing a core–shell nanocomposite to meet the above requirements. The superparamagnetic Fe₃O₄ nanoparticles were chosen as the core to introduce the magnetic guiding as well as site-specific properties in this novel drug carrier. The core was further encapsulated by silica-based molecular sieve MCM-41 (briefly denoted as MS in this research), which was consisted by immense highly ordered hexagonal tunnels to offer plenty cavity for molecules of drug. A light stimuli-responsive ligand, which is a derivative from light-responsive precursor 4,5-diazafluoren-9-one (indicated in the paper as DAFO), was further connected to the MCM-41 tunnels. The ligand can be excited by light and will flip over, making the tunnels of MCM-41 switch from close to open with light on and light off. The nanocomposite thus became capable of releasing drug molecules at certain wavelength of light. In the final, the nanoparticles were tested via SEM/TEM, XRD, FT-IR spectra, thermogravimetry and N₂ adsorption/desorption to verify the structure. The MTT testing of our nanocomposite reveals no obvious cytotoxicity with non-morbid L929 murine fibroblast cells line, indicating that it could be used as a DDS candidate. The cargo releasing behaviors were studied on cytarabine loaded composite: DAFO@MS@Fe₃O₄ in simulated body fluids.     

Unresolved issues in the preparation and characterization of thermoresponsive microgels

The preparation and properties of colloidal thermal responsive microgels based on poly(N-isopropylacrylamide) are described with an emphasis on the unresolved issues which will impair commercial implementation. The main difficulties are: 1) removal of sol, surfactants and other impurities; 2) obtaining colloidally stable particles less than 50 nm in diameter; 3) synthesis of concentrated, colloidally stable microgel dispersions; 4) accurate measurement of water content; and, 5) control of microgel particle morphology.     

Fluorine-containing pH-responsive core/shell microgel particles: preparation,characterization, and their applications in controlled drug release

A kind of novel fluorine-containing pH-responsive core/shell microgels poly(DMAEMA-co-HFMA)-g-PEG were prepared via surfactant-free emulsion polymerization using water as the solvent. The well-defined chemical structure of the copolymers was characterized by FTIR, ¹H-NMR, ¹⁹F-NMR, and elemental analysis. The microgel particles were studied by florescence probe technique, dynamic light scattering, and zeta potential measurement; the microgels displayed a significant pH-responsive behavior. Furthermore, the cytotoxicity assay indicated that the copolymer microgels had low toxicity, and 5-FU-loaded microgels offered a certain killing potency against cancer cells. In addition, the drug loading and in vitro drug release demonstrated that 5-FU was successfully incorporated into polymeric microgels, and the drug-loaded microgels showed a marked pH-dependent drug release behavior. This study suggests that the poly(DMAEMA-co-HFMA)-g-PEG microgels play an important role in the release mechanism stimulated by the change in the pH and have potential applications as a controlled drug release carrier.     

Synthesis, characterization, and in vitro pH-controllable drug release from mesoporous silica spheres with switchable gates

To accomplish pH-controllable drug release on mesoporous carrier, one of the best ways is to graft stimuli-responsive organic molecules around mesopore outlets. In this work, the pH-responsive propyldiethylenetriamine groups (abbreviative phrase: multiamine chains) were grafted around mesopore outlets of mesoporous silica spheres (MSS) and expected to act as pH-responsive gates. To this end, three multiamine-grafted MSS (i.e., NM1, NM2, and NM3) were synthesized under different reaction temperatures and reaction times. The reaction temperature and time for multiamine grafting were 25 °C and 12 h for NM1, 100 °C and 1 h for NM2, and 100 °C and 12 h for NM3, respectively. Through systematic investigations of TEM, SEM, N(2) adsorption/desorption, TG, and (29)Si MAS NMR, it was found that NM3 had the highest grafting amount of multiamine chains. It was further confirmed that the multiamine chains around the pore outlets of NM3 played the role of "molecular switch" that could well control the transport of guest drug molecules. In contrast, the multiamine chains around the pore outlets of NM2 and NM3 did not show gate effect. The difference should be decided by the fact whether the grafting amount of multiamine chains around mesopore outlets were sufficient under determined reaction temperature and time. In the tests of in vitro drug release, multiamine-gated MSS (i.e., NM3) showed highly sensitive response to the solution pH. At high pH (pH 7.5), ibuprofen (IBU) in this carrier released rapidly and completely within 2 h; at low pH (pH 4.0 or 5.0), only a small part of the IBU (13 wt %) was slowly released from this carrier and the most of IBU was effectively confined in mesopores.     

含可脱除侧基的功能化微凝胶及其在药物释放中的应用

环境敏感微凝胶由于其对外界刺激的快速响应能力在药物传输和释放领域得到广泛的关注.本文报道了一种侧链含可脱除基团的温敏微凝胶,并探讨了其在药物释放中的潜在应用.通过分子设计,合成出含侧链N-叔丁氧羰基(N-Boc)的疏水单体N-(N-叔丁氧羰基-乙二胺)甘氨酸二肽甲基丙烯酰胺(BEMAGG),然后将其与N-异丙基丙烯酰胺(NIPAAm)沉淀共聚合直接得到侧链含Boc基团的微凝胶MG-Boc.通过浊点法、粒径和Zeta电位测定研究了微凝胶中Boc基团在酸中的脱除过程及其对微凝胶性能的影响,研究表明Boc基团的脱除显著影响微凝胶的体积相转变温度、粒径和Zeta电位.对盐酸阿霉素药物的释放研究表明,释放明显依赖于释放介质的pH值.该响应性的微凝胶在药物控制释放领域具有潜在的应用前景.     

In-line prediction of drug release profiles for pH-sensitive coated pellets

A new method for the prediction of the drug release profiles during a running pellet coating process from in-line near infrared (NIR) measurements has been developed. The NIR spectra were acquired during a manufacturing process through an immersion probe. These spectra reflect the coating thickness that is inherently connected with the drug release. Pellets sampled at nine process time points from thirteen designed laboratory-scale coating batches were subjected to the dissolution testing. In the case of the pH-sensitive Acryl-EZE coating the drug release kinetics for the acidic medium has a sigmoid form with a pronounced induction period that tends to grow along with the coating thickness. In this work the autocatalytic model adopted from the chemical kinetics has been successfully applied to describe the drug release. A generalized interpretation of the kinetic constants in terms of the process and product parameters has been suggested. A combination of the kinetic model with the multivariate Partial Least Squares (PLS) regression enabled prediction of the release profiles from the process NIR data. The method can be used to monitor the final pellet quality in the course of a coating process.     

The use of hydrophobic spacers in the development of new temperature- and pH-sensitive polymers

The preparation and characterization of two series of methacrylic acid derivative polymers is described. One series contains aliphatic spacers with one to ten methylene units, while the other series includes an aromatic ring with changes in the position of the acid, as spacer. Both series of polymers were obtained as methoxy-ester protected acid polymers and as polymers containing free acid groups in different amounts. pH-sensitive gels and temperature-sensitive N-isopropylacrylamide (NIPAAm) copolymers were prepared by using some of the monomeric structures described. The pH of the swelling transition of the gels changed from 3.5 up to 9.0 as a function of the spacer length and type. The lower critical solution temperature (LCST) of NIPAAm copolymers in water was lowered from 33.6°C to 6°C as a function of the co-monomer content and type. The observed changes in the pH of the swelling transition of gels and in the LCST of NIPAAm copolymers can only be explained if hydrophobic-hydrophobic and hydrogen-bonding interactions are considered in connection with the specific chemical structure of the monomers used.     

Composite microparticle drug delivery systems based on chitosan, alginate and pectin with improved pH-sensitive drug release property

Composite microparticle drug delivery systems based on chitosan, alginate and pectin with improved pH sensitivity were developed for oral delivery of protein drugs, using bovine serum albumin (BSA) as a model drug. The composite drug-loaded microparticles with a mean particle size less than 200 μm were prepared by a convenient shredding method. Since the microparticles were formed by tripolyphosphate cross-linking, electrostatic complexation by alginate and/or pectin, as well as ionotropic gelation with calcium ions, the microparticles exhibited an improved pH-sensitive drug release property. The in vitro drug release behaviors of the microparticles were studied in simulated gastric (pH 1.2 and pH 5.0), intestinal (pH 7.4) and colonic (pH 6.0 and pH 6.8 with enzyme) media. For the composite microparticles with suitable compositions, the releases of BSA at pH 1.2 and pH 5.0 could be effectively sustained, while the releases at pH 7.4, pH 6.8 and pH 6.0 increased significantly, especially in the presence of pectinase. These results clearly suggested that the microparticles had potential for site-specific protein drug delivery through oral administration.     

5-氟尿嘧啶在pH敏感型分子筛控释载体中的缓释行为

以肠溶性的羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)作为包覆材料,制备了HPMCP包覆的SBA-15介孔分子筛药物控释载体(HPMCP/SBA-15),并考察了抗癌药物5-氟尿嘧啶(5-Fu)负载于控释载体后,在不同pH释放环境中的释放行为.结果表明,在模拟胃液中(pH=1.2),HPMCP能明显地延缓5-Fu的释放速度;药物释放4h后,其释放率仅为15%.而在模拟肠液中(pH=7.5)HPMCP迅速溶解,对5-Fu释放速度的影响甚微;药物释放4h后,释放率可达到80%.与此同时,包覆膜的干燥温度影响5-Fu的释放行为,干燥温度越高,药物在模拟胃液中的释放速度越慢.     

Thermosensitive phase behavior and drug release of in situ gelable poly(N-isopropylacrylamide-co-acrylamide) microgels

In situ gelable poly(N-isopropylacrylamide-co-acrylamide) microgels were prepared by precipitation polymerization in the presence of various amounts of N,N′-methlenebisacrylamide as a crosslinker. The diameters of microgels were in the range of 200–300 nm with narrow distributions as determined by photo correlation spectroscopy. The equilibrium swelling ratio and thermosensitive properties of the microgels increased with decreasing crosslinker content. The volume phase transition of microgels dispersions at high concentrations were investigated by phase diagrams. The microgels dispersions experienced four phases when the temperature was increased: semitranslucent swollen gel, clear flowable suspension, cloud flowable suspension, and white shrunken gel. The related phase transition temperatures were influenced by crosslinker content and the concentration of the microgel dispersions. Herein, the gelation temperature was changed by more than 20 °C, shrinking temperatures were slightly changed by about 3 °C, and cloud point temperatures showed almost no change. The three phase transition temperatures of microgels dispersed in phosphate-buffered saline solutions were lower than that in water. As drug carriers, the release rates of bleomycin from bleomycin-loaded microgel dispersions exhibited diffusion control at human body temperature.     

Colon-specific devices based on methacrylic functionalized Tween monomer networks: Swelling studies and in vitro drug release

Colon-targeted delivery devices based on methacrylic functionalized Tween monomer networks, useful for 5-FU or Ferulic acid site-specific release, were synthesized. The basic design consists of methacrylic functionalized Tween monomer-based networks prepared with or without acrylic acid as co-monomer. The swelling behaviour and loaded drugs release from these gels was studied as a function of pH. The devices showed a strong pH-dependent swelling behaviour, allowing a maximum release at pH 7.4. The acrylic acid introduction increased the polymeric gels pores size, as evidenced by the loading efficiency increase, but also reduced the amount of released drug in basic media compared to analogous network not containing the co-monomer. This behaviour, already found in the matrix swelling, could be attributed to a slower hydrolysis kinetics of the ester bond in functionalized Tween monomers, which implies a reduced ability to absorb water from a basic medium, resulting in a lower capacity to release the loaded drug.Since our device possesses a maximum drug release in the media at pH 7.4, it could be used for colon-targeted drug delivery of both 5-FU and Ferulic acid.