Additives in Sunscreens
With the rise of cosmeceuticals and additives in sunscreens, it is important to evaluate the safety and efficacy of these substances. Although the exact mechanism of UVR- and VL-induced photoaging is still being explored, the downstream effects of increased ROS, MMPs, and DNA damage have been widely reported.[8,11] To combat the deleterious effects of sunlight on the skin, additives have been used or proposed in sunscreens to enhance photoprotection and help prevent photoaging.
Antioxidants play an important role in preventing, ameliorating, and dampening free radicals and oxidative stress. Although our bodies produce natural antioxidants, UVR and other stressors can often overwhelm our endogenous supply. Topical antioxidants have been formulated into sunscreens to replenish depleted antioxidant supplies and diminish oxidative stress on the skin. Yet the exact role and efficacy of antioxidants in sunscreens remains controversial. A 2011 ex vivo study by Wang et al. evaluated the radical skin protection factor (RSF) and antioxidant power (AP) of 12 sunscreen products containing vitamin C, vitamin E, or other antioxidant substances against simulated UVA- and UVB-induced ROS. RSF was defined as the ratio of free radicals in unprotected skin to protected skin, and AP evaluates the capacity and reaction time of antioxidants by measuring free electron spin. They demonstrated that the RSF correlated with the UVA RSF rather than any antioxidant ingredients. However, the study was performed ex vivo and may not correlate to in vivo responses in humans. More recent reviews and studies have demonstrated positive effects of the addition of antioxidants into sunscreen formulations. For example, a study looking at skin irradiated with UVB found that sunscreens with SPF 25 and a mixture of caffeine, vitamin E, vitamin C, Echinacea pallida extract, gorgonian extract, and chamomile essential oil demonstrated less MMP-1 expression than those with only SPF 25. The variability in the efficacy of antioxidants in sunscreens may depend on the formulation of the sunscreen. It has been proposed that, for antioxidants to be efficacious, they must have high antioxidative capacities, be present in high concentrations, be stable in the final formulation, and be able to penetrate the stratum corneum and still exist at high enough concentrations in the epidermis and dermis to be effective.
In terms of antioxidants that have been explored in topical formulations, vitamin C (l-ascorbic acid) is the predominant antioxidant in the skin and plays an important role in the skin's aqueous compartments because of its water solubility. It also helps replenish vitamin E, acts as a cofactor in collagen synthesis, and reduces elastin accumulation. It is not synthesized by the human body and must be replenished via oral intake. Additionally, because of its ionic charge at physiologic pH, it cannot penetrate the stratum corneum without becoming unstable. Fortunately, a stable formulation can be made by compounding it with other antioxidants: vitamin E (alpha-tocopherol) and ferulic acid.[61,64] Murray et al. demonstrated that skin irradiated with solarsimulated UVR after application of a topical formulation of 15% l-ascorbic acid, 1% alpha-tocopherol, and 0.5% ferulic acid (CEFer) for 4 days significantly decreased UV-induced erythema, sunburn cells, thymine dimers, and p53 induction when compared with untreated skin. Furthermore, vitamin E has been shown to be effective in the reduction of lipid peroxidation, photoaging, immunosuppression, and photocarcinogenesis in multiple animal and human studies. This suggests a role for topical CEFer in protecting against photoaging and skin cancers.[64,65]
Vitamin A and its derivatives, mainly retinoids and carotenoids, have been well studied in the realm of antiaging and have shown benefit in the prevention and reversal of photoaging. They bind to cytoplasmic receptors such as cellular retinoic acid-binding protein types I and II and cellular retinol-binding protein as well as nuclear receptors such as nuclear retinoic acid receptors and retinoid X receptors to inhibit activation of protein-1 and MMP-1 expression. This leads to increased epidermal proliferation, leading to epidermal thickening, compaction of the stratum corneum, synthesis and deposition of glycosaminoglycans, and increased collagen production.[61,67] Furthermore, there is evidence that topical retinoids may play a role in chemoprevention of nonmelanoma skin cancers through initiating growth arrest of tumor cells and normal cellular differentiation. However, given the relative instability of retinol and retinoids when exposed to UV and visible light, their use as a sunscreen additive is predominantly for their anti-aging effects and not for increased photoprotection. They are rarely found in recreational sunscreens, and their stability is highly dependent on their formulation and chemical structure. For example, when tretinoin is compounded in ethanol, it undergoes isomerization within just a few seconds when irradiated with light of 300–800 nm. The stability of tretinoin is improved when incorporated into liposomes. Retinyl palmitate is an ester of retinol that is widely used in cosmetic products because of their high thermal stability when compared with retinol. A study of 11 healthy volunteers using two formulations of retinyl palmitate for 60 days reported significant improvements in skin smoothness, skin roughness, scaliness, and wrinkles with both formulations. Retinyl palmitate can be compounded with photostabilizers and UV filters and loaded onto nanotechnology-based drug-delivery systems to improve stability and drug penetration, but large-scale randomized controlled trials are needed to study the antiaging properties of these formulations.[70,72] Additionally, concerns have been raised regarding an increase in cutaneous malignancy with simultaneous use of topical retinyl palmitate and UVR exposure. A recent study looking at SKH-1 hairless mice treated with control cream or creams containing retinyl palmitate and subsequently irradiated with simulated solar light demonstrated an increased risk of photo-co-carcinogenesis in the group using cream containing retinyl palmitate. However, these claims have not been largely substantiated or reported in humans and need to be further studied.
Other antioxidants that have been reported in the literature include soy extracts, polyphenols, melatonin, algae extract, and Polypodium leucotomos extract. A study of 68 participants observed that soy moisturizer containing soybean-derived serine protease inhibitors (soybean trypsin inhibitor and Bowman–Birk protease inhibitor) significantly improved mottled pigmentation, blotchiness, dullness, fine lines, overall texture, overall skin tone, and overall appearance when compared with vehicle. This positive clinical effect may be related to the role of soybean-derived serine protease inhibitors on the regulation of keratinocytes through keratinocyte protease-activated receptor 2, but additional studies must be performed to further elucidate its mechanism.
Polyphenols are found in many botanicals, including tea leaves, grape seeds (Vitis vinifera), blueberries, almond seeds, and pomegranate extract. In a study of five participants, sunscreen compounded with tea extracts containing polyphenols such as epigallocatechin-3-gallate better protected human skin against solar-simulated UVR over sunscreen alone in regards to decreasing MMP-1. Additionally, green tea extract compounded with resveratrol, another polyphenol, provided SPF protection independent of physical and chemical UV filters, but additional in vivo studies must be performed to fully assess its effectiveness.
Melatonin acts as an antioxidant in three different but complementary ways. It can act as a free radical scavenger, decrease free radical generation, and upregulate antioxidant enzymes. It has shown promise against both UVB- and UVA-induced oxidative stress. In studies of human melanocytes and keratinocytes, cells pretreated with melatonin decreased p53 expression, improved DNA repair, and decreased CPD generation.[78,79] An in vitro study of mouse fibroblast cells (NIH3T3) pretreated with melatonin and irradiated with UVA demonstrated increased heme-degrading enzymes and suppression of UVA-induced photodamage when compared with untreated irradiated cells. Additionally, melatonin protected against UV-induced erythema and activated endogenous enzymes to act against oxidative stress. This suggests a potential role of melatonin as an additive to protect keratinocytes, melanocytes, and fibroblasts against UV-induced photoaging.
Many studies have shown that multicellular algae not only have UV-absorbing properties but also provide benefits against oxidative stress. Mycosporine-like amino acids (MAAs) produced by algae are potent UV filters with maximum absorption between 310 and 362 nm. Shinorine is a commercialized MAA extracted from a type of red algae, Porphyra umbilicalis, and has already been used in sunscreens produced by two European companies. Furthermore, the algae and algae products have also demonstrated protective properties against photoaging. Alga Corallina pilulifera methanol extract reduced MMP-2 and MMP-9 in UV-irradiated human dermal fibroblasts. Additionally, many species of brown algae are protective against photo-oxidative stress. With controversies around chemical sunscreens and their effects on marine life, algae-derived sunscreens may provide a future solution for eco-friendly photoprotection; however, most formulations of sunscreens with MAAs currently contain only a very small percentage of this active ingredient, and it functions as an adjuvant to UV filters and other sources of photoprotection.
Polypodium leucotomos extract (PLE) is derived from a tropical fern found in Central and South America and has antioxidative, chemoprotective, immunomodulatory, and anti-inflammatory effects.[84,85] In a recent study of 22 individuals irradiated with UVB, UVA, and VL, oral PLE demonstrated suppressive effects on UVB-induced erythema within 2 h of administration. Oral PLE demonstrated similar photoprotective effects against VL. In a cross-over study, subjects taking PLE 480 mg daily demonstrated a significant decrease in persistent pigment darkening, delayed tanning, and cyclooxygenase-2 compared with pre-PLE.[86,87] Oral PLE should be taken daily to receive benefit and is meant to be an adjuvant to sunscreen, not a replacement. Topical formulations of PLE were also effective in reducing sunburn cells and reducing CPD in an in vitro reconstructed human epidermis model. However, future in vivo studies must be performed to better assess the feasibility of topical PLE as a sunscreen additive.
In addition to antioxidants, photolyases are also beneficial additives in sunscreens. Photolyases are enzymes with a unique ability to repair DNA damage, specifically CPDs. They are flavoproteins and require flavonoids as cofactors to absorb UV radiation. The absorbed energy from UV radiation is then transferred to damaged DNA to break CPD bonds in both in vivo and in vitro studies. It also significantly reduced markers of photoaging when added to SPF 50 sunscreen and antioxidants compared with sunscreen alone or sunscreen and antioxidants. This suggests that photolyases may synergistically enhance the photoprotective effects of sunscreens and antioxidants.
Am J Clin Dermatol. 2021;22(6):819-828. © 2021 Adis Springer International Publishing AG