Composite Polymeric Delivery for Use as a Single Dose Vaccine
Type of DegreePhD Dissertation
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Vaccinology in the 21st century is characterized by refinement of Jenner’s principle of protection using less pathogenic organisms with natural or induced reduction of virulence. The approach to the treatment of the new diseases as well as stopping the pandemic from known diseases has generally been reactive, and specific medical interventions have not been available in time to make a substantial impact. Developing better ways to anticipate and modulate the ongoing microbial challenge will be critical for achieving the ability to prevent the spread of diseases. Technical advances in the field of vaccines and understanding the molecular mechanisms of the immune system have provided tools that have made a more proactive approach feasible. There is a necessity for rapid diagnosis, the definition of transmission pathways, availability of antimicrobial agents and predominantly the delivery of these antimicrobial agents to battle the diseases. Traditional vaccines are effective for disease prevention, but they still face various limitations like the requirement of repeated administration to boost immune response, the potential side effects of inflammation and difficulty in the administration to patients which has motivated the use of nanomedicine for vaccine delivery. Nanomedicine can help achieve the long-lasting controlled burst release of vaccines, the capability of co-encapsulating adjuvants or immune modulators for enhanced immune response and targeting to a group of immune cells. New and powerful vaccine technologies, combined with nanotechnologies, could revolutionize vaccines. Controlled drug delivery for small molecule drugs has advanced tremendously in the past few decades that we no longer depend only on the conventional pharmaceutical formulations. The ease of manufacture and the ability to modify the properties of these controlled drug delivery devices will provide an excellent opportunity to use these novel approaches for the delivery of vaccines. The primary goal of this work is to develop a controlled pulsed delivery system which can be utilized as a single dose vaccine, which will help avoid the need for the repeated administration to achieve full and sustained protection. Vaccine release from these devices mainly depends on the way it is incorporated within the delivery device, i.e., encapsulated/entrapped into or merely adsorbed /associated onto the device and the choice of the delivery device (liposomes, polymeric delivery). Biodegradable polymeric nanoparticles are preferred devices for controlled release because of ease of manufacturing, high encapsulation efficiencies, tunable properties, and long-term stability. The advantage of nanoparticle formulations against conventional systems is that they might increase the efficacy of treatment as well as reduce side effects due to their specific targeting action. There have been a variety of biodegradable delivery devices that are being studied currently including biodegradable polymers such as poly-(D, L-lactic-co-glycolic) acid (PLGA) and polysaccharides such as alginate and chitosan. PLGA has emerged as a promising candidate and is FDA approved for use in sutures in humans for controlled drug delivery. A composite polymeric delivery approach with PLGA and chitosan is used in this work to achieve a pulsed delivery system. In the present work, adenoviral vectors are used as model vaccines which are encapsulated inside biodegradable and biocompatible composite polymeric delivery device produced with PLGA and chitosan. These composite particles are produced using a modified double emulsion solvent evaporation process. Varying process conditions achieve modulation of size and surface properties of these particles. It is possible to modulate the size of the particles in a range of 300nm to 4.5 μm along with changing the distribution of chitosan in the particle. It is demonstrated that adenoviral vector (Ad-eGFP) retained its activity after the encapsulation process. The particles demonstrated a controlled delivery of Ad-eGFP, and it is possible to vary the release kinetics by varying various process parameters. Furthermore, Ad-flu is encapsulated in these composite particles and in vitro and in vivo release behavior is observed. In vivo immune response in mice is checked using the HAI assay. Mechanism of release kinetics is explained using some of the established models. It is observed that the release of the viral vectors from these composites follows Non-Fickian diffusion kinetics. The composite polymeric delivery device developed using PLGA and chitosan shows a promising controlled delivery device for vaccine delivery; they could be further explored by tailoring their properties to achieve a pulsed delivery system. These composite particles can be used as potential candidates to encapsulate various macromolecules like proteins, peptides, and cancer vaccines for the future generation of controlled delivery devices.