Biodegradable, multi-layered coatings for controlled release of small molecules

Incorporation of orthogonal functional groups into biodegradable polymers permits the fabrication of multi-layered thin films with improved adhesion and tunable degradation profiles. The bi-layer structure also allows for accurate control over small molecule release.     

Hepatic-targeting microcapsules construction by self-assembly of bioactive galactose-branched polyelectrolyte for controlled drug release system

We describe the construction of hepatic-targeting microcapsules by self-assembly of chemo-enzymatic synthesized poly(vinyl galactose ester-co-methacryloxyethyl trimethylammonium chloride) (PGEDMC) containing galactose branches, which can be specifically recognized by membrane bound galactose receptors (ASGPR), for acyclovir (ACV) controlled release system. Alternate deposition of PGEDMC and poly(sodium 4-styrenesulfonate) (PSS) was carried out on ACV microcrystals. It was revealed that the drug release rate decreases with the increase of coated layer number and a microcapsule-drying treatment would enhance the sustained release effect probably because of a multilayer shrink and tightness during the process. The complete release of ACV yielded a hollow PGEDMC/PSS multilayered network with favorable integrity and nano-thickness by TEM and SEM. The potential targetability of the system was proved in vitro by PNA lectin recognition. Lectin hardly adsorbed on the film where the outmost layer was a polyanion or a polycation without galactose component. Whilst the galactose-containing layer (PGEDMC) was the outmost layer, a significant lectin combination was observed. This technique could provide a promising way to encapsulate and deliver various target substances in biological and pharmaceutical applications.     

Single-component layer-by-layer weak polyelectrolyte films and capsules: Loading and release of functional molecules

Poly(carboxylic acid) hydrogel films and hollow capsules undergo reversible size changes in response to variations in pH and/or ionic strength. The films and capsules were obtained from hydrogenbonded poly-N-vinylpyrrolidone/poly(carboxylic acid) layer-by-layer films by chemical crosslinking of the polyacid, followed by pH-induced removal of poly-N-vinylpyrrolidone. Surface-attached hydrogel films present attractive matrices for reversible pH-stimulated loading and/or controlled release of large amounts of synthetic or natural macromolecules including proteins. By varying acidity of poly(carboxylic acids), the hydrogel swelling and the corresponding values of pH for encapsulation/release of functional molecules could be tuned in a wide range from pH 5 to 10. In addition, the capsules are capable of entrapping macromolecules by “locking” the capsule wall with an electrostatically associating polycation, followed by the release of the encapsulated macromolecules at high salt concentrations. The text was submitted by the authors in English.     

A novel layer-by-layer approach for the fabrication of conducting polymer/RNA multilayer films for controlled release

Poly(anilineboronic acid) (PABA)/ribonucleic acid (RNA) multilayer films were prepared under neutral condition using a layer-by-layer deposition of PABA and RNA. RNA was used both as a polyelectrolyte for multilayer formation as well as dopant for PABA. Photoelastic modulated infrared reflection absorption spectroscopy measurements suggest that PABA interacts covalently with RNA through the formation of a boronate ester, a boron-nitrogen dative bond, as well as electrostatic interactions of anionic phosphates with cationic amines. The deposition procedure was monitored with UV-vis absorption spectroscopy, showing a linear dependence of absorbance with the number of PABA/RNA bilayers deposited. The multilayer films were further characterized using X-ray photoelectron spectroscopy and ellipsometry, which yielded a PABA/RNA bilayer thickness of approximately 10 nm. The PABA/RNA multilayer films are redox-active at neutral pH, consistent with the formation of a self-doped polymer. Electrochemical control of PABA under these conditions allows potential-induced controlled release of RNA from a multilayer at neutral pH, suggesting that this may serve as a novel method for controlled release of RNA under physiological conditions.     

Thermal behavior of polyelectrolyte multilayer microcapsules: 2. Insight into molecular mechanisms for the PDADMAC/PSS system

Polyelectrolyte multilayer capsules consisting of poly(diallyldimethylammonium chloride) (PDADMAC) and poly(styrene sulfonate) (PSS) were used as a model system to study the temperature-dependent behavior of polyelectrolyte multilayer films in aqueous media. Shells terminated with PSS shrink upon heating, whereas PDADMAC-terminated ones swell, independent of the nature of the first layer, as measured by means of confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Elemental analysis shows that the initial exponential layer growth of the film leads to a nearly neutral overall charge in the first case or a high positive excess charge in the latter. Depending on this overall charge either surface tension, due to an unfavorable polymer-solvent interaction, or electrostatics dominates, resulting in a shrinkage or expansion of capsules, respectively. Thus, it is possible to swell temperature-shrunk capsules by coating them with an additional PDADMAC layer. Micro-DSC measurements prove that polyelectrolyte multilayers undergo a glass transition in water at which the wall material softens, allowing the rearrangements to occur. It is found that the thermal history has an influence on the temperature behavior of capsules, especially on those ones terminated with PDADMAC. Also, the molecular weight of the polyelectrolytes affects the rearrangement of capsules. The lower the molecular weight and thus the smaller the entanglement of chains, the easier polyelectrolytes can rearrange.     

Immobilization of camptothecin with surfactant into hydrogel for controlled drug release

A new strategy has been developed for the controlled release of a hydrophobic anticancer drug, camptothecin (CPT), which suffers a limited therapeutical utility because of its poor water solubility. CPT was first solubilized in the solution of a cationic surfactant, dodecyltrimethylammonium bromide (DTAB). It has been demonstrated that the presence of DTAB has increased the solubility of CPT significantly. In a 50 mM DTAB solution, the drug’s solubility was enhanced to 85 μM, 22 times of its solubility in pure water. The micellar drug solution of CPT-DTAB was subsequently used to prepare agarose hydrogels, which act as the drug carriers in the release studies. To fully take advantage of the cationic property of DTAB, negatively charged κ-carrageenan was added as a guest polymer in some hydrogel samples. The release of CPT from these hydrogel-surfactant systems was performed at 37 °C and the effects of DTAB and κ-carrageenan on the release of CPT were studied respectively. By fitting to the well-known Fickian diffusion model, the diffusion coefficients of CPT were obtained.     

Synthesis of modified conformationally fixed tricarbocyanine dyes for conjugation with therapeutic agents

New β-alanine modified tricarbocyanines containing various substituents at quaternized nitrogen atoms were obtained. The peptide synthesis method has been utilized for further conjugation thus giving promising tricarbocyanines containing two sulfonate groups and total negative charge of the fluorophore.     

A general strategy for one-step fabrication of biocompatible microcapsules with controlled active release

Fabrication of biocompatible core-shell microcapsules in a controllable and scalable manner remains an important but challenging task.Here,we develop a one-step microfluidic approach for the highthroughput production of biocompatible microcapsules,which utilizes single emulsions as templates and controls the precipitation of biocompatible polymer at the water/oil interface.The facile method enables the loading of various oils in the core and the enhancement of polymer shell strength by polyelectrolyte coating.The resulting microcapsules have the advantages of controllability,scalability,biocompatibility,high encapsulation efficiency and high loading capacity.The core-shell microcapsules are ideal delivery vehicles for programmable active release and various controlled release mechanisms are demonstrated,including burst release by vigorous shaking,pH-triggered release for targeted intestinal release and sustained release of perfume over a long period of time.The utility of our technique paves the way for practical applications of core-shell microcapsules.     

Vertically-aligned carbon nanotubes infiltrated with temperature-responsive polymers: smart nanocomposite films for self-cleaning and controlled release

We have demonstrated that the infiltration of temperature-responsive polymers (e.g., PNIPAAm) into vertically-aligned carbon nanotube forests created synergetic effects, which provided the basis for the development of smart nanocomposite films with temperature-induced self-cleaning and/or controlled release capabilities.     

The therapeutic potential of metal-based antimalarial agents: implications for the mechanism of action

Despite recent encouraging advances against the disease, malaria remains a major public health problem affecting almost half a billion people and killing almost a million per annum. Due to a short arsenal of efficient antimalarial agents and the frequent appearance of resistance to the drugs in current use, which consequently reduce our means to treat patients, there is a very urgent and continuous need to develop new compounds. This perspective outlines a unique strategy for that purpose through the development of metal-based antimalarial agents. The examples presented here illustrate an attractive alternative to classical drugs.     

Oral colon-targeted mucoadhesive micelles with enzyme-responsive controlled release of curcumin for ulcerative colitis therapy

Although multitudinous nanoscale drug-delivery systems (DDSs) have been recommended to improve anti-ulcerative colitis (UC) outcomes, to enhance the mucoadhesion of nanosystems on the colon and specifically release the loaded drugs in response to the colon micro-environment would be critical factors. The application of curcumin (Cur), an acknowledged anti-UC phytochemical compound, for UC therapy requires more efficient nano-carriers to improve its therapeutic outcome. Herein, we developed the colon-targeted nano-micelles with mucoadhesive effect and Azo reductase-triggered drug release profiles for Cur delivery in UC treatment. Specifically, the amphiphilic block polymer containing the Azo-reductase sensitive linkage (PEG-Azo-PLGA), and catechol-modified TPGS (Cat-TPGS) were synthesized respectively. Based on the self-assembly of the mixed polymers, Cur-micelles (142.7 ± 1.7 nm of average size, 72.36% ± 1.54% of DEE) were obtained. Interestingly, the Cur-micelles exhibited the Azo-reductase sensitive particle dissociation and drug release, the enhanced cellular uptake and the prolonged retention on colonic mucosa, mediated by the strong mucoadhesion of catechol structure. Ultimately, Cur-micelles significantly mitigated colitis symptoms and accelerated colitis repair in DSS-treated mice by regulating the intestinal flora and the levels of pro-inflammatory factors (MPO, IL-6, IL-1β, and TNF-α) related to TLR4/MyD88/NF-κB signaling pathway. This work provides an effective drug delivery strategy for anti-UC drugs by oral administration.     

Fabrication of biofunctional complex micelles with tunable structure for application in controlled drug release

In acidic solution, complex micelles were formed by diblock copolymers of poly (ethylene glycol)-b-poly (ε-caprolactone) (PEG-b-PCL) and folate-poly (2-(dimethylamino) ethyl methylacrylate)-b-poly (ε-caprolactone) (Fol-PDMAEMA-b-PCL) with a PCL core, a mixed PEG/Fol-PDMAEMA shell. The surface charge of the complex micelles was positive at acidic surroundings for the protonated PDMAEMA. With increasing pH value to 7.4 (above pK _a of PDMAEMA), these micelles could convert into a core-shell-corona (CSC) structure composing a hydrophobic PCL core, a collapsed PDMAEMA shell, and a soluble PEG corona. Compared to core-shell micelles formed by PEG-b-PCL, micelles with CSC structure can prolong degradation by enzyme. Doxorubicin was physically loaded into the PCL core. The drug release rate was pH-dependent. At pH 5.5, complex micelles with core-shell structure showed faster drug release rate, while at pH 7.4, complex micelles gained CSC structure which control the drug release at a lower rate. The multifunctional complex micelles were prepared for enhanced tumor therapy.     

Differential magnetic catch and release: experimental parameters for controlled separation of magnetic nanoparticles

Differential magnetic catch and release (DMCR) has been used as a method for the purification and separation of magnetic nanoparticles. DMCR separates nanoparticles in the mobile phase by magnetic trapping of magnetic nanoparticles against the wall of an open tubular capillary wrapped between two narrowly spaced electromagnetic poles. Using Au and CoFe(2)O(4) nanoparticles as model systems, the loading capacity of the 250 μm diameter capillary is determined to be ～130 μg, and is scalable to higher quantities with larger bore capillary. Peak resolution in DMCR is externally controlled by selection of the release time (R(t)) at which the magnetic flux density is removed, however, longer capture times are shown to reduce the capture yield. In addition, the magnetic nanoparticle capture yields are observed to depend on the nanoparticle diameter, mobile phase viscosity and velocity, and applied magnetic flux. Using these optimized parameters, three samples of CoFe(2)O(4) nanoparticles whose diameters are different by less than 10 nm are separated with excellent resolution and capture yield, demonstrating the capability of DMCR for separation and purification of magnetic nanoparticles.     

Photo-cured pH-responsive polyampholyte-coated membranes for controlled release of drugs with different molecular weights and charges

Intelligent drug delivery membranes were synthesised by photocuring poly(acrylic acid) (PAA) or polyampholytes comprised of copolymers of acrylic acid (AA)/2-(diethylamino)ethyl methacrylate (DEAEMA) with varying monomeric compositions onto poly(2-hydroxyethyl methacrylate) (PHEMA) membranes, each with model drugs of different molecular weights and charges being incorporated. pH-responsive release behaviours of the model drugs which included methylene blue (cationic), metanil yellow (anionic) and caffeine (neutral) were studied. Only membranes with methylene blue and caffeine incorporated displayed clear pH-responsive releases though all coatings. This study demonstrates that drug diffusion through pH-responsive membranes depends to a large extent on the attractive interaction between the drug and the appropriate functional group/s in the coating.     

Mass transfer coupled with the relaxation of a polymeric matrix: A controlled release process

A solution to Fick's equation is presented which accurately predicts the transfer of mass out of a polymeric rod or sheet undergoing relaxation by a solvent permeating it by Case II transport. There is a critical length. Before the solvent permeates to this length the diffusible material can diffuse away from the moving boundary faster than it is becoming available at the boundary. Afterward the reverse is true. Five sets of experimental data from three different sources have been used to test the model. The agreement is excellent.     

Amphiphilic depsipeptide‐based block copolymers as nanocarriers for controlled release of ibuprofen with doxorubicin

Well‐defined amphiphilic multiblock copolymers PDMAEMA‐b‐P(IBMD‐co‐PDO)‐b‐PEG‐b‐P(IBMD‐co‐PDO)‐b‐PDMAEMA [PDMAEMA‐PIBMD‐PPDO‐PEG], based on poly(2‐(dimethylamino)ethyl methacrylate) block (PDMAEMA), poly(3(S)‐isobutyl‐morpholine‐2,5‐dione‐co‐p‐dioxanone) block (P(IBMD‐co‐PDO)), and poly(ethylene glycol) block (PEG) were successfully synthesized by combination of ring‐opening polymerization (using 3(S)‐isobutyl‐morpholine‐2,5‐dione and p‐dioxanone initiated by hydroxyl end of PEG) and atom transfer radical polymerization (ATRP). Furthermore, all these copolymers were characterized by ¹H NMR, ¹³C NMR, Fourier transformed‐infrared, gel permeation chromatography, differential scanning calorimetry, and thermogravimetric analysis measurements. The degradation experiments showed that the molecular weight of PDMAEMA‐PIBMD‐PPDO‐PEG decreased along with degradation time. In addition, these copolymers could readily self‐assemble into nanosized microspheres in phosphate buffered solution. Ibuprofen (IBU) and doxorubicin (DOX) as a kind of combined model drugs were loaded into these microspheres by the combination of ionic interaction and hydrophobic effect. These copolymer microspheres exhibited high loading capacity (LC, up to 26.88%), encapsulation efficiency (EE, up to 61.29%), and sustained release behavior of IBU–DOX in phosphate buffered solution. The results of transmission electron microscopy and dynamic light scattering showed that the microspheres were well‐defined uniform spherical particles with average diameter less than 120 nm. Therefore, it can be envisaged that these copolymer systems are promising candidates for controlled release application. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3213–3226     

AC-magnetic field controlled drug release from magnetoliposomes: design of a method for site-specific chemotherapy.

Large unilamellar magnetoliposomes (MLs) with encapsulated doxorubicin (DOX) (anticancer drug) were prepared by reverse-phase evaporation. They were exposed to an alternating magnetic field with a frequency of 3.5 MHz and an induction of 1.5 mT produced in three-turn pancake coil. The results showed that magnetoliposomes could be specifically heated to 42 degrees C (phase transition temperature of a used lipid) in a few minutes and during this, the encapsulated doxorubicin is massively released.