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. R etinoic acid (RA) signaling is one of the most important biological pathways in nature, triggered by RA interaction with nuclear receptors that control gene expression. The chemical structure of retinol (vitamin A, a RA precursor) was first described by Paul Karrer in 1931 1 , who was awarded a Nobel Prize in 1937 for the discovery. The use of RA for skin disorders 2 and cancer treatment (acute myeloid leukemia (AML) 3 and cervical neoplasia 4,5) started in the 1960s and 1980s (Fig. 1). By the 2000s, RA had been incorporated in many tissue engineering scaffolds as a stem cell differentiation agent 6,7. Over the last 10 years, many discoveries related to the biological role of RA in controlling the biology of hematopoietic stem cells 8,9 , tumor-initiating cells 10-12 , immune cells 13 , intestinal mucosa wound repair 14 , cancer resistance 15 , and cell reprogramming and differentiation 16,17 , have further stimulated the interest in this drug for many other biomedical applications. This interest is confirmed by more than 50 active clinical trials (according to ClinicalTrials.gov) evaluating the effect of RA in cancer (28 trials), mostly in hematological (16 trials) and brain tumors (8 trials), skin pathologies (e.g., acne, photoaging, eczema) (5 trials), and in other conditions such as inflammation, olfactory loss, and neuropsychiatric diseases (Table 1). Clinical applications of RA have highlighted three main limitations of its pharmacological use. First, RA is poorly soluble in aqueous solutions 18 and photosensitive 19 , which makes its administration challenging. Secondly, RA induces irritation when applied onto the skin and increases its catabolism, when it is administered intravenously, reducing its therapeutic efficacy 20. Lastly, RA is involved in many biological processes and thus the systemic delivery of RA causes side effects. All these limitations motivated researchers to synthesize novel and

Bioactive Compounds for Skin Health: A Review

“…They play an active role in protein production, cellular metabolism and cell division [ 28 , 34 , 37 ]. Retinoids also affect the thickness and color of the skin, regulate the function of the sebaceous glands, and limit sebum production, as well as being responsible for hair and nail growth, and also influencing the distribution of melanin in the skin [ 27 , 30 , 35 ].…”

“…The anti-ageing effects of retinoids are mediated by three major types of skin cells: epidermal keratinocytes, dermal endothelial cells and fibroblasts [ 38 ]. Topically applied retinoids penetrate the keratinized epidermis and, to a lesser extent, the dermis and subcutaneous tissue [ 27 , 30 , 35 ]. A study in mice by Törmä et al showed that retinol esters accounted for 90% of the vitamin A in the epidermis, with retinol making up the remaining 10% [ 39 ].…”

“…After penetrating the epidermis, retinoids play a role in the release of transcription and growth factors. They are responsible for the renewal of the epidermis through their active role in the exfoliation of dead cells in the stratum corneum and the proliferation of live cells in the epidermal layers [ 28 , 34 , 35 ]. Moreover, vitamin A promotes the compaction of the stratum corneum and deposition of GAGs in the stratum corneum and intercellular spaces in the epidermis [ 40 ].…”

“…A study conducted by Kang et al showed that the application of all-trans-retinol on normal human skin induced epidermal thickening and increased the mRNA expression of cellular retinoic acid binding protein and cellular retinol binding protein [ 41 ]. Retinoids also reduce transepidermal water loss (TEWL) by strengthening the epidermal barrier [ 28 , 34 , 35 ]. After penetrating the dermis, retinoids increase the synthesis of elastin and collagen by stimulating the fibroblasts [ 42 ].…”

“…Retinoids and all biologically active forms of vitamin A also promote the remodeling of reticulin fibers and synthesis of a new capillary network in the dermis. This process influences the condition of the connective tissue of the dermis, improving its firmness, hydration and elasticity [ 35 , 42 ]. Retinoids protect collagen against the destruction induced by MMPs, as well as enhancing the synthesis of tissue inhibitors of metalloproteinases (TIMPs) [ 32 , 42 ].…”