Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine

Abstract

Retinoids regulate a wide spectrum of cellular functions from the embryo throughout adulthood, including cell differentiation, metabolic regulation, and inflammation. These traits make retinoids very attractive molecules for medical purposes. In light of some of the physicochemical limitations of retinoids, the development of drug delivery systems offers several advantages for clinical translation of retinoid-based therapies, including improved solubilization, prolonged circulation, reduced toxicity, sustained release, and improved efficacy. In this Review, we discuss advances in preclinical and clinical tests regarding retinoid formulations, specifically the ones based in natural retinoids, evaluated in the context of regenerative medicine, brain, cancer, skin, and immune diseases. Advantages and limitations of retinoid formulations, as well as prospects to push the field forward, will be presented.

Fig. 1. Milestones in RA formulations research.

ATRA all-trans retinoic acid, FDA Food and Drug Administration, RA retinoic acid.

Fig. 2

Retinoid chemical structures (a) and RA signaling pathway (b). Blood-circulating retinol is internalized through membrane transporter and receptor stimulated by retinoic acid 6 (STRA6) and converted into all-trans retinoic acid (RA), which binds to cellular retinoic acid-binding protein type 2 for signaling in the nucleus. RA triggers gene transcription by binding to RA receptors (RAR) and to the retinoid X receptor (RXR). In the presence of the ligand, RAR and RXR heterodimerize on retinoic acid-response element (RARE) sequences located in promoter regions inducing the transcription of target genes. Of note, RXR may also homodimerize and trigger gene transcription (not depicted in the illustration). RA signaling may also occur via activation of receptors associated with lipid rafts located on the cell surface, which trigger transcriptional activation of target genes by histone and receptor phosphorylation in the cell nucleus. ADH alcohol dehydrogenase, CRBP cellular retinol-binding protein 1, CYP26 cytochrome P450 family 26, Gαq Gq protein alpha subunit, MAPK mitogen activated protein kinases, P phosphorylation, RALDH retinaldehyde dehydrogenase, RBP4 retinol-binding protein 4, RDH retinol dehydrogenase.

Fig. 3. Main outcomes of RA-based therapies in pathological contexts.

AD Alzheimer’s disease, PD Parkinson’s disease, RA retinoic acid, ↑ = increased effect, ↓ = decreased effect, ● = regulatory effect.

Fig. 4. Challenges and advances in topical and systemic administration of RA-containing formulations.

Challenges include: a crossing endothelial barriers for extravasation of RA-containing formulations into a specific body region; b targeting of RA-containing formulations to specific cells; c development of formulations that combine RA with other pharmacological agents, able to release each agent with a specific release kinetics. Advances include: a development of formulations with less toxicity; b release of RA with variable release kinetics to achieve variable biological actions; c action mechanism of RA during development and disease; d use of cells to transport RA-containing formulations to specific regions in the body followed by the triggering of the formulations by intrinsic (e.g., temperature, pH) or extrinsic (e.g., ultrasound, light) stimuli. RA retinoic acid.