Review and Modern Advances of Retinoids for Cosmetics

The vitamin A metabolite retinol is essential for life, and has been shown to exhibit a diverse range of biological functions. Natural as well as synthetic molecules that are structurally related to vitamin A are referred to as retinoids, and typically consist of a polyene chain linking a cyclic end group to a polar end group (see Figure 1). Within the cell, retinoids function as signaling molecules, and play important roles in vision, embryonic development, cell proliferation, cell differentiation and immune functions.¹ Vitamin A is stored intracellularly as retinyl esters, which after conversion to retinol, are oxidized to more bioactive retinaldehydes or retinoic acids. The structural abundance of retinoids (see Figure 2) and subsequent bioactivity allow for a variety of therapeutic applications within the pharmaceutical and cosmetic space.

Chemotherapy and Cancer Prevention

In carcinogenesis, the intracellular levels of retinyl esters are greatly reduced, compromising retinoid signaling.² In relation, extensive work has been conducted to examine the efficacy of retinoids to restore signaling for cancer therapy. These studies show retinoids are both chemopreventive and chemotherapeutic, with their activity attributed to abilities to induce cell differentiation, arrest cell proliferation and promote apoptosis in cancer cells.³

All-trans retinoic acid, or tretinoin, is the most extensively studied retinoid for cancer therapies, and has been evaluated in clinical trials for the treatment of lymphoma, melanoma, lung cancer, neuroblastoma and leukemia.³ Retinoids have shown efficacy at preventing the onset and development of cancer, especially precancerous skin lesions. UV irradiation can cause a deficiency of vitamin A; as such, retinoid treatment can prevent aberrant signaling and skin cancer development.³

Anti-Aging Properties

Intrinsic skin aging is a natural process, although the majority of changes in skin appearance and health are attributed to sun exposure.⁴ Natural skin aging is mainly characterized by fine wrinkling and sagging, whereas photoaging causes increased pigmentation, deep wrinkling, sallowness and dryness. Further differences between intrinsic aging and photoaging can be seen at the cellular level. Intrinsically aged skin is thinner, with lower levels of collagen and fibroblasts. Photoaged skin is thicker, with the accumulation of elastin and disorganization of collagen.⁵

Retinoids can be effective at repairing photodamaged skin by repairing or halting the degradation of collagen, elastin and hyaluronic acid, the main structural constituents of skin. All-trans retinoic acid is commonly prescribed to successfully improve the appearance of aged skin as well as prevent the unfavorable effects of aging. This is accomplished by stimulating dermal collagen production, reducing collagen degradation, and promoting epidermal turnover.^{6, 7} Non-prescription retinoids such as retinol, retinaldehyde and retinyl propionate also effectively lessen skin wrinkling by stimulating extracellular collagen production.⁸ In the skin, these derivatives are converted to the more active retinoic acid,⁹ which results in similar effects to retinoic acid.¹⁰

Retinoid efficacy is backed by numerous clinical trials, and thus remains the gold standard for the treatment of skin aging.¹¹

Effective Acne Treatment

The use of retinoids to improve acne has been successful as well.¹² Here, retinoids function by exhibiting immunomodulatory and anti-inflammatory responses, in addition to stimulating collagen production and increasing epithelial turnover.¹³ These activities also treat acne scarring.¹⁴

All-trans retinoic acid has repeatedly been proven to significantly reduce mild to moderate inflammatory acne and blackheads, making it a frequently prescribed acne medication.¹³ The most effective acne therapy, however, is oral 13-cis-retinoic acid, isotretinoin, which typically cures acne when other treatments fail.¹⁵ Unfortunately, the use of oral retinoids, which is most commonly isotretinoin, is limited due to side effects such as teratogenicity, caused by increased levels of retinoic acid throughout the body.¹⁶ The topical application of retinol, however, has not been shown to affect levels of retinoic acid in blood plasma, therefore avoiding teratogenic risks¹⁷—although both tretinoin and isotretinoin treatments have high irritation potential, and are light and air sensitive. Newer generations of synthetic retinoids, including adapalene and tazarotene, represent molecules that are beginning to overcome these limitations (see Figure 3).

A New Retinoid for Cosmetics

The pharmaceutical and cosmetic utility of retinoids is impressive, but recent work aims to push the skin care benefits even further. One common goal is to avert the skin irritation and dryness commonly associated with topical retinoid treatments. Structural alterations to vitamin A—such as molecular alterations to the cyclic group, polar group or linker—have enabled the construction of synthetic retinoids that harness the desired activities while simultaneously reducing adverse side effects.¹⁸ Taking inspiration from stored retinyl esters, novel esterified forms of retinoic acid are also being investigated. Typically, natural retinyl esters, such as retinyl propionate, are less active than retinol.⁸ However, new synthetic esters, such as hydroxypinacolone retinoate, are proving to be viable alternatives (see Figure 3).

Hydroxypinacolone retinoate is of great interest because it is capable of interacting with retinoid receptors without first being converted to retinol or retinoic acid.¹⁹ This allows for the effective treatment of skin while eliminating the irritation and dryness caused by acidic retinoids. Furthermore, topically applied hydroxypinacolone retinoate effectively diffuses into skin, comparable to topically applied retinoic acid, again without elevating the levels of retinoic acid in blood plasma, thus eliminating the risk of teratogenicity.¹⁹

Conclusion

Clearly, retinoids possess a wide spectrum of functions. For skin cancer, skin aging and acne, they have proven both preventive and therapeutic. Successful efforts to create more bioavailable vitamin A derivatives and retinoid formulations have increased the industry’s reliance on them for cosmetic benefits. Recent work to further optimize retinoids and reduce their side effects for cosmetic applications has yielded a new generation of promising molecules.

References

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