Without doubt, the development of vaccines constitutes one of themajor breakthroughs of humanmedicine, allowing us to prevent numerous infectious diseases. Nevertheless, for major killers such as HIV, malaria, and tuberculosis, no effective vaccine is currently available. The failure of current vaccination strategies to elicit cellular immune responses, especially CD8 cytotoxic T cells (CTLs) that can recognize and eliminate infected cells, is considered to be one of the major reasons for this failure. Consequently, there is an urgent need to develop new vaccine formulations that can induce such CTL responses. One of the most promising approaches to achieve this goal is the encapsulation of antigens in particulate carriers with dimensions between 0.1 and 10 mm. A plethora of studies has now demonstrated that such carriers can strongly enhance antigen presentation by dendritic cells (DCs), the most potent antigen presenting cells capable of priming effector T cell responses, not only quantitatively but also qualitatively. Antigen being presented by a DC as an MHC/peptide complex (MHC=major histocompatibility complex) to the T cell receptor indeed constitutes the first step in the initiation of T cell responses. Two different pathways occur for antigen presentation by MHC I and MHC II to CD8 and CD4 T-cells, respectively. MHC I presentation is responsible for the processing and presentation of cytosolic proteins, which are cleaved by the proteasome, transported to the endoplasmatic reticulum, and subsequently loaded onto MHC I molecules. By contrast, MHC II presentation occurs for endocytosed proteins, which are degraded in endolysosomal compartments, loaded onto MHC II molecules and subsequently presented at the cell surface. The way in which antigen is internalized by a DC, however, strongly affects how the antigen is processed and presented by a DC, and consequently also the type and strength of immune response induced. Although soluble antigens are almost exclusively presented by MHC II to CD4 T cells, particulate antigens not only are far more efficiently taken up by DCs, but are also presented by MHC I to CD8 T cells, thus enabling the induction of CTL responses. Although particulate carriers have the capacity to evoke potent cellular immunity, their clinical application has been impeded largely by practical problems involving their generation, including a low antigen encapsulation efficiency, the use of chemical solvents and physical stresses that negatively affect antigen stability, and the involvement of complex and labor-intensive multistep processes to generate them. Polymeric multilayer capsules have emerged as promising microscopic carriers for the delivery of antigens to DCs, overcoming some of the problems described above. These capsules are based on alternate deposition of polymers (so-called layer-by-layer technology), either through electrostatic interaction or hydrogen bonding, onto a sacrificial template, followed by decomposition of the template, resulting in hollow capsules and allowing efficient antigen encapsulation under non-denaturing conditions. Several papers have now demonstrated the potential of these capsules to target antigens to APCs both in vitro and in vivo, resulting in strongly enhanced antigen presentation to CD4 and CD8 T cells and the induction of broad and strong immune responses. The major advantage for their success is presumably threefold: 1) They protect the antigen from degradation before reaching DCs; 2) Because of their size (1–10 mm), they are preferably targeted to DCs; and 3) Because of their soft thin shell, which is prone to the reductive conditions or endosomal proteases depending on the nature of the capsule shell, they allow the antigen to be readily processed upon internalization by DCs. Moreover, these capsules have been shown to be biocompatible and degradable, both in vitro and in vivo. Notwithstanding their excellent performance, polymeric multilayer capsules are fabricated in multiple steps, which is a rather cost-inefficient fashion involving the use of a large excess of polymer and several centrifugation steps during deposition of each single layer. Therefore, a simple and versatile strategy involving a minimum of process steps that mimics polymeric multilayer capsules would be of uttermost importance to allow this type of antigen carriers to reach the clinical stage. Herein, we report on the synthesis of porous antigenloaded degradable polyelectrolyte microspheres using spray drying as a simple, yet efficient, and scalable production [*] M. Dierendonck, Dr. S. De Koker, Prof. Dr. C. Vervaet, Prof. Dr. J.-P. Remon, Dr. B. G. De Geest Laboratory of Pharmaceutical Technology Department of Pharmaceutics, Ghent University Harelbekestraat 72, 9000 Ghent (Belgium) E-mail: br.degeest@ugent.be
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Dec 1, 2023
Reghan J Hill 
Open Access