Inherent charge-shifting polyelectrolyte multilayer blends: a facile route for tunable protein release from surfaces

Recent research has highlighted degradable multilayer films that enable the programmed release of different therapeutics. Multilayers constructed by the layer-by-layer (LbL) deposition that can undergo disassembly have been demonstrated to be of considerable interest, particularly for biomedical surface coatings due to their versatility and mild aqueous processing conditions, enabling the inclusion of biologic drugs with high activity. In this study, we examine the controlled release of a protein using a different mechanism for film disassembly, the gradual dissociation of film interactions under release conditions. Poly(β-amino ester)s and poly(L-lysine) (PLL) were used as the positively charged multilayer components coassembled with a model negatively charged antigen protein, ovalbumin (Ova). The release of the protein from these multilayer films is dominated by the slow shift in the charge of components under physiological pH conditions rather than by hydrolytic degradative release. The time scale of release can be varied over almost 2 orders of magnitude by varying the ratio of the two polyamines in the deposition solution. The highly versatile and tunable properties of these films form a basis for designing controlled and sequential delivery of drug coatings using a variety of polyions.     

Poly (l-lysine) based semi-interpenetrating polymer network as pH-responsive hydrogel for controlled release of a model protein drug streptokinase

With the aim of developing a pH-sensitive controlled drug release system, a poly (L-lysine) (PLL) based cationic semi-interpenetrating polymer network (semi-IPN) has been synthesized. This cationic hydrogel was designed to swell at lower pH and de-swell at higher pH and therefore be applicable for achieving regulated drug release at a specific pH range. In addition to the pH sensitivity, this hydrogel was anticipated to interact with an ionic drug, providing another means to regulate the release rate of ionic drugs. This semi-IPN hydrogel was prepared using a free-radical polymerization method and by crosslinking of the polyethylene glycol (PEG)-methacrylate polymer through the PLL network. The two polymers were penetrated with each other via interpolymer complexation to yield the semi-IPN structures. The PLL hydrogel thus prepared showed dynamic swelling/de-swelling behavior in response to pH change, and such a behavior was influenced by both the concentrations of PLL and PEG-methacrylate. Drug release from this semi-IPN hydrogel was also investigated using a model protein drug, streptokinase. Streptokinase release was found to be dependent on its ionic interaction with the PLL backbones as well as on the swelling of the semi-IPN hydrogel. These results suggest that a PLL semi-IPN hydrogel could potentially be used as a drug delivery platform to modulate drug release by pH-sensitivity and ionic interaction.     

pH-sensitive polymer blends used as coating materials to control drug release from spherical beads: importance of the type of core

The aim of this study was to coat theophylline-loaded spherical beads with pH-sensitive polymer blends to control the resulting drug release kinetics. Various mixtures of ethylcellulose (water-insoluble) and Eudragit L (methacrylic-acid-ethyl-acrylate-copolymer; water-insoluble/water-soluble below/above pH 5.5) were used as coating materials. Two types of theophylline cores were studied: pure drug matrixes and theophylline-layered sugar cores. Importantly, the type of core significantly affected the resulting drug release patterns. Interestingly, not only the slope, but also the shape of the release curves was altered, indicating changes in the underlying mass transport mechanisms, despite of the identical composition of the polymeric coatings. The observed differences could be explained based on the physicochemical properties of the film coatings and the swelling behavior of the beads upon exposure to the release media. Using this knowledge the development/optimization of this type of drug delivery system can be facilitated and the safety of the pharmacotherapies be improved.     

Mesoporous bioactive glass as a multifunctional system for bone regeneration and controlled drug release

Purpose: Coupling the potential for bone regeneration and the ability for in situ controlled drug release in a single device is a challenging field of research in bone tissue engineering; in an attempt to pursue this aim, mesoporous bioactive glass (MBG) membranes belonging to the SiO2-P2O5-CaO ternary system were produced and characterized. Methods: The glass was synthesized via a sol-gel route coupled with an evaporation-induced self-assembly process by using a non-ionic block co-polymer as a mesostructure former. MBG structure and morphology, as well as mesopores size and shape, were investigated by x-ray diffraction, transmission electron microscopy, and N2 adsorption-desorption measurements. In vitro bioactivity was investigated by soaking MBG membranes in simulated body fluid (SBF) for different time frames. Ibuprofen was encapsulated into MBG pores and drug release kinetics in SBF were assessed. Biological tests by using SAOS-2 cells were performed to assess the material cytocompatibility. Results: The material revealed significant ability to induce hydroxyapatite formation on its surface (bioactivity). Drug release kinetics in SBF are very similar to those obtained for mesoporous silica having mesopore size comparable to that of the prepared MBG (～5 nm). No evidence of cell viability depression was detected during in vitro culture, which demonstrates the good biological compatibility of the material. Conclusions: The easiness of tailoring and shaping, the highly bioactive and biocompatible behavior, and the drug uptake/release ability of the prepared materials may suggest their use as "smart" multifunctional grafts for bone reconstructive surgery.     

Preparation and characterization of a novel starch-based interpolyelectrolyte complex as matrix for controlled drug release

A novel cationized starch-based interpolyelectrolyte complex (IPEC) was formed using kappa-carrageenan as the counter polyion. Characterization of the product by turbidity measurements and elemental analyses indicated a 1:1 interaction of the repeating units. FT-IR spectra for the IPEC showed some differences in comparison with either IPEC constituents or physical mixture. The swelling of tablets obtained by direct compression was independent of pH, and a maximum value of 742% was attained after 24 h. The performance of the IPEC as matrix for controlled release of ibuprofen indicates that drug delivery takes place in a zero-order manner. Experimental dissolution data in the buffer stage were properly represented by a model accounting for contributions of Fickian diffusion and relaxation phenomena; this model suggests that the former predominates over the latter, for the modeled range.     

Steroid release from polymer vaginal devices. Effect on fertility inhibition

Ring-shaped polymer delivering systems (PDS) were made with dimethyl-polysiloxane tubing filled with progestagens that have shown fertility-inhibiting properties by oral administration. PDS were inserted in the vagina by 148 women in 166 experiments accumulating 744 months of observation. Tolerance was good: No side effects nor aggravating action on pre-existing vaginal or cervical infections were observed. Too soft or small PDS were expelled.Release and absorption of progestagen compounds induced modifications in cervical, endometrial and ovarian parameters. Anovulation was demonstrated in two subjects. Changes of PDS weight are related to compound diffusion and moisture influx. Initial and final weight suggest daily average release from 0.5 to 1.0 mg. Contraceptive effect was not satisfactory as compared to oral use. Improvements in polymer and device design are necessary.     

Photodegradation as a mechanism for controlled drug delivery

A drug‐releasing model compound based on photosensitive acrylated ortho‐nitrobenzylether (o‐NBE) moiety and fluorescein was synthesized to demonstrate photolysis as a mechanism for drug release. Release of this model compound from a hydrogel network can be controlled with light intensity (5–20 mW/cm²), exposure duration (0–20 min) and wavelength (365, 405, 436 nm). Due to the high molar absorptivity of the compound (5,984 M^?1 cm^?1), light attenuation is significant in this system. Light attenuation can be used to self‐limit the dosing from a hydrogel, and allow subsequent release from the drug reservoir after equilibration, or attenuation can be utilized to create a chemical gradient within the hydrogel. A model of photodegradation that uses an integrated form of Beer–Lambert's law quantitatively predicts release from hydrophilic hydrogels with low crosslink density, but fails to quantitatively predict release from more hydrophobic systems, presumably due to partitioning of the hydrophobic model compound in the hydrogel. In contrast to other mechanisms of release (enzymolysis, hydrolysis), photolysis provides real‐time on demand control over drug release along with the unique ability to create chemical gradients within the hydrogel. Biotechnol. Bioeng. 2010;107: 1012–1019. © 2010 Wiley Periodicals, Inc.     

A photochemical approach for controlled drug release in targeted drug delivery

Photochemistry provides a unique mechanism that enables the active control of drug release in cancer-targeting drug delivery. This study investigates the light-mediated release of methotrexate, an anticancer drug, using a photocleavable linker strategy based on o-nitrobenzyl protection. We evaluated two types of the o-nitrobenzyl-linked methotrexate for the drug release study and further extended the study to a fifth-generation poly(amidoamine) dendrimer carrier covalently conjugated with methotrexate via the o-nitrobenzyl linker. We performed the drug release studies by using a combination of three standard analytical methods that include UV/vis spectrometry, (1)H NMR spectroscopy, and anal. HPLC. This article reports that methotrexate is released by the photochemical mechanism in an actively controlled manner. The rate of the drug release varies in response to multiple control parameters, including linker design, light wavelength, exposure time, and the pH of the medium where the drug release occurs.     

Cross-linked amylose as matrix for drug controlled release. X-ray and FT-IR structural analysis

For cross-linked amylose (CLA) tablets prepared by direct compression, a linear increase in cross-linking degree (cld) defined as percentage of epichlorohydrin cross-linker/polymer, generates non-monotonous variation of drug release time. Controlled release (up to 20–24 h) properties were obtained only for tablets from CLA (Contramid^TM) with relatively low cld (CLA-2 up to CLA-6). Moderate increase in cld (CLA-15) generates a sharp decrease in the release time (2–6 h). This is a particular characteristic of the CLA matrix. The controlled release properties were related to the X-ray pattern of the dry CLA network. The increase in cld induces a transition from B-type (double helix) to a predominat V-type (single helix) and to more amorphous conformation of CLA powders. Furthermore, FT-IR data indicated low free water content at low cld. For low cross-linked CLA, chains are closely located and stabilized by HO groups involved in hydrogen bonding and thus more resistant to hydration and more appropriate for the control of drug release.     

Morphology control in co-continuous poly(L-lactide)/polystyrene blends: a route towards highly structured and interconnected porosity in poly(L-lactide) materials

Poly(L-lactide) is a biodegradable polymer primarily used in biomedical applications. In this paper, both the microstructure and the region of dual-phase continuity are examined for binary and compatibilized poly(L-lactide)/polystyrene blends (PLLA/PS) prepared by melt mixing. The blends are shown to be completely immiscible with an interfacial tension of 6.1 mN/m. The PS-b-PLLA (24,000-b-28,000) diblock copolymer compatibilizer has an asymmetric effect on the blend. It is effective at compatibilizing 50/50 PLLA/PS blends but is only a marginal emulsifier for blends where PLLA is the dominant matrix. Percent continuity, as estimated by solvent extraction/gravimetry and also torque/composition diagrams clearly indicate an onset of the region of dual-phase continuity at 40-45%PS. It is demonstrated that highly percolated blends of the above materials exist from 40 to 75% PS and 40 to 60% PS for the binary and compatibilized blends, respectively. The scale of the microstructure of the continuous morphology is measured using BET and mercury intrusion porosimetry techniques, after extraction of the PS phase. Both the pore size and extent of continuity can be controlled through composition and interfacial modification. Static annealing of the blend after melt mixing can also be used to substantially increase the pore size of the system. Extraction of the PS phase in the blend, carried out after the above preparation protocols, is a route to generating completely interconnected porosity of highly controlled morphologies (pore size, void volume) in poly(L-lactide) materials. In this study, the pore diameter was controlled from 0.9 to 72 microm for a constant void volume of 45-47%, and the void volume was modified from 35 to 74% depending on the blend composition.     

Chitosan bearing pendant cyclodextrin as a carrier for controlled protein release

The objective of this work was to investigate the possibility of chitosan bearing β-cyclodextrin (CDen-g-CS) nanocomplexes for controlled protein release. CDen-g-CS was synthesized by a one-step procedure with N-succinylated chitosan and mono(6-(2-aminoethyl)amino-6-deoxy)-β-cyclodextrin in the presence of the water-soluble carbodiimide. The amount of β-CD grafted was up to 62.1 wt%. In vitro cytotoxicity against NIH 3T3 cells showed that CDen-g-CS was not cytotoxic and no significant difference of cytotoxicity was found between CDen-g-CS groups. Self-assembled nanocomplexes between CDen-g-CS and insulin were in the size range of 190–328 nm, with positive electrical charge (+3.7 to +25.5 mV) and high loading efficiency (37.7%). Insulin release in vitro was affected by the medium pH and the composition of copolymer. These results demonstrated that CDen-g-CS copolymer was a new promising vehicle for controlled protein release.     

pH-sensitive polymer nanospheres for use as a potential drug delivery vehicle

We report the development and characterization of pH-sensitive poly(2-tetrahydropyranyl methacrylate) [poly(THPMA)] nanospheres and demonstrate their feasibility as an effective drug delivery vehicle. Poly(THPMA) nanospheres were prepared using either the double emulsion or single emulsion method for the encapsulation of, respectively, water soluble (rhodamine B) or organic soluble (paclitaxel) payloads. The resulting nanospheres showed pH-dependent dissolution behavior, resulting in significant morphologic changes and loss of nanoparticle mass under mild acidic conditions (pH 5.1) with a half-life of 3.3 days, as compared to physiologic condition (pH 7.4) with a half-life of 6.2 days. The in vitro drug release profile of the paclitaxel-loaded poly(THPMA) nanospheres revealed that the rate of drug release in pH 5.1 acetate buffer was relatively faster than that in pH 7.4 HEPES buffer. Furthermore, poly(THPMA) nanospheres showed lower cytotoxicity and higher cellular uptake as compared to the FDA-approved PLGA-based nanospheres currently in clinical practice.     

Biocompatible drug delivery system for photo-triggered controlled release of 5-Fluorouracil

The synthesis of a photo-triggered biocompatible drug delivery system on the basis of coumarin-functionalized block copolymers is reported. The coumarin-functionalized block copolymers poly(ethylene oxide)-b-poly(n-butyl methacrylate-co-4-methyl-[7-(methacryloyl)oxyethyloxy]coumarin)) (PEO-b-P(BMA- co-CMA)) were synthesized via atom transfer radical polymerization (ATRP). The micelle-drug conjugates were made by covalent bonding of anticancer drug 5-fluorouracil (5-FU) to the coumarin under UV irradiation at wavelength >310 nm. These micelle-drug conjugates possessed spherical morphology with diameters of 70 nm from TEM images. In vitro drug release experiments showed the controlled release of anticancer drug 5-FU from the micelle-drug conjugates under UV irradiation (254 nm). These micelle-drug conjugates also showed excellent biocompatibility by the in vitro cytotoxicity experiments. The results suggest that these micelle-drug conjugates could be a promising candidate for the delivery of anticancer agents with low side effects on normal cells and excellent therapeutic efficacy to cancer cells.     

Biodegradable and pH-sensitive hydrogels for cell encapsulation and controlled drug release

Hydrogels with pH-sensitive poly(acrylic acid) (PAAc) chains and biodegradable acryloyl-poly(-caprolactone)-2-hydroxylethyl methacrylate (AC-PCL-HEMA) chains were designed and synthesized. The morphology of hydrogel was observed by scanning electron microscopy. The degradation of the hydrogel in the presence of Pseudomonas lipase was studied. The in vitro release of bovine serum albumin from the hydrogel was investigated. Cytotoxicity study shows that the AC-PCL-HEMA/AAc copolymer exhibits good biocompatibility. Cell adhesion and migration into the hydrogel networks were evaluated by using different cell lines. The hydrogel with a lower cross-linking density and a larger pore size exhibited a better performance for cells migration.     

Mucoadhesive vaginal tablets as veterinary delivery system for the controlled release of an antimicrobial drug,acriflavine

The aim of the study was the development of mucoadhesive vaginal tablets designed for the local controlled release of acriflavine, an antimicrobial drug used as a model. The tablets were prepared using drug-loaded chitosan microspheres and additional excipients (methylcellulose, sodium alginate, sodium carboxymethylcellulose, or Carbopol 974). The microspheres were prepared by a spray-drying method, using the drug to polymer weight ratios 1:1 and 1:2 and were characterized in terms of morphology, encapsulation efficiency, and in vitro release behavior, as MIC (Minimum Inhibitory Concentration), MBC (Minimum Bacterial Concentration), and killing time (KT). The tablets were prepared by direct compression, characterized by in vitro drug release and in vitro mucoadhesive tests. The microparticles have sizes of 4 to 12 microm; the mean encapsulation yields are about 90%. Acriflavine, encapsulated into the polymer, maintains its antibacterial activity; killing time of the encapsulated drug is similar to that of the free drug. In vitro release profiles of tablets show differences depending on the excipient used. In particular Carbopol 974, which is highly cross-linked, is able to determine a drug-controlled release from the matrix tablets for more than 8 hours. The in vitro adhesion tests, carried out on the same formulation, show a good adhesive behavior. The formulation containing microspheres with drug to polymer weight ratios of 1:1 and Carbopol 974 is characterized by the best release behavior and shows good mucoadhesive properties. These preliminary data indicate that this formulation can be proposed as a mucoadhesive vaginal delivery system for the controlled release of acriflavine.     

Synthesis and characterization of an ELP-conjugated liposome with thermo-sensitivity for controlled release of a drug

Liposome, one of various drug carriers, has been extensively studied as an inert carrier for the delivery of protein, DNA, and biologically active agents into cells. Recently, much effort has been directed to the development of stimuli-sensitive liposomes that are able to respond to certain internal or external stimuli, such as, pH, electricity, temperature, magnet, or light. Among them, to obtain liposomes which release the contents in response to ambient temperature, liposomes have been modified with chemically synthetic polymers having various lower critical solution temperatures (LCST). In this study, instead of chemically synthetic polymers, a biologically produced elastin-like polypeptide (ELP), which was composed of oligomeric repeats of the pentapeptide sequence (Val-Pro-Gly-Val- Gly), was used for endowing the liposome with thermosensitivity. A model drug was encapsulated in the ELPconjugated liposomes and the release behavior of the drug caused by the liposome disruption due to the aggregation of ELPs was investigated. In addition, conjugation of ELP to liposome was identified with Fourier Transformed Infrared (FT-IR) and Scanning Electron Microscope (SEM) analyses.     

Interpenetrating polymer network (IPN) hydrogel microspheres for oral controlled release application

Interpenetrating polymer network (IPN) hydrogel microspheres of sodium carboxymethyl cellulose (NaCMC) and poly(vinyl alcohol) (PVA) were prepared by water-in-oil (w/o) emulsion crosslinking method for oral controlled release delivery of a non-steroidal anti-inflammatory drug, diclofenac sodium (DS). The microspheres were prepared with various ratios of NaCMC to PVA, % drug loading and extent of crosslinking density at a fixed polymer weight. The prepared microspheres with loose and rigid surfaces were evidenced by scanning electron microscope (SEM). Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis confirmed the IPN formation. Differential scanning calorimetry (DSC) study was performed to understand the dispersion nature of drug after encapsulation. The in vitro drug release study was extensively evaluated depending on the process variables in both acid and alkaline media. All the formulations exhibited satisfactory physicochemical and in vitro release characteristics. Release data indicated a non-Fickian trend of drug release from the formulations. Based on the results of this study suggest that DS loaded IPN microspheres were suitable for oral controlled release application.     

Biodegradable polymer based encapsulation of neem oil nanoemulsion for controlled release of Aza-A

Azadirachtin a biological compound found in neem have medicinal and pesticidal properties. The present work reports on the encapsulation of neem oil nanoemulsion using sodium alginate (Na-Alg) by cross linking with glutaraldehyde. Starch and polyethylene glycol (PEG) were used as coating agents for smooth surface of beads. The SEM images showed beads exhibited nearly spherical shape. Swelling of the polymeric beads reduced with coating which in turn decreased the rate of release of Aza-A. Starch coated encapsulation of neem oil nanoemulsion was found to be effective when compared to PEG coated encapsulation of neem oil nanoemulsion. The release rate of neem Aza-A from the beads into an aqueous environment was analyzed by UV-visible spectrophotometer (214nm). The encapsulated neem oil nanoemulsion have the potential for controlled release of Aza-A. Neem oil nanoemulsion encapsulated beads coated with PEG was found to be toxic in lymphocyte cells.     

Structure-properties relationship in cross-linked high-amylose starch for use in controlled drug release

Cross-linked high-amylose starch (CLHAS), obtained by high-amylose starch cross-linking, was recently introduced as an excipient (Contramid) for monolithic dosage forms that are able to control drug release over 18-24 h. These control properties are related to tablet swelling and are strongly dependent on the degree of the cross-linking of CLHAS. The permeability of solutes through CLHAS hydrogels depends on the chemical structure of the polymer. The aim of this study was to obtain a better understanding of how modifications in CLHAS molecular structures at the level of long-range and short-range order during the cross-linking and processing conditions relate to the release properties of the CLHAS matrices. Structural parameters such as crystallinity contribute significantly to the physical and mechanical aspects of starch products. X-ray diffractometry, FTIR spectroscopy, dissolution tests in vitro, and mechanical hardness (of dry tablets) were found to be sensitive to the cross-linking degree (cld) variation. Best release properties and highest mechanical hardness were obtained from CLHAS matrices with low-to-moderate crystallinity, where the V- and the B-type structures coexist with amorphous regions. X-ray and FTIR profiles of dry CLHAS powders were found to be predictive for release properties of CLHAS tablets.     

Microfluidic synthesis of microfibers for magnetic-responsive controlled drug release and cell culture

This study demonstrated the fabrication of alginate microfibers using a modular microfluidic system for magnetic-responsive controlled drug release and cell culture. A novel two-dimensional fluid-focusing technique with multi-inlets and junctions was used to spatiotemporally control the continuous laminar flow of alginate solutions. The diameter of the manufactured microfibers, which ranged from 211 μm to 364 μm, could be well controlled by changing the flow rate of the continuous phase. While the model drug, diclofenac, was encapsulated into microfibers, the drug release profile exhibited the characteristic of a proper and steady release. Furthermore, the diclofenac release kinetics from the magnetic iron oxide-loaded microfibers could be controlled externally, allowing for a rapid drug release by applying a magnetic force. In addition, the successful culture of glioblastoma multiforme cells in the microfibers demonstrated a good structural integrity and environment to grow cells that could be applied in drug screening for targeting cancer cells. The proposed microfluidic system has the advantages of ease of fabrication, simplicity, and a fast and low-cost process that is capable of generating functional microfibers with the potential for biomedical applications, such as drug controlled release and cell culture.