Dual Drug Delivery Microcapsules via Layer-by-Layer Self-Assembly

The integration of hydrophobic and hydrophilic drugs in the polymer microcapsule offers the possibility of developing a new drug delivery system that combines the best features of these two distinct classes of material. Recently, we have reported the encapsulation of an uncharged water-insoluble drug in the polymer membrane. The hydrophobic drug is deposited using a layer-by-layer (LbL) technique, which is based on the sequential adsorption of oppositely charged polyelectrolytes onto a charged substrate. In this paper, we report the encapsulation of two different drugs, which are invariably different in structure and in their solubility in water. We have characterized these dual drug vehicular capsules by confocal laser scanning microscopy, atomic force microscopy, visible microscopy, and transmission electron microscopy. The growth of a thin film on a flat substrate by LbL was monitored by UV−vis spectra. The desorption kinetics of two drugs from the thin film was modeled by a second-order rate model.

Multilayer single-component thin films and microcapsules via covalent bonded layer-by-layer self-assembly

Fabrication of single-component multilayer thin films still remains a challenging task via the layer-by-layer (LbL) approach. In this communication, we report the self-assembly of single-component multilayer thin films on flat and colloidal substrates through glutaraldehyde mediated covalent bonding.

Hollow hemisphere and microcapsules of nonionic copolymer

Hemispherical colloidal nanowells or microwells with hollow interiors are becoming increasingly important for the encapsulation of functional materials. There has been rapid progress to develop new methods to obtain such structures. In this work, we present emulsification approach to generate hemisphere and microcapsules of biocompatible organic polymer. The precise control over the size is exhibited by applying variable vortex effect. The hemispheres and microcapsules of a copolymer (BPVA-PVA) were characterized by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). These structures were used for loading of hydrophilic molecules and submicron colloidal particles to demonstrate their potential application. The introduction of hydrophobic groups on poly(vinyl alcohol) was crucial to obtain these structures.

Polyelectrolyte microcapsules for sustained delivery of water-soluble drugs

Polyelectrolyte capsules composed of weak polyelectrolytes are introduced as a simple and efficient system for spontaneous encapsulation of low molecular weight water-soluble drugs. Polyelectrolyte capsules were prepared by layer-by-layer (LbL) assembling of weak polyelectrolytes, poly(allylamine hydrochloride) (PAH) and poly (methacrylic acid) (PMA) on polystyrene sulfonate (PSS) doped CaCO3 particles followed by core removal with ethylene-diaminetetraacetic add (EDTA). The loading process was observed by confocal laser scanning microscopy (CLSM) using tetramethylrhodamineisothiocyanate labeled dextran (TRITC-dextran) as a fluorescent probe. The intensity of fluorescent probe inside the capsule decreased with increase in cross-linking time. Ciprofloxacin hydrochloride (a model water-soluble drug) was spontaneously deposited into PAH/PMA capsules and their morphological changes were investigated by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The quantitative study of drug loading was also elucidated which showed that drug loading increased with initial drug concentration, but decreased with increase in pH. The loaded drug was released in a sustained manner for 6 h, which could be further extended by cross-linking the capsule wall. The released drug showed significant antibacterial activity against E. coli. These findings indicate that such capsules can be potential carriers for water-soluble drugs in sustained/controlled drug delivery applications. (C) 2010 Elsevier B.V. All rights reserved.

Biologically triggered exploding protein based microcapsules for drug delivery

Biologically triggered exploding microcapsules were synthesized by layer-by-layer assembly of biopolymers. The microcapsules showed controlled rupturing behaviour upon exposure to a pathologically relevant biomolecule, trypsin. These microcapsules offer significant potential for clinical applications.

LbL-coated microcapsules as systems for encapsulation of optical brightening agent

We report the encapsulation of optical brightening agent (OBA) into hollow microcapsules prepared by the controlled Layer- by-Layer (LbL) self-assembly process, achieved by the sequential adsorption of oppositely charged polyelectrolytes using negatively charged silica template. Loading takes place by spontaneous deposition method which was proved by confocal laser scanning microscopy (CLSM) using rhodamine 6G (Rd6G) as a fluorescent probe. The loading of the OBA into the microcapsules was found to be dependent on the feeding concentration, pH of the medium, and loading temperature. The encapsulation efficiency of OBA decreased on increasing feeding concentration. Maximum loading was observed at pH 4 and amount of OBA loaded decreased with increase in pH. The loaded OBA was released in a sustained manner for 8 h. No degradation of the OBA was observed during the process of encapsulation and release. Polyelectrolyte capsules potentially offer an innovative way of encapsulating large amounts of active materials for a variety of applications. (c) 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 127: 1609-1614, 2013

Dual enzyme responsive microcapsules simulating an ``OR'' logic gate for biologically triggered drug delivery applications

Hollow microcapsules capable of disintegrating in response to dual biological stimuli have been synthesized from two FDA approved drug molecules. The capsules fabricated from protamine and chondroitin sulphate disintegrate in the presence of either trypsin or hyaluronidase enzymes, which are documented to be simultaneously over-expressed under some pathological conditions.

Albumin-mediated incorporation of water-insoluble therapeutics in layer-by-layer assembled thin films and microcapsules

The present study demonstrates a method to deliver hydrophobic drugs by incorporation into thin films and microcapsules fabricated via a layer-by-layer assembly approach. The hydrophobic molecule binding properties of albumin have been exploited for solubilization of a water-insoluble molecule, pyrene (model drug), by preparation of non-covalent conjugates with bovine serum albumin (BSA). Conjugation with BSA renders a highly negative zeta potential to the previously uncharged pyrene which favors the assembly formation by electrostatic interaction with a positively charged polyelectrolyte, chitosan (at acidic pH). The growth of the assembly was followed by monitoring pyrene absorbance with successive layer deposition. The thin film assembly was demonstrated to be capable of releasing its hydrophobic cargo under physiological conditions. We demonstrated the applicability of this approach by encapsulating a water-insoluble drug, curcumin. These assemblies were further loaded with the anti-cancer drug Doxorubicin. Biocompatible calcium carbonate microparticles were used for capsule preparation. The porous nature of the microparticles allows for the pre-encapsulation of therapeutic macromolecules like protein. The fabrication of protein encapsulated stable microcapsules with hydrophobic molecules incorporated into the shell of the microcapsules has been demonstrated. The microcapsules were further capable of loading hydrophilic molecules like Rhodamine B. Thus, using the approach described, a multi-agent carrier for hydrophobic and hydrophilic drugs as well as therapeutic macromolecules can be envisioned.

Layer-by-Layer Assembled Thin Films and Microcapsules of Nanocrystalline Cellulose for Hydrophobic Drug Delivery

A layer-by-layer (LbL) approach has been employed for the fabrication of multilayer thin films and microcapsules having nanofibrous morphology using nanocrystalline cellulose (NCC) as one of the components of the assembly. The applicability of these nanoassemblies as drug delivery carriers has been explored by the loading of an anticancer drug, doxorubicin hydrochloride, and a water-insoluble drug, curcumin. Doxorubicin hydrochloride, having a good water solubility, is postloaded in the assembly. In the case of curcumin, which is very hydrophobic and has limited solubility in water, a stable dispersion is prepared via noncovalent interaction with NCC prior to incorporation in the LbL assembly. The interaction of various other lipophilic drugs with NCC was analyzed theoretically by molecular docking in consideration of NCC as a general carrier for hydrophobic drugs.

Photonic monitoring of chitosan nanostructured alginate microcapsules for drug release

By using a novel microfluidic set-up for drug screening applications, this study examines delivery of a novel risedronate based drug formulation for treatment of osteoporosis that was developed to overcome the usual shortcomings of risedronate, such as its low bioavailability and adverse gastric effects. Risedronate nanoparticles were prepared using muco-adhesive polymers such as chitosan as matrix for improving the intestinal cellular absorption of risedronate and also using a gastric-resistant polymer such as sodium alginate for reducing the gastric inflammation of risedronate. The in-vitro characteristics of the alginate encapsulated chitosan nanoparticles are investigated, including their stability, muco-adhesiveness, and Caco-2 cell permeability. Fluorescent markers are tagged with the polymers and their morphology within the microcapsules is imaged at various stages of drug release.

Borax Mediated Layer-by-Layer Self-Assembly of Neutral Poly(vinyl alcohol) and Chitosan

We report a multilayer film of poly(vinyl alcohol) (PVA)-borate complex and chitosan by using a layer-by-layer approach. PVA is an uncharged polymer, but hydroxyl functional groups of PVA can be crosslinked by using borax as a cross-linking agent. As a result electrostatic charges and intra- and interchain cross-links are introduced in the PVA chain and provide physically cross-linked networks. The PVA-borate was then deposited on a flat Substrate as well as on colloidal particles with chitosan as an oppositely charged polyelectrolyte. Quartz crystal microbalance. scanning electron microscopy, and atomic force microscopy were used to follow the growth of thin film oil flat substrate. Analogous experiments were performed on melamine formaldehyde colloidal particles (3-3.5 mu m) to quantify the process for the preparation of hollow rnicrocapsules. Removal of the core in 0.1 N HCI results in hollow microcapsules. Characterization of microcapsules by transmission electron microscopy revealed formation of stable microcapsules. Further, self-assembly of PVA-borate/chitosan was loaded with the anticancer drug doxorubicin, and release rates were determined at different pH Values to highlight the drug delivery potential of this system.

Self-Assembly of Biopolymers on Colloidal Particles via Hydrogen Bonding

Fabrication of multilayer microcapsules via layer-by-layer approach through hydrogen bonding has attracted enormous interest due to its strong response to pH. In this communication, we have prepared hydrogen-bonded multilayer microcapsule without using any cross-linking agent by using DNA base pair (adenine and thymine) modified biocompatible polymers. The growth of the self-assembly on colloidal (melamine formaldehyde: MF) particles has been monitored with zeta potential measurement. The capsules were obtained on dissolution of MF particles at 0.1N HCl. The capsules were characterized with scanning electron microscopy. Moreover, we have observed the salt induced microscopic change in self-assembly of this system on the surface of colloidal particles.

Reversible polyelectrolyte capsules as carriers for protein delivery

A reversible drug delivery system based on spontaneous deposition of a model protein into preformed microcapsules has been demonstrated for protein delivery applications. Layer-by-Layer assembly of poly(allylamine hydrochloride) (PAH) and poly(methacrylic acid) (PMA) onto polystyrene sulfonate (PSS) doped CaCO3 particles, followed by core removal yielded intact hollow microcapsules having a unique property to induce spontaneous deposition of bovine serum albumin (BSA) at pH below its isoelectric point of 4.8, where it was positively charged. These capsules showed reversible pH dependent open and closed states to fluorescence labeled dextran (FITC-Dextran) and BSA (FITC-BSA). The loading capacity of BSA increased from 9.1 x 10(7) to 2.03 x 10(8) molecules per capsule with decrease in pH from 4.5 to 3.The loading of BSA-FITC was observed by confocal laser scanning microscopy (CLSM), which showed homogeneous distribution of protein inside the capsule. Efficient loading of BSA was further confirmed by atomic force microscopy (AFM) and scanning electron microscopy (SEM).The interior capsule concentration was as high as 209 times the feeding concentration when the feeding concentration was increased from 1 to 10 mg/ml. The deposition was initially controlled by spontaneous loading mechanism at lower BSA concentration followed by diffusion controlled loading at higher concentration; which decreased the loading efficiency from 35% to 7%. Circular dichroism (CD) measurements and Fourier transform infrared spectroscopy (FTIR) confirmed that there was no significant change in conformation of released BSA in comparison with native BSA. The release was initially burst in the first 0.5 h and sustained up to 5 h. The hollow capsules were found to be biocompatible with mouse embryonic fibroblast (MEF) cells during in vitro cell culture studies. Thus these pH sensitive polyelectrolyte microcapsules may offer a promising delivery system for water soluble proteins and peptides. (C) 2010 Elsevier B.V. All rights reserved.

Glucose-Triggered Drug Delivery from Borate Mediated Layer-by-Layer Self-Assembly

In this study, we report a novel approach for glucose-triggered anticancer drug delivery from the self-assembly of neutral poly(vinyln alcohol) (PVA) and chitosan. In the present study, we have fabricated multilayer thin film of PVA-borate and chitosan on colloidal particle (MF particle) and monitored the layer-by-layer growth using Zetapotential measurements. Formation of multilayer membrane on MF particle has been further characterized with transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM). Subsequently,disintegration of multilayer thin film and microcapsules was observed in presence of glucose. We investigated the disassembly of PVA-borate and chitosan self-assembly under CLSM and atomic force microscopy. These results suggest that this multilayer thin film is very efficient for encapsulation and release of DOX molecules above certain concentration of glucose (25 mM). This glucose-sensitive self-assembly is relevant for the application of anticancer therapeutic drug delivery.

Designing carboxymethyl cellulose based layer-by-layer capsules as a carrier for protein delivery

Stable hollow microcapsules composed of sodium carboxymethyl cellulose (CMC) and poly (allylamine hydrochloride) (PAH) were produced by layer-by-layer adsorption of polyelectrolytes onto CaCO 3 microparticles. Subsequently the core was removed by addition of chelating agents for calcium ions. Zeta potential studies showed charge reversal with deposition of successive polyelectrolyte layers, indicating that the alternate electrostatic adsorption of polyelectrolytes of opposite charge was successfully achieved. The size and surface morphology of the capsules was characterized by various microscopy techniques. The pH responsive loading behavior was elucidated by confocal laser scanning microscopy (CLSM) studies using fluorescence labeled dextran (FITC-dextran) and labeled BSA (FITC-BSA). CLSM images confirmed the open (pH ≤ 6) and closed state (pH ≥ 7) of the capsules. A model drug bovine serum albumin (BSA) was spontaneously loaded below its isoelectric point into hollow microcapsules, where BSA is positively charged. The loading of the BSA into the microcapsules was found to be dependent on the feeding concentration and pH of the medium. 65 of the loaded BSA was released over 7h of which about 34 was released in the first hour. These findings demonstrate that (CMC/PAH) 2 hollow capsules can be further exploited as a potential drug delivery system.