Novel Drug Delivery Systems Tailored for Improved Administration of Glucocorticoids

Abstract

Glucocorticoids (GC) are one of the most popular and versatile classes of drugs available to treat chronic inflammation and cancer, but side effects and resistance constrain their use. To overcome these hurdles, which are often related to the uniform tissue distribution of free GC and their short half-life in biological fluids, new delivery vehicles have been developed including PEGylated liposomes, polymeric micelles, polymer-drug conjugates, inorganic scaffolds, and hybrid nanoparticles. While each of these nanoformulations has individual drawbacks, they are often superior to free GC in many aspects including therapeutic efficacy when tested in cell culture or animal models. Successful application of nanomedicines has been demonstrated in various models of neuroinflammatory diseases, cancer, rheumatoid arthritis, and several other disorders. Moreover, investigations using human cells and first clinical trials raise the hope that the new delivery vehicles may have the potential to make GC therapies more tolerable, specific and efficient in the future.

Keywords: cancer; drug delivery systems; glucocorticoids; liposomes; nanoparticles; neuroinflammation; rheumatoid arthristis.

Figure 1

Current material concepts for GC delivery. Liposomes are vesicles composed of a phospholipid bilayer that are able to carry GC in their lumen. Modification of their surface by polyethylene glycol (PEG) results in the generation of so-called PEGylated liposomes with improved characteristics. GC are mostly encapsulated in the liposomal cavity in the form of their hydrophilic phosphate or acetate derivatives. In a polymer-drug conjugate, the GC is covalently bound to a macromolecular carrier via a linker, whereas polymeric micelles are spherical structures consisting of a hydrophilic block that can be PEG and a central hydrophobic block where the GC are contained. Besides organic vehicles, there are also inorganic material concepts such as large scaffolds to which GC can be adsorbed. Inorganic-organic hybrid nanoparticles are a new development which is composed of an inorganic cation, e.g., [ZrO]²⁺ or [GdO]²⁺, and a functional organic anion such as a phosphorylated GC with the composition [GC-OPO₃]²⁻, both of which assemble into particles in a similar manner as sodium chloride.

Figure 2

Comparison of different delivery vehicles in modulating EAE and immune cell functions in mice. Treatment of EAE in mice using free GC is mostly mediated via their effects on T cells, namely apoptosis induction and a reduction of adhesion molecules and cytokines such as IFNγ and interleukin (IL)-17. In contrast, GC delivered via PEGylated liposomes or inorganic–organic hybrid nanoparticles (IOH-NP) rather impact on myeloid cells by lowering MHC II surface levels and NO production, and inhibiting TNFα and IL-1β expression. These effects result in a shift of macrophage polarization from M1 to M2. In general, the activity of IOH-NP depends more strictly on the targeting of myeloid cells than it is the case for PEGylated liposomes.

Figure 3

Current state of preclinical and clinical research on GC nanoformulations. Liposomes, polymeric micelles, polymer-drug conjugates, inorganic materials and IOH-NP have been intensively tested in vitro and in vivo. The majority of analyses were performed in animal models of various diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), cancer and GC-related side effects, but translational studies in human cells were also started and even a few clinical trials were already initiated. However, none of the current concepts made it into clinical practice so far.