A Review of Topical Tapinarof for the Treatment of Plaque Psoriasis.

OBJECTIVE: This article reviews the efficacy and safety of 1% tapinarof cream for plaque psoriasis. DATA SOURCES: A literature search was conducted from August 2022 to February 2023. The terms tapinarof, VTAMA, benvitimod, GSK2894512, DMVT-505, and WBI-1001 were queried in PubMed. ClinicalTrials.gov was searched to identify ongoing or unpublished studies. STUDY SELECTION AND DATA EXTRACTION: All clinical trials written in English and relevant to pharmacology, efficacy, and safety were included. DATA SYNTHESIS: In two 12-week phase III clinical trials, disease severity assessed by a Physician's Global Assessment (PGA) score of clear or almost clear and a 2-point PGA improvement was 35.4% and 40.2% at week 12 in the 2 trials, respectively. In the 40-week, open-label extension trial, the efficacy and safety results were similar: 40.9% of patients achieved a PGA of 0 at least once during the trial, and 58.2% of patients with PGA ≥ 2 achieved PGA 0/1 at least once. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: Tapinarof is a topical aryl hydrocarbon receptor agonist and a first-in-class, potentially promising treatment for plaque psoriasis recently approved by the U.S. Food and Drug Administration. CONCLUSION: Compared with placebo, tapinarof may be an effective and safe topical treatment for mild to severe plaque psoriasis. Head-to-head trials to compare the efficacy and adverse effect profile of tapinarof to other topical treatments are still needed, as are investigation in patients with recent or current use of phototherapy or biologic or nonbiologic systemics. Cost and adherence to treatment may be barriers for treatment efficacy.

Tapinarof cream for the topical treatment of plaque psoriasis in adults.

INTRODUCTION: Plaque psoriasis, a chronic immune-mediated skin disorder, is characterized by well-demarcated erythematous plaques with silvery scales. This condition stems from complex interactions between genetic predisposition, immune dysregulation, and environmental triggers. Tapinarof downregulates the cytokine IL-17, diminishes the inflammatory infiltrate, and provides antioxidant properties while enhancing the expression of skin barrier proteins. AREAS COVERED: This review begins by assessing tapinarof's mechanism in treating plaque psoriasis. Subsequently, it examines the effectiveness and safety of tapinarof 1% cream in adult patients. EXPERT OPINION: Tapinarof 1% cream, which works by activating the aryl hydrocarbon receptor, is an FDA-approved treatment for adult plaque psoriasis. This therapy introduces a novel, nonsteroidal method for addressing inflammation and skin barrier issues, potentially serving as an alternative to conventional treatments. The once-daily, convenient cream formulation and favorable safety profile may enhance patient adherence, which is often poor with topical treatments. Tapinarof also maintains disease clearance for a mean of 4 months after treatment cessation.

Tapinarof cream 1% once daily for the treatment of adults with mild to severe plaque psoriasis: A novel topical therapy targeting the aryl hydrocarbon receptor.

Plaque psoriasis is a chronic, immunemediated skin disease characterized by scaly, erythematous, pruritic plaques. The effects of psoriasis are often debilitating and stigmatizing, significantly impacting patients' physical and psychological well-being and quality of life. Current guideline-recommended psoriasis therapies (topicals, oral systemics, and biologics) have substantial limitations that include overall efficacy, safety, tolerability, sites of application, disease severity, and duration and extent of body surface area treated. Due to these limitations, psoriasis treatment regimens often require combination therapy, especially for moderate to severe disease, leading to increased treatment burden. Psoriasis is also associated with increased indirect costs (eg, reduced work productivity), leading to greater total costs expenditures. Thus, more effective, safe, well-tolerated, and cost-effective therapeutic options are needed. Tapinarof cream 1% once daily is a first-in-class, nonsteroidal, topical aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration in 2022 for the treatment of plaque psoriasis in adults. Tapinarof cream has been evaluated in plaque psoriasis, including 2 pivotal phase 3 trials (NCT03956355 and NCT03983980) and a long-term extension trial (NCT04053387). These trials demonstrated high rates of complete skin clearance with tapinarof cream, durable effects while on treatment (a lack of tachyphylaxis for up to 52 weeks), an approximately 4-month remittive effect off therapy after achieving complete clearance and stopping treatment (ie, duration during which psoriasis does not recur off therapy), and no rebound effects after cessation of therapy. According to the US Food and Drug Administration-approved prescribing information, tapinarof may be used to treat plaque psoriasis of any severity and in any location, has no restrictions on duration of use or extent of total body surface area treated, and has no contraindications, warnings, precautions, or drug-drug interactions. Tapinarof cream is thus an efficacious, well-tolerated, steroid-free topical option that addresses many of the limitations of current recommended therapies. Here we review current knowledge on the physical, psychological, and financial burdens of plaque psoriasis and identify how the clinical profile of tapinarof cream can address key treatment gaps important in the management of plaque psoriasis and patient quality of life. In this article, we aim to assist pharmacists and other managed care practitioners by providing an evidence-based overview of tapinarof cream to support patient-centric decision-making.

Tapinarof cream 1% once daily for the treatment of adults with mild to severe plaque psoriasis: A novel topical therapy targeting the aryl hydrocarbon receptor.

Plaque psoriasis is a chronic, immunemediated skin disease characterized by scaly, erythematous, pruritic plaques. The effects of psoriasis are often debilitating and stigmatizing, significantly impacting patients' physical and psychological well-being and quality of life. Current guideline-recommended psoriasis therapies (topicals, oral systemics, and biologics) have substantial limitations that include overall efficacy, safety, tolerability, sites of application, disease severity, and duration and extent of body surface area treated. Due to these limitations, psoriasis treatment regimens often require combination therapy, especially for moderate to severe disease, leading to increased treatment burden. Psoriasis is also associated with increased indirect costs (eg, reduced work productivity), leading to greater total costs expenditures. Thus, more effective, safe, well-tolerated, and cost-effective therapeutic options are needed. Tapinarof cream 1% once daily is a first-in-class, nonsteroidal, topical aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration in 2022 for the treatment of plaque psoriasis in adults. Tapinarof cream has been evaluated in plaque psoriasis, including 2 pivotal phase 3 trials (NCT03956355 and NCT03983980) and a long-term extension trial (NCT04053387). These trials demonstrated high rates of complete skin clearance with tapinarof cream, durable effects while on treatment (a lack of tachyphylaxis for up to 52 weeks), an approximately 4-month remittive effect off therapy after achieving complete clearance and stopping treatment (ie, duration during which psoriasis does not recur off therapy), and no rebound effects after cessation of therapy. According to the US Food and Drug Administration-approved prescribing information, tapinarof may be used to treat plaque psoriasis of any severity and in any location, has no restrictions on duration of use or extent of total body surface area treated, and has no contraindications, warnings, precautions, or drug-drug interactions. Tapinarof cream is thus an efficacious, well-tolerated, steroid-free topical option that addresses many of the limitations of current recommended therapies. Here we review current knowledge on the physical, psychological, and financial burdens of plaque psoriasis and identify how the clinical profile of tapinarof cream can address key treatment gaps important in the management of plaque psoriasis and patient quality of life. In this article, we aim to assist pharmacists and other managed care practitioners by providing an evidence-based overview of tapinarof cream to support patient-centric decision-making.

Discovery of novel resorcinol biphenyl ether-based macrocyclic small molecules as PD-1/PD-L1 inhibitors with favorable pharmacokinetics for cancer immunotherapy.

Programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1) is one of the most promising immune checkpoints (ICs) in tumor immunology and has been actively pursued as a target for anticancer drug discovery. Based on our previous research in small molecule PD-1/PD-L1 modulators, we designed and synthesized a series of resorcinol biphenyl ether-bearing macrocyclic compounds and evaluated their anti-PD-1/PD-L1 activities. Among them, compound 8d exhibited the highest inhibitory activity against PD-1/PD-L1 interaction with IC50 of 259.7 nM in the homogenous time-resolved fluorescence (HTRF) assay. In addition, 8d displayed in vitro immunomodulatory effects by promoting HepG2 cell death in a HepG2/Jurkat cell co-culture model. Furthermore, 8d effectively inhibited tumor growth (TGI = 74.6% at 40 mg/kg) in a melanoma tumor model in mice without causing obvious toxicity. Moreover, 8d exhibited favorable pharmacokinetics [e.g. high stability, reasonable half-life, and good oral bioavailability (F = 21.5%)]. Finally, molecular modeling studies showed that 8d bound to PD-L1 with high affinity. These results suggest that 8d may serve as a starting point for further development of macrocyclic small molecule-based PD-1/PD-L1 inhibitors for cancer treatment.

Heat shock protein 90 (HSP90) inhibitors in gastrointestinal cancer: where do we currently stand?-A systematic review.

PURPOSE: Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target in oncology, including the treatment of gastrointestinal cancers. METHODS: We carried out a systematic review of data extracted from clinicaltrials.gov and pubmed.gov, which included all studies available until January 1st, 2022. The published data was evaluated using primary and secondary endpoints, particularly with focus on overall survival, progression-free survival, and rate of stable disease. RESULTS: Twenty trials used HSP90 inhibitors in GI cancers, ranging from phase I to III clinical trials. Most studies assessed HSP90 inhibitors as a second line treatment. Seventeen of the 20 studies were performed prior to 2015 and only few studies have results pending. Several studies were terminated prematurely, due to insufficient efficacy or toxicity. Thus far, the data suggests that HSP90 inhibitor NVP-AUY922 might improve outcome for colorectal cancer and gastrointestinal stromal tumors. CONCLUSION: It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade.

Benvitimod inhibits MCM6-meditated proliferation of keratinocytes by regulating the JAK/STAT3 pathway.

BACKGROUND: Benvitimod (Tapinarof), as a small-molecule topical therapeutical aryl hydrocarbon receptor (AHR)-modulating agent, is in clinical development for treating psoriasis and atopic dermatitis. Benvitimod reduces proinflammatory cytokines in psoriasis by specifically binding and activation of AHR. However, whether benvitimod can inhibit keratinocyte proliferation remains unclear. Minichromosome maintenance protein 6 (MCM6) is a key element of the prereplication complex (pre-RC) assembly which is one of the essential steps in the initiation of DNA replication for cell proliferation. OBJECTIVES: This study aimed to determine whether benvitimod could reduce the excessive proliferation of psoriatic keratinocytes by inhibiting MCM6. METHODS: We examined the inhibitory effect of benvitimod on MCM6-mediated proliferation of keratinocytes by HaCaT cells in vitro and an IMQ-induced psoriatic model of mice in vivo. RESULTS: Epidermal MCM6 expression was enhanced in the skin lesions of psoriatic patients. The experiments further revealed that MCM6 was required for the proliferation of keratinocytes and governed by the IL-22/STAT3 pathway. In addition, the antiproliferation effect of benvitimod is achieved by the inhibition of p-JAK1 and p-JAK2, which further restrained the activation of STAT3 in keratinocytes. Lastly, benvitimod could repressed imiquimod-induced skin lesions and the expression of epidermal MCM6 and p-STAT3 in mice. Moreover, knockdown of AHR in keratinocytes enhanced the activation of JAK1 and JAK2. CONCLUSION: The findings reveal that benvitimod could decrease MCM6-mediated proliferation of keratinocytes by affecting the JAK/STAT3 pathway, thereby serving as a new treatment modality for psoriasis.

Tapinarof for psoriasis and atopic dermatitis: 15 years of clinical research.

Tapinarof is a topical, aryl-hydrocarbon receptor agonist that has recently received FDA-approval for the treatment of psoriasis. This novel therapeutic has also been shown to be effective for atopic dermatitis and is currently in phase 3 for this indication. Beyond good efficacy and fast onset of action in patients with psoriasis, the clinical response to tapinarof is notable for durable remission or near remission, maintained for an average of 130 days beyond treatment discontinuation in patients with psoriasis in phase 3 studies. Tapinarof is usually well tolerated but can induce a follicular inflammatory reaction and dermatitis in some patients. This narrative review covers the historical development of this molecule, safety and efficacy data from clinical trials conducted with various topical formulations, and practical considerations derived from our 15 years of clinical trial experience with the drug.

VTAMA® (Tapinarof) Cream* for Plaque Psoriasis.

VTAMA® (Tapinarof) 1% cream is a newly approved topical agent for treating plaque psoriasis. The active ingredient, tapinarof, binds to and activates aryl hydrocarbon receptors that positively regulate immune response and skin homeostasis. Tapinarof has presented promising results in two identical phase 3 randomized, double-blind, vehicle-controlled trials, where the primary efficacy end points were observed in 35.4% and 40.2% of patients in the tapinarof group compared to 6.0% and 6.3% of patients in the vehicle group. Tapinarof was applied once daily to affected psoriasis lesions for 12 weeks. Adverse events associated with tapinarof application were folliculitis, contact dermatitis, and headache. (SKINmed. 2022;20:298-300).

Topical application of TAK1 inhibitor encapsulated by gelatin particle alleviates corneal neovascularization.

Rationale: Corneal neovascularization (CoNV) is a severe complication of various types of corneal diseases, that leads to permanent visual impairment. Current treatments for CoNV, such as steroids or anti-vascular endothelial growth factor agents, are argued over their therapeutic efficacy and adverse effects. Here, we demonstrate that transforming growth factor-ß (TGF-ß)-activated kinase 1 (TAK1) plays an important role in the pathogenesis of CoNV. Methods: Angiogenic activities were assessed in ex vivo and in vitro models subjected to TAK1 inhibition by 5Z-7-oxozeaenol, a selective inhibitor of TAK1. RNA-Seq was used to examine pathways that could be potentially affected by TAK1 inhibition. A gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol was developed as the eyedrop to treat CoNV in a rodent model. Results: We showed that 5Z-7-oxozeaenol reduced angiogenic processes through impeding cell proliferation. Transcriptome analysis suggested 5Z-7-oxozeaenol principally suppresses cell cycle and DNA replication, thereby restraining cell proliferation. In addition, inhibition of TAK1 by 5Z-7-oxozeaenol blocked TNFα-mediated NFκB signalling, and its downstream genes related to angiogenesis and inflammation. 5Z-7-oxozeaenol also ameliorated pro-angiogenic activity, including endothelial migration and tube formation. Furthermore, topical administration of the gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol led to significantly greater suppression of CoNV in a mouse model compared to the free form of 5Z-7-oxozeaenol, likely due to extended retention of 5Z-7-oxozeaenol in the cornea. Conclusion: Our study shows the potential of TAK1 as a therapeutic target for pathological angiogenesis, and the gelatin nanoparticle coupled with 5Z-7-oxozeaenol as a promising new eyedrop administration model in treatment of CoNV.

Tapinarof Cream 1% for Extensive Plaque Psoriasis: A Maximal Use Trial on Safety, Tolerability, and Pharmacokinetics.

BACKGROUND: Tapinarof is a novel topical therapeutic aryl hydrocarbon receptor modulating agent in development for the treatment of psoriasis and atopic dermatitis. OBJECTIVE: This multicenter, open-label trial assessed the safety, tolerability, pharmacokinetics (PK), and efficacy of tapinarof cream 1% once daily (QD) under maximal use conditions in extensive plaque psoriasis. METHODS: Adults with a baseline Physician Global Assessment (PGA) score of ≥ 3 and body surface area (BSA) involvement ≥ 20% received tapinarof cream 1% QD for 29 days. Safety and tolerability assessments included adverse events (AEs) and local tolerability scales. PK parameters were calculated using non-compartmental analysis. Efficacy assessments included change in PGA, Psoriasis Area and Severity Index score, and %BSA affected. RESULTS: Twenty-one patients were enrolled. Common AEs were folliculitis, headache, back pain, and pruritus (none led to discontinuation). Tapinarof plasma exposure was low, with the majority of concentrations being below detectable limits. At day 29, 14 patients (73.7%) had a ≥ 1-grade improvement in PGA score and six patients (31.6%) had a ≥ 2-grade improvement; four patients (21.1%) achieved treatment success (PGA 0 or 1 and ≥ 2-grade improvement). CONCLUSION: Tapinarof cream 1% QD was well tolerated, with limited systemic exposure and significant efficacy at 4 weeks in patients with extensive plaque psoriasis. ClinicalTrials.gov Identifier NCT04042103.

Application of benvitimod on psoriasis: A systematic review and meta-analysis of randomized controlled trials. A systematic review of benvitimod on psoriasis.

BACKGROUND: We conducted this systematic review to clarify the efficacy and safety of benvitimod on psoriasis. METHODS: We searched the databases of PubMed, China National Knowledge infrastructure, Cochrane Library, Embase, Web of science to identify randomized controlled trials (RCTs) of benvitimod on psoriasis up to April 2021. RESULTS: Five RCTs of benvitimod on psoriasis were included. A total of 1237 patients were included. 0.5% or 1.0% benvitimod was applied topically once or twice a day. More patients in benvitimod group achieved PASI 90, PASI 75, PASI 50 and BSA reduction than placebo at Week 12. More patients in benvitimod group achieved PGA 0 or 1 than placebo since Week 6. There were no statistical significances in efficacies of benvitimod at different concentrations and frequencies. CONCLUSIONS: Benvitimod was effective and safe for psoriasis. More RCTs with high qualities are needed to further verify the current conclusion.

New Topical Therapies for Psoriasis.

Psoriasis is a chronic immune-mediated skin disease with a significant impact on patients' quality of life. Mild-to-moderate forms of the disease usually require long-term topical treatment, but prolonged use of corticosteroids and vitamin D analogues is limited by adverse effects. With further understanding of psoriasis pathogenesis, new molecules are emerging aiming to fulfil these clinical needs. Tapinarof, an aryl hydrocarbon receptor modulator, has completed a phase III study and demonstrated good efficacy results, even in long treatment courses, with a favourable safety profile. It additionally appears to have a promising remitting effect as patients presented with an average relapsing time of over 3 months. Roflumilast, a phosphodiesterase type 4 inhibitor, also underwent a phase III study with significant lesion improvement and notable pruritus management, and with no reported side effects. Roflumilast was evaluated as an option for intertriginous areas with good outcomes in a small sample, but larger trials are required. The Janus kinase-signal transducer and activator of transcription pathway has been targeted in recent clinical investigations with promising options, currently with brepocitinib pending phase IIb results. Ongoing preclinical studies involving interleukin-2 inhibition, RNA modulators and amygdalin analogues may lead to forthcoming clinical trials. New topical drugs are successfully emerging and future research comparing them to classical options will dictate their clinical role in the treatment of psoriasis.

A molecular explanation of cardiovascular protection through abnormal cannabidiol: Involving the dysfunctional ß-adrenergic and ATP-sensitive K+ channel activity in cardiovascular compromised preterm infants.

Growing cannabis efficacy, usage frequency, legal supply, and declining awareness of danger recently led to expanded United States cannabis exposure. In turn, cannabis use among elderly people over 50 has more than tripled in a decade and has contributed toward a positive association of cannabis use with pathological conditions, which include type II diabetes, metabolic syndrome, neurovascular and cardiovascular disease. Remarkably, all these outcome results are mediated by the involvement of the ATP-sensitive K+ channel. Cardiovascular compromise is a common syndrome in preterm infants that leads to incidence and death and has been distinguished by poor systemic flow or hypotension. Conditions of cardiovascular compromise include vasodysregulation and myocardial malfunction through dysfunctional ß-adrenergic activity. To avoid organ hypoperfusion progressing to tissue hypoxia-ischemia, inotropic drugs are used. Many premature children, however, respond insufficiently to inotropic activity with adrenergic agonists. The clinical disturbance including myocardial dysfunction through the activation of the ATP-sensitive K+ channel is often involved and the comparative efficacy of the nonpsychotropic cannabinoid, abnormal cannabidiol (Abn-CBD) is not yet known. Therefore, our primary aim was to investigate the molecular exploration of the cannabinoid system specifically Abn-CBD in cardiovascular protection involving dysregulated KATP.

Heat Shock Proteins in Lymphoma Immunotherapy.

Immunotherapy harnessing the host immune system for tumor destruction revolutionized oncology research and advanced treatment strategies for lymphoma patients. Lymphoma is a heterogeneous group of cancer, where the central roles in pathogenesis play immune evasion and dysregulation of multiple signaling pathways. Immunotherapy-based approaches such as engineered T cells (CAR T), immune checkpoint modulators and NK cell-based therapies are now in the frontline of lymphoma research. Even though emerging immunotherapies showed promising results in treating lymphoma patients, low efficacy and on-target/off-tumor toxicity are of a major concern. To address that issue it is suggested to look into the emerging role of heat shock proteins. Heat shock proteins (HSPs) showed to be highly expressed in lymphoma cells. HSPs are known for their abilities to modulate immune responses and inhibit apoptosis, which made their successful entry into cancer clinical trials. Here, we explore the role of HSPs in Hodgkin and Non-Hodgkin lymphoma and their involvement in CAR T therapy, checkpoint blockade and NK cell- based therapies. Understanding the role of HSPs in lymphoma pathogenesis and the ways how HSPs may enhance anti-tumor responses, may help in the development of more effective, specific and safe immunotherapy.

Synthesis and pharmacological evaluation of novel resorcinol biphenyl ether analogs as small molecule inhibitors of PD-1/PD-L1 with benign toxicity profiles for cancer treatment.

Programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1) pathway is one of the most actively pursued targets in cancer immunotherapy. In a continuation of our research interest in this pathway, we synthesized and evaluated the pharmacological activities of a series of resorcinol biphenyl ether analogs as small molecule PD-1/PD-L1 inhibitors for cancer treatment. Among the 27 newly synthesized compounds, CH1 was found to have the highest inhibitory effect against PD-1/PDL-1 with an IC50 value of 56.58 nM in the HTRF (homogenous time-resolved fluorescence) assay. In addition, CH1 dose-dependently promoted HepG2 cell death in a co-culture model of HepG2/hPD-L1 and Jurkat T cells. Furthermore, molecular modeling study indicated that CH1 binds with high affinity to the binding interface of PD-L1. Moreover, CH1 effectively inhibited tumor growth (TGI of 76.4% at 90 mg/kg) in an immune checkpoint humanized mouse model with no obvious toxicity. Finally, CH1 did not cause in vivo cardiotoxicity and bone marrow suppression (myelosuppression) to BALB/c mice. Taken together, these results suggest that CH1 deserves further investigation as a potent and safe PD-1/PDL-1 inhibitor for cancer treatment.

Modified Jessner's Solution Combined With Trichloroacetic Acid 20% Versus Glycolic Acid 70% Combined With Trichloroacetic Acid 20% in the Treatment of Melasma.

BACKGROUND: Melasma is an acquired challenging pigmentary skin problem, which commonly affects the face. A wide range of therapeutic modalities is available, yet none is satisfactory. OBJECTIVE: To compare efficacy and safety of trichloroacetic acid (TCA) 20% peeling with either modified Jessner's solution (MJs) or with glycolic acid (GA) 70% peeling in the treatment of melasma. PATIENTS AND METHODS: Thirty adult Egyptian women with melasma were recruited in the study. After cleansing the face, MJs was applied on one side of the face and GA 70% on the other side. Then, TCA 20% was applied in one uniform coat on both sides of the face. Assessment of the clinical response was guided by calculating the melasma area, severity index (MASI), modified MASI, and hemi-MASI scores before and after the end of treatment. RESULTS: Both combinations showed significant reduction in MASI, modified MASI, and hemi-MASI scores (p value = .000, for each). Moreover, the hemi-MASI score after MJs and TCA20% showed a significant decrease compared with GA70% and TCA20% (p value = .013). CONCLUSION: Both modalities are successful, safe options for treating melasma. Moreover, combining MJs with TCA 20% is more efficacious.

Spherical Nucleic Acids for Topical Treatment of Hyperpigmentation.

Oligonucleotide-based materials such as spherical nucleic acid (SNA) have been reported to exhibit improved penetration through the epidermis and the dermis of the skin upon topical application. Herein, we report a self-assembled, skin-depigmenting SNA structure, which is based upon a bifunctional oligonucleotide amphiphile containing an antisense oligonucleotide and a tyrosinase inhibitor prodrug. The two components work synergistically to increase oligonucleotide cellular uptake, enhance drug solubility, and promote skin penetration. The particles were shown to reduce melanin content in B16F10 melanoma cells and exhibited a potent antimelanogenic effect in an ultraviolet B-induced hyperpigmentation mouse model.