Bruno G. De Geest

Release mechanisms for polyelectrolyte capsules

Polyelectrolyte capsules have recently been introduced as new microscopic vehicles which could have high potential in the biomedical field. In this critical review we give an introduction to the layer-by-layer (LbL) technique which is used to fabricate these polyelectrolyte capsules as well as to the different triggers that have been exploited to obtain drug release from these capsules. Furthermore, other types of triggered delivery systems are compared and critically discussed with regard to their clinical relevance. (171 references.).

Polymeric multilayer capsules for drug delivery

The advent of Layer-by-Layer (LbL) assembly to fabricate polymeric as well as hybrid multilayer thin films has opened exciting avenues for the design of multifunctional drug carriers with extreme control over their physico-chemical properties. These polymeric multilayer capsules (PMLC) are typically fabricated by sequential adsorption of polymers onto a spherical substrate with dimensions varying from 10 nm to several microns and larger. In this critical review, we give an overview of the recent advances in the field of PMLC with respect to drug delivery and point out how sophisticated capsule engineering can lead to well-defined drug carriers with unique properties (139 references).

Polyelectrolyte microcapsules for biomedical applications

In this paper we review the recent contributions of polyelectrolyte microcapsules in the biomedical field, comprising in vitro and in vivodrug delivery as well as their applications as biosensors.

Polyelectrolyte Microcapsules as Antigen Delivery Vehicles To Dendritic Cells: Uptake, Processing, and Cross‐Presentation of Encapsulated Antigens

Degradable polyelectrolyte microcapsules (PMs; see picture) as antigen delivery vehicles are taken up by dendritic cells (DCs) by macropinocytosis. Following uptake, the shell of the microcapsules ruptures, resulting in the invasion of the capsules by the cellular cytoplasm, thus allowing DCs to efficiently process encapsulated antigen.

Intracellular Processing of Proteins Mediated by Biodegradable Polyelectrolyte Capsules

Multilayer polyelectrolyte capsules made by layer-by-layer assembly of oppositely charged biodegradable polyelectrolytes were filled with a model of a nonactive prodrug, a self-quenched fluorescence-labeled protein. After capsule uptake by living cells, the walls of the capsules were actively degraded and digested by intracellular proteases. Upon capsule wall degradation, intracellular proteases could reach the protein cargo in the cavity of the capsules. Enzymatic fragmentation of the self-quenched fluorescence-labeled protein by proteases led to individual fluorescence-labeled peptides and thus revoked self-quenching of the dye. In this way nonactive (nonfluorescent) molecules were converted into active (fluorescent) molecules. The data demonstrates that biodegradable capsules are able to convert nonactive molecules (prodrugs) to active molecules (drugs) specifically only inside cells where appropriate enzymes are at hand. In this way only cargo inside the capsules reaching cells is activated, but not the cargo in capsules which remain extracellular. The peptide fragments undergo further processing inside the cells, leading ultimately to exocytosis.

Polymeric microcapsules with light responsive properties for encapsulation and release.

This review is dedicated to recent developments on the topic of light sensitive polymer-based microcapsules. The microcapsules discussed are constructed using the layer-by-layer self-assembly method, which consists in absorbing oppositely charged polyelectrolytes onto charged sacrificial particles. Microcapsules display a broad spectrum of qualities over other existing microdelivery systems such as high stability, longevity, versatile construction and a variety of methods to encapsulate and release substances. Release and encapsulation of materials by light is a particularly interesting topic. Microcapsules can be made sensitive to light by incorporation of light sensitive polymers, functional dyes and metal nanoparticles. Optically active substances can be inserted into the shell during their assembly as a polymer complex or following the shell preparation. Ultraviolet-addressable microcapsules were shown to allow for remote encapsulation and release of materials. Visible- and infrared- addressable microcapsules offer a large array of release strategies for capsules, from destructive to highly sensitive reversible approaches. Besides the Introduction and Conclusions, this review contains in four sections reviewing the effects of light 1) on polymer-based microcapsules, 2) microcapsules containing metal nanoparticles and 3) functional dyes, as well as a fourth section that revisits the implications of light addressable polymeric microcapsules as a microdelivery system for biological applications.

Ultrasound stimulated release and catalysis using polyelectrolyte multilayer capsules

Ultrasound has been used to trigger release of encapsulated material from polyelectrolyte multilayer capsules. Sonication was found to destroy both plain and nanoparticle-modified capsules. Cavitation occurs through the collapse of generated microbubbles and the resulting shear forces should cause the destruction of the polyelectrolyte capsules. Application in catalysis is demonstrated in this paper, while further potential usage of ultrasound triggered release is anticipated in bio-medical applications.

Polymeric multilayer capsule-mediated vaccination induces protective immunity against cancer and viral infection

Recombinant antigens hold high potential to develop vaccines against lethal intracellular pathogens and cancer. However, they are poorly immunogenic and fail to induce potent cellular immunity. In this paper, we demonstrate that polymeric multilayer capsules (PMLC) strongly increase antigen delivery toward professional antigen-presenting cells in vivo, including dendritic cells (DCs), macrophages, and B cells, thereby enforcing antigen presentation and stimulating T cell proliferation. A thorough analysis of the T cell response demonstrated their capacity to induce IFN-γ secreting CD4 and CD8 T cells, in addition to follicular T-helper cells, a recently identified CD4 T cell subset supporting antibody responses. On the B cell level, PMLC-mediated antigen delivery promoted the formation of germinal centers, resulting in increased numbers of antibody-secreting plasma cells and elevated antibody titers. The functional relevance of the induced immune responses was validated in murine models of influenza and melanoma. On a mechanistic level, we have demonstrated the capacity of PMLC to activate the NALP3 inflammasome and trigger the release of the potent pro-inflammatory cytokine IL-1β. Finally, using DC-depleted mice, we have identified DCs as the key mediators of the immunogenic properties of PMLC.

Designing Hyaluronic Acid-Based Layer-by-Layer Capsules as a Carrier for Intracellular Drug Delivery

Polyelectrolyte microcapsules were prepared by the layer-by-layer assembly of hyaluronic acid (HA) and a polycationic polymer, poly(allylamine) (PAH) or poly(lysine) (PLL). The influence of the polycationic partner on the morphology, stability, permeability properties, and enzymatic degradation of microcapsules was thoroughly analyzed. It was found that these properties could be tuned by shell cross-linking. Confocal microscopy studies of cellular uptake of the capsules showed that the polyelectrolyte shells remain stable outside the cells but readily break open once internalized by cells, suggesting their potential as carrier for intracellular drug delivery.

The pros and cons of polyelectrolyte capsules in drug delivery

Polyelectrolyte multilayer microcapsules and nanocapsules are under review as multifunctional delivery systems. Tailoring functions in the entity of a single capsule is done by incorporation of functional polyelectrolytes or nanoparticles in between the layers during electrostatic self-assembly. The resulting capsules possess different properties such as controlled and triggered release, responsiveness to temperature, pH and light and could be navigated with a magnetic field. A variety of substances can be encapsulated and delivered to cells and tissues. Potential applications as well as in vivo experiments have recently been explored. Capsules made of biodegradable polymers showed low toxicity in vivo. Perspectives on and obstacles to a way of broader application are discussed.