Transforming the Stability, Encapsulation, and Sustained Release Properties of Calcium Alginate Beads through Gel-Confined Coacervation.

Calcium alginate (Ca/alginate) gel beads find use in diverse applications, ranging from drug delivery and tissue engineering to bioprocessing, food formulation, and agriculture. Unless modified, however, these gels have limited stability in alkaline media (including phosphate buffers), and their high solute permeability limits their ability to efficiently encapsulate and slowly release water-soluble small molecules. Here, we show how these limitations can be addressed by mixing the alginate solutions used in the bead preparation with the nontoxic anionic polymer polyphosphate (PP).

Smart exosomes enhance PDAC targeted therapy.

Exosomes continue to attract interest as a promising nanocarrier drug delivery technology. They are naturally derived nanoscale extracellular vesicles with innate properties well suited to shuttle proteins, lipids, and nucleic acids between cells. Nonetheless, their clinical utility is currently limited by several major challenges, such as their inability to target tumor cells and a high proportion of clearance by the mononuclear phagocyte system (MPS) of the liver and spleen.

Accelerating Payload Release from Complex Coacervates through Mechanical Stimulation.

Complex coacervates formed through the association of charged polymers with oppositely charged species are often investigated for controlled release applications and can provide highly sustained (multi-day, -week or -month) release of both small-molecule and macromolecular actives. This release, however, can sometimes be too slow to deliver the active molecules in the doses needed to achieve the desired effect. Here, we explore how the slow release of small molecules from coacervate matrices can be accelerated through mechanical stimulation.

Highly Sustained Release of Bactericides from Complex Coacervates.

Materials for preventing harmful bacterial contamination attract widespread interest in areas that include healthcare, home/personal care products, and crop protection. One approach to achieving this functionality is through the sustained release of antibacterial compounds. To this end, we show how putty-like complex coacervates, formed through the association of poly(allylamine hydrochloride) (PAH) with pentavalent tripolyphosphate (TPP) ions, can provide a sustained antibacterial effect by slowly releasing bactericides.

Biomolecular uptake effects on chitosan/tripolyphosphate micro- and nanoparticle stability.

Colloidal chitosan/tripolyphosphate (TPP) particles have attracted significant attention as potential delivery vehicles for drugs, genes and vaccines. Yet, there have been several fundamental studies that showed these particles to disintegrate at physiological pH and ionic strength levels. To reconcile these findings with the published drug, gene and vaccine delivery research where chitosan/TPP particle disintegration was not reported, it has been postulated that the particles could be stabilized by their bioactive payloads.

PEGylation and folate conjugation effects on the stability of chitosan-tripolyphosphate nanoparticles.

Chitosan-based nanoparticles (Ch-NPs) prepared via ionotropic gelation of Ch with sodium tripolyphosphate (TPP) have been widely examined as potential drug carriers. Yet, recent studies have shown these particles to be unstable in model (pH 7.2-7.

Pitfalls in analyzing release from chitosan/tripolyphosphate micro- and nanoparticles.

Submicron particles prepared by complexing chitosan with tripolyphosphate (TPP) attract widespread interest as potential drug, gene and vaccine delivery vehicles, and many published studies examine their release properties. Despite these sustained efforts, however, literature on the release performance of chitosan/TPP micro- and nanoparticles is filled with conflicting results, with some reporting nearly instantaneous release, while others showing the release to be sustained for up to multiple days. To resolve these opposing findings, we recently postulated that the in vitro release profiles obtained from chitosan/TPP particles by the standard "sample and separate" or "solvent replacement" method (where the solvent was periodically replaced with fresh buffer and analyzed for the released bioactive molecule content) may have been subject to strong experimental artifacts and not have reflected their true release behavior.

Supramolecular Strategy Effects on Chitosan Bead Stability in Acidic Media: A Comparative Study.

Chitosan beads attract interest in diverse applications, including drug delivery, biocatalysis and water treatment. They can be formed through several supramolecular pathways, ranging from phase inversion in alkaline solutions, to the ionic crosslinking of chitosan with multivalent anions, to polyelectrolyte or surfactant/polyelectrolyte complexation. Many chitosan bead uses require control over their stability to dissolution.

Photolithographically assembled polyelectrolyte complexes as shape-directing templates for thermoreversible gels.

Preparation of soft materials with diverse, customized shapes has been a topic of intense research interest. To this end, we have recently demonstrated photolithographic directed assembly as a strategy for customizing polyelectrolyte complex (PEC) shape. This process uses in situ photopolymerization of an anionic monomer in the presence of a cationic polymer, which drives localized PEC formation at the irradiation sites.

Poly(allylamine)/tripolyphosphate coacervates enable high loading and multiple-month release of weakly amphiphilic anionic drugs: an study with ibuprofen.

When synthetic polyamines, such poly(allylamine hydrochloride) (PAH), are mixed with crosslink-forming multivalent anions, they can undergo complex coacervation. This phenomenon has recently been exploited in various applications, ranging from inorganic material synthesis, to underwater adhesion, to multiple-month release of small, water-soluble molecules. Here, using ibuprofen as a model drug molecule, we show that these coacervates may be especially effective in the long-term release of weakly amphiphilic anionic drugs.

Effect of small molecules on the phase behavior and coacervation of aqueous solutions of poly(diallyldimethylammonium chloride) and poly(sodium 4-styrene sulfonate).

Hypothesis: Complex coacervates are capable of easily partitioning solutes within them based on relative affinities of solute-water and solute-polyelectrolyte pairs, as the coacervate phase has low surface tension with water, facilitating the transport of small molecules into the coacervate phase. The uptake of small molecules is expected to influence the physicochemical properties of the complex coacervate, including the hydrophobicity within coacervate droplets, phase boundaries of coacervation and precipitation, solute uptake capacity, as well as the coacervate rheological properties.

Experiments: Phase behavior of aqueous solutions of poly(diallyldimethylammonium chloride) (PDAC) and poly(sodium 4-styrene sulfonate) (SPS) was investigated in the presence of various concentrations of two different dyes, positively charged methylene blue (MB) or non-charged bromothymol blue (BtB), using turbidity measurements.

Customizing polyelectrolyte complex shapes through photolithographic directed assembly.

Polyelectrolyte complexes (PECs) form through the association of oppositely charged polymers and, due to their attractive properties, such as their mild/simple preparation and stimulus-sensitivity, attract widespread interest. The diverse applications of these materials often require control over PEC shapes. As a versatile approach to achieving such control, we report a new photolithographic directed assembly method for tailoring their structure.

Preparation of chitosan/tripolyphosphate nanoparticles with highly tunable size and low polydispersity.

Nanoparticles prepared through the ionotropic gelation of chitosan with tripolyphosphate (TPP) have been extensively studied as vehicles for drug and gene delivery. Though a number of these works have focused on preparing particles with narrow size distributions, the monodisperse particles produced by these methods have been limited to narrow size ranges (where the average particle size was not varied by more than twofold). Here we show how, by tuning the NaCl concentration in the parent chitosan and TPP solutions, low-polydispersity particles with z-average diameters ranging between roughly 100 and 900nm can be prepared.

Analysis of chitosan/tripolyphosphate micro- and nanogel yields is key to understanding their protein uptake performance.

Chitosan/tripolyphosphate (TPP) micro- and nanogels are widely explored as vehicles for protein drug and vaccine delivery. Yet, aside from the consensus that protein uptake into these particles is enhanced by stronger protein/particle binding, factors that control their uptake performance, such as differences in the chitosan, TPP and protein concentrations, remain poorly understood. Here, we show that many of the differences in the reported association efficiencies (AE-values) for protein uptake likely reflect the largely-ignored variability in the particle yield (X), which is the fraction of the added chitosan that self-assembles into particles and (like the AE) varies with the chitosan, TPP and protein concentrations.

On the kinetics of chitosan/tripolyphosphate micro- and nanogel aggregation and their effects on particle polydispersity.

Submicron chitosan/tripolyphosphate (TPP) particles are widely investigated as nanocarriers for drugs, genes and vaccines. One of the key particle properties that requires control is their size distribution, which depends on the extent of chitosan/TPP primary nanoparticle aggregation into higher-order submicron colloids. To provide a better understanding of this higher-order aggregation process, this study analyzes the factors that control chitosan/TPP particle aggregation kinetics in the presence of free TPP (such as present during particle formation).

Preparation and Timed Release Properties of Self-Rupturing Gels.

Swelling of polymeric hydrogels is sensitive to their cross-link densities. Here, we exploit this principle to prepare self-rupturing gels which are based on a commonly-used, nontoxic, and inexpensive polyelectrolyte, poly(acrylic acid), and are prepared through a simple and low-cost polymerization-based technique. The self-rupture of these covalently cross-linked gels is achieved by preparing them to have highly nonuniform cross-link densities.

Ionically Cross-Linked Polymer Networks for the Multiple-Month Release of Small Molecules.

Long-term (multiple-week or -month) release of small, water-soluble molecules from hydrogels remains a significant pharmaceutical challenge, which is typically overcome at the expense of more-complicated drug carrier designs. Such approaches are payload-specific and include covalent conjugation of drugs to base materials or incorporation of micro- and nanoparticles. As a simpler alternative, here we report a mild and simple method for achieving multiple-month release of small molecules from gel-like polymer networks.

Factors affecting the stability of chitosan/tripolyphosphate micro- and nanogels: resolving the opposing findings.

Micro- and nanogels prepared by ionically crosslinking chitosan with tripolyphosphate (TPP) attract keen interest as potential drug carriers. To achieve their optimal performance, it is essential to control their stability to aggregation and dissolution. Yet, literature on this subject (especially at physiological ionic strength and pH) remains filled with opposing reports.

Ionically cross-linked poly(allylamine) as a stimulus-responsive underwater adhesive: ionic strength and pH effects.

Gel-like coacervates that adhere to both hydrophilic and hydrophobic substrates under water have recently been prepared by ionically cross-linking poly(allylamine) (PAH) with pyrophosphate (PPi) and tripolyphosphate (TPP). Among the many advantages of these underwater adhesives (which include their simple preparation and low cost) is their ability to dissolve on demand when exposed to high or low pH. To further analyze their stimulus-responsive properties, we have investigated the pH and ionic strength effects on the formation, rheology and adhesion of PAH/PPi and PAH/TPP complexes.

Simple preparation of polyelectrolyte complex beads for the long-term release of small molecules.

We report a simple method for preparing solid polyelectrolyte complex (PEC) beads, which provide effective barriers to diffusion and can be used for the multiple-day release of small molecules. Single-phase poly(allylamine) (PAH) and poly(styrenesulfonate) (PSS) mixtures were prepared at pH 11.6 (significantly above the effective pKa of PAH), where the PAH amine groups were deprotonated and therefore neutral.

Self-assembly of stiff, adhesive and self-healing gels from common polyelectrolytes.

Underwater adhesion has numerous potential medical, household, and industrial applications. It is typically achieved through covalent polymerization and cross-linking reactions and/or the use of highly specialized biological or biomimetic polymers. As a simpler alternative to these covalent and biomimetic strategies, this article shows that stiff, gel-like complexes that adhere to various substrates under water can also be prepared through the ionic cross-linking of common, commercial polyelectrolytes.

Formation and dissolution of chitosan/pyrophosphate nanoparticles: is the ionic crosslinking of chitosan reversible?

Ionically crosslinked chitosan particles with submicron dimensions attract widespread interest as materials for controlled release. To this end, we have examined the formation and dissolution of nanoparticles prepared by crosslinking chitosan with pyrophosphate (PPi). The formation of these particles required a critical PPi concentration (which increased with the chitosan concentration), and their z-average hydrodynamic diameters could be predictably tuned from roughly 60 to 220 nm by varying the concentration of the parent chitosan solutions.

Determining the colloidal behavior of ionically cross-linked polyelectrolytes with isothermal titration calorimetry.

Mixtures of polyelectrolytes and multivalent counterions can self-assemble into colloidal complexes. These complexes attract widespread interest in applications such as medicine, household product formulations, and separation processes. To facilitate the development of these colloidal dispersions, we examined isothermal titration calorimetry (ITC) as an automated screening tool for identifying the polymer and multivalent counterion compositions that (1) form ionically cross-linked colloidal complexes and (2) lead to their rapid coagulation (and macroscopic phase separation).

Physicochemical and antibacterial properties of surfactant mixtures with quaternized chitosan microgels.

Antibacterial surfactant mixtures attract widespread interest in the design of consumer product formulations, but often use toxic biocidal agents such as cationic surfactants, triclosan or bleach. To address this, we explored replacing these toxic ingredients with quaternized chitosan microgels, which combine high antibacterial activity with cytocompatibility with mammalian cells. Specifically, three essential properties of microgel mixtures with model anionic (sodium dodecyl sulfate, SDS) and nonionic (Triton X-100, TX-100) surfactants (and with SDS/TX-100 mixtures) were investigated: (1) colloidal stability, (2) antibacterial activity, and (3) hydrophobe solubilization.

Salt-assisted mechanistic analysis of chitosan/tripolyphosphate micro- and nanogel formation.

Self-assembled micro- and nanogels are frequently prepared by mixing tripolyphosphate (TPP) with dilute chitosan solutions. Upon its addition, the TPP ionically cross-links the chitosan molecules into gel-like colloids that range from tens of nanometers to micrometers in diameter. These particles are biocompatible, mucoadhesive and, because they are easy to prepare under very mild conditions, attract widespread interest in the encapsulation of drugs, neutraceuticals, and other bioactive payloads.