Parenteral Lipid-Based Nanoparticles for CNS Disorders: Integrating Various Facets of Preclinical Evaluation towards More Effective Clinical Translation

Abstract

Contemporary trends in combinatorial chemistry and the design of pharmaceuticals targeting brain disorders have favored the development of drug candidates with increased lipophilicity and poorer water solubility, with the expected improvement in delivery across the blood-brain barrier (BBB). The growing availability of innovative excipients/ligands allowing improved brain targeting and controlled drug release makes the lipid nanocarriers a reasonable choice to overcome the factors impeding drug delivery through the BBB. However, a wide variety of methods, study designs and experimental conditions utilized in the literature hinder their systematic comparison, and thus slows the advances in brain-targeting by lipid-based nanoparticles. This review provides an overview of the methods most commonly utilized during the preclinical testing of liposomes, nanoemulsions, solid lipid nanoparticles and nanostructured lipid carriers intended for the treatment of various CNS disorders via the parenteral route. In order to fully elucidate the structure, stability, safety profiles, biodistribution, metabolism, pharmacokinetics and immunological effects of such lipid-based nanoparticles, a transdisciplinary approach to preclinical characterization is mandatory, covering a comprehensive set of physical, chemical, in vitro and in vivo biological testing.

Keywords: blood–brain barrier; brain targeting ligands; critical quality attributes; liposomes; nanoemulsions; nanostructured lipid carriers; pharmacokinetic and biodistribution studies; solid lipid nanoparticles.

Figure 1

Key areas in the preclinical development of parenteral lipid-based nanoparticles specifically intended for neurological and other CNS disorders. The list is not exhaustive, as indicated by the last bullets with “…” following every list.

Figure 2

Necessary steps in the size characterization of nanoparticles (from bottom up): testing general sample properties applying low-resolution techniques; resolving multiple size populations of nanoparticles, aggregates, and larger particles; investigation on nanoparticle-protein interactions. Created with BioRender.com (accessed on 31 December 2022).

Figure 3

Proposed drug-delivery mechanisms across BBB in interaction with lipid nanoparticles [5,10,54,140]. Created with BioRender.com (accessed on 16 February 2022).

Figure 4

Different methodologies used in pharmacokinetic and biodistribution studies of lipid nanocarriers. Created with BioRender.com (accessed on 29 December 2022).