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Preparation and Characterization of Polymersomes for Nose-to-Brain Delivery of Combination Therapeutics in Neuroinflammation Treatment

Manickavasagam, Dharani
http://orcid.org/0000-0001-7542-9483
http://rave.ohiolink.edu/etdc/view?acc_num=kent1555522694193999

Abstract Details

2019, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Neuroinflammation, a hallmark of many neurodegenerative diseases is mediated by microglia, the primary immune cells of the central nervous system (CNS). Activated microglial cells respond to neuronal injury and remove cellular debris, infectious agents via phagocytosis conferring neuroprotection. However, the chronic activation of these cells impairs neuronal function through the excessive release of NO and proinflammatory cytokines TNF-α and interleukins (IL-6, IL-1β and IL-12) which contributes to neuroinflammation and subsequent neurodegeneration in the brain. Thus, suppressing microglial activation is an effective therapeutic strategy to combat neuroinflammation associated with degenerative brain diseases. While anti-inflammatory agents are required to treat neurodegeneration, they may not be sufficient on their own as the disorder is multifaceted and complex but may be effective as part of a combination therapy. Therefore, improved treatment options focused on combinatory neuroprotective effects of simvastatin (Sim) and brain derived neurotrophic factor (BDNF), seem most beneficial in restoring CNS damage, as Sim is known to inhibit inflammation, promote cell survival and BDNF is a predominant neurotrophic factor that mediates survival and growth of a variety of neurons in the CNS. However, the delivery of combination therapeutics that hold promise for the treatment of neurological disorders lack clinical efficacy due to their inability in reaching high enough concentrations in the brain primarily due to the blood brain barrier (BBB), blood-cerebrospinal fluid (CSF) barrier, presence of efflux systems, enzymatic degradation, and several other factors such as rapid clearance from circulation and off-target effects. This calls for the need to develop an efficient drug delivery system (DDS) to overcome obstacles that impede CNS drug delivery and alternate approaches to bypass the BBB. Since microglia function as macrophages, the DDS must be also be effectively removed after the drug has been delivered to prevent the activation of microglial cells. Thus, biocompatible nano-sized delivery systems that specifically target pathways involved in microglial activation and eliminated via natural pathways in the body shows suitability and promise in treatment of neuroinflammation associated with neurodegeneration. The multiple challenges associated with brain drug delivery prompted the proposed investigation. Nano-sized systems (polymeric vesicles) such as polymersomes composed of bilayer membrane will be a suitable platform as they provide dual aqueous compartments that can store and deliver hydrophilic (BDNF) and hydrophobic (Sim) drugs. Therefore, the objective of this research work is to design and characterize polymersomes using diblock copolymers PEG-PLA (polyethylene glycol-polylactic acid) and evaluate its suitability for intranasal delivery of dual neuroprotective drugs (Sim/BDNF), in inhibiting microglial mediated inflammatory responses and protecting toxic environment surrounding neurons in LPS-induced animal model of neuroinflammation. The proposed project is attempting to tackle obstacles associated with drug delivery in CNS disorders. Given that, PEG-PLA is biocompatible, biodegradable, physiologically well tolerated and has low immunogenicity, this work provides preliminary evidence for the application of polymersomes to effectively deliver combination drugs to the brain via the non-invasive nasal route to bypass the BBB.
Moses Oyewumi, Ph.D. (Committee Chair)
Werner Geldenhuys, Ph.D. (Committee Member)
Fayez Safadi, Ph.D. (Committee Member)
Denise Inman, Ph.D. (Committee Member)
Douglas Delahanty, Ph.D. (Committee Member)
204 p.
Biomedical Research; Nanoscience; Nanotechnology; Pharmacology
Microglia, Neuroinflammation, Polymersomes, Simvastatin, BDNF, Combination therapy, Intranasal delivery, Neuroprotection, LPS, Brain, Drug delivery

Recommended Citations

Citations

  • Manickavasagam, D. (2019). Preparation and Characterization of Polymersomes for Nose-to-Brain Delivery of Combination Therapeutics in Neuroinflammation Treatment [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1555522694193999

    APA Style (7th edition)

  • Manickavasagam, Dharani. Preparation and Characterization of Polymersomes for Nose-to-Brain Delivery of Combination Therapeutics in Neuroinflammation Treatment. 2019. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1555522694193999.

    MLA Style (8th edition)

  • Manickavasagam, Dharani. "Preparation and Characterization of Polymersomes for Nose-to-Brain Delivery of Combination Therapeutics in Neuroinflammation Treatment." Doctoral dissertation, Kent State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=kent1555522694193999

    Chicago Manual of Style (17th edition)

kent1555522694193999
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© 2019, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.