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Development of Immunosupressant and Peptide Loaded Microparticles as Tolerogenic Vaccines for Treatment of Autoimmune Diseases

Kanthamneni, Naveen
http://rave.ohiolink.edu/etdc/view?acc_num=osu1331050212

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Pharmacy.
Multiple Sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS) and most current treatments for the disease dampen the overall immune system. An antigen-specific T-regulatory (T-reg) population that would suppress the autoimmune signaling could treat MS. To this end a microparticle loaded with dexamethasone and autoimmune antigen that can passively target dendritic cells (DCs) was developed. To formulate the microparticle, a recently described polymer acetalated dextran (Ac-DEX) was used. Ac-DEX is a biocompatible biopolymer which undergoes tunable burst degradation at the acidic conditions that can be present in the phagosome after phagocytosis (pH 5) but slower degradation at extracellular conditions (pH 7.4), thereby making it an ideal candidate for immune applications. Dexamethasone-encapsulated Ac-DEX microparticles exhibited a dose sparing response when cultured with macrophages and bone marrow derived dendritic cells in vitro. Furthermore, a significant reduction in overall experimental autoimmune encephalomyelitis (EAE) score was observed in vivo with prophylactic administration of dexamethasone and peptide loaded Ac-DEX particles. Overall, this system displays good progress towards development of a tolerogenic vaccine for MS. To optimize microparticle preparation for better drug encapsulation, particles size and degradation rates, studies were done with rapamycin (immunosuppressant) loaded Ac-DEX microparticles using various molecular weights of dextran. Optimized microparticles were determined by varying the chemical and physical parameters during particle synthesis. Results showed that rapamycin-loaded microparticles prepared with 71k molecular weight Ac-DEX had higher encapsulation efficiency and slower overall degradation than microparticles synthesized from 10k Ac-DEX. These particles will be advantageous for future applications in immune suppression therapies. Finally studies were carried out to investigate the stability of enzyme-loaded Ac-DEX particles over prolonged periods under various storage conditions. Horseradish peroxidase (HRP) was selected as a model enzyme for this study. Particles were prepared by sonication or homogenization techniques and were stored at different temperatures (-20°C, 4 °C, 25 °C, and 45 °C) over a period of 3 months. Irrespective of the preparation method, temperature, and storage time, all the particles were spherically shaped with no signs of degradation. However, in terms of retaining the enzyme activity, homogenized particles showed better shielding of HRP than probe sonicated particles at 25 °C or 45 °C. Overall Ac-DEX particles provided better stabilization of model enzyme as compared to the free enzyme, and can be advantageous in loading drugs or enzymes that need to be stored or protected at temperatures outside the cold chain.
Thomas Schmittgen, PhD (Advisor)
Cynthia Carnes, PharmD, PhD (Committee Member)
Sylvan Frank, PhD (Committee Member)
Pharmaceuticals; Polymers
dexamethasone; Ac-DEX; EAE; multiple sclerosis

Recommended Citations

Citations

  • Kanthamneni, N. (2012). Development of Immunosupressant and Peptide Loaded Microparticles as Tolerogenic Vaccines for Treatment of Autoimmune Diseases [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1331050212

    APA Style (7th edition)

  • Kanthamneni, Naveen. Development of Immunosupressant and Peptide Loaded Microparticles as Tolerogenic Vaccines for Treatment of Autoimmune Diseases. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1331050212.

    MLA Style (8th edition)

  • Kanthamneni, Naveen. "Development of Immunosupressant and Peptide Loaded Microparticles as Tolerogenic Vaccines for Treatment of Autoimmune Diseases." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1331050212

    Chicago Manual of Style (17th edition)

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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.