Experimental investigation and mathematical modeling for nanoemulsion-based drug delivery to the central nervous system (CNS)

Abstract

Novel therapies for treating neurological diseases have resulted in limited success - not only because of the lack of pharmacological activity, but also due to the ineffective delivery of drugs into the brain. Nano-scale drug delivery system such as nanoemulsions have received significant attention for improving central nervous system (CNS) drug delivery. The objective of this doctoral thesis project was to investigate the transport mechanisms and CNS drug delivery potential of systemically and intranasally administered nanoemulsions. First - a hypothesis on sensitive formulation attributes to increase the cellular permeability of nanoemulsions was generated by modeling the cellular permeability data of fish oil nanoemulsions in Caco-2 cells. Next, rapamycin-containing fish oil nanoemulsions were dose systemically to mice, where the pharmacokinetic results suggested that the circulation half-life and particle size distribution did not impact the brain targeting efficiency of nanoemulsions, and in the absence of any improvement in the systemic exposures of rapamycin, nanoemulsions did not outperform their aqueous counterpart with respect to the extent of CNS drug delivery. Going forward, a semi-mechanistic model was developed to investigate the CNS targeting potential and transport mechanisms of intranasally administered nanoemulsions. Our work not only confirmed that nanoemulsions consistently resulted in enhanced CNS drug delivery and targeting efficiency than drug solutions, but also provided insights on their transport mechanisms. Our work established that following systemic dosing nanoemulsions do not provide a robust drug delivery approach to enhance brain targeting, and BBB penetration, which primarily depends on intrinsic drug-related properties, may not be significantly improved following encapsulation of drugs in nanoemulsions. However, the mathematical modeling and simulation results demonstrated that following intranasal dosing, nanoemulsions improve drug permeability and bioavailability in the nasal cavity to significantly enhance CNS drug delivery, thereby providing an effective delivery system for targeting drugs to the CNS.