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Focal Controlled Drug Delivery pp 195–213Cite as

Intranasal Delivery of Neuropeptide-Loaded Nanoparticles and Their Application to Nervous System Therapeutics

Part of the Advances in Delivery Science and Technology book series (ADST)

Abstract

The neuropeptides represent a rapidly expanding class of promising new CNS drugs. Unfortunately, the delivery of neuropeptides to the brain has been a major obstacle in their therapeutic development. Rapid metabolism in all tissue compartments and a lack of blood–brain barrier (BBB) penetration are two daunting issues related to neuropeptide bioavailability. Interestingly, within the nasal cavity the olfactory epithelium contains olfactory neurons that are the only nerves in direct contact with the external environment. This unique neuroanatomical relationship presents a means to limit metabolism and bypass the BBB to enhance access to olfactory neuronal transport mechanisms to target the CNS. However, several transolfactory barriers exist. Airborne particles entering the nasal cavity are destined for three epithelial regions: vestibular, respiratory, and olfactory. The olfactory region is an important site for access to the brain. Three major barriers to neuropeptide bioavailability exist in this region: the presence of tight junctions between sensory neurons and supporting cells, preventing epithelial transport to the submucous space; a mucous layer containing protective proteolytic/hydrolytic enzymes that impart an enzymatic barrier; and a mucous layer clearance that influences time-dependent neuropeptide absorption (uptake). Following olfactory neuroepithelium uptake, neuropeptides are susceptible to further degradation during transneuronal transport as they are carried to primary olfactory structures. Next, sufficient sustained neuropeptide release is necessary for a pharmacological effect. The development of newer surface-eroding biodegradable nanoparticle (NP) carriers could provide a means of mitigating these impediments to better exploit this nose-to-brain pathway. In order to evaluate this delivery approach, we utilized a rat model of temporal lobe epilepsy (kindling) to show (1) that copolymer microdisks loaded with the neuropeptide thyrotropin-releasing hormone (TRH) implanted in the seizure focus could attenuate kindling development (seizureogenesis); (2) intranasal administration of an unprotected TRH analog could acutely suppress generalized seizures in a concentration-dependent manner; and (3) intranasal administration of TRH-loaded nanoparticles (TRH-NPs) could release sufficient TRH at the seizure focus to impede kindling development (seizureogenesis). Additionally, we utilized intranasal delivery of fluorescent dye-loaded NPs in rats and application of dye-loaded or dye-attached NPs to cortical neurons in culture to demonstrate NP uptake and distribution over time in vivo and in vitro, respectively. Also, an NP immunostaining method was developed to directly visualize the tissue density and distribution of TRH-NPs. Taken together, our preclinical data provides further proof of concept for intranasal administration of neuropeptide-loaded NPs as a feasible means to noninvasively deliver these compounds safely and repeatedly as a novel delivery platform for neuropeptide CNS therapeutics.

Keywords

  • Nasal Cavity
  • Olfactory Epithelium
  • Mucous Layer
  • Intranasal Administration
  • Seizure Focus

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Michael J. Kubek & Daniel J. Kubek

  2. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Michael J. Kubek

  3. Program in Medical Neuroscience, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Michael J. Kubek

  4. Faculty of Medicine, Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem, 91120, Israel

    Abraham J. Domb

  5. School of Dentistry, University of Louisville, 501 South Preston, Louisville, KY, 40202-1701, USA

    Daniel J. Kubek

  6. Department of Radiology, University of Chicago School of Medicine, 5841 S. Maryland Avenue- MC 2026, Chicago, IL, 60637, USA

    Michael C. Veronesi

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  1. Michael J. Kubek
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  2. Abraham J. Domb
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  3. Daniel J. Kubek
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  4. Michael C. Veronesi
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Correspondence to Michael J. Kubek .

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Editors and Affiliations

  1. School of Pharmacy-Faculty of Medicine The Hebrew University of Jerusalem, Jerusalem, Israel

    Abraham J. Domb

  2. Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research (NIPER), Balanagar, Hyderabad, Andhra Pradesh, India

    Wahid Khan

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Kubek, M.J., Domb, A.J., Kubek, D.J., Veronesi, M.C. (2014). Intranasal Delivery of Neuropeptide-Loaded Nanoparticles and Their Application to Nervous System Therapeutics. In: Domb, A., Khan, W. (eds) Focal Controlled Drug Delivery. Advances in Delivery Science and Technology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-9434-8_8

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