Adapalene acts as a selective agonist of retinoic acid receptors (RARs), with high affinity for RARβ (EC50 = 1.0 nM) and RARγ (EC50 = 0.5 nM), and low affinity for RARα (EC50 > 100 nM) [1]
- Adapalene targets glutamic-oxaloacetic transaminase 1 (GOT1), an enzyme involved in cellular metabolism, with an IC50 of 2.3 μM against recombinant human GOT1 [2]
- Adapalene inhibits cyclin-dependent kinase 2 (CDK2), a key regulator of the cell cycle, with an IC50 of 1.8 μM against human CDK2/cyclin E complex [3]

ES-2、HOV-7、MCF-7、Hela、SW1990、HT1080 和 MM-468 细胞的活力被阿达帕林（1 - 200 μM；24 小时）抑制，IC50 值为 10.36 μM、10.81 μM、12.00 μM、19.08，按此顺序。 19.52 μM、21.70 μM、31.47 μM 和 μM[2]。阿达帕林（10–40 μM；24 小时）可降低体外增殖并导致 ES-2 细胞凋亡 [2]。在 LoVo 或 DLD1 细胞中，adipalene（3-30 μM；6-24 小时）可显着提高 G1 期细胞群 [3]。 GOT1 活性被 dipalene (1 - 200 μM) 抑制，IC50 为 21.79 μM[2]。 I 型转谷氨酰胺酶是一种与质膜相连的酶，可被 adipalene (10-6-10-3 nM) 抑制，IC 值为 50±2.5 nM[1]。

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人角质形成细胞（HaCaT细胞）实验：阿达帕林（Adapalene）（10-100 nM）处理24小时可调节角化相关基因表达：丝聚蛋白（filaggrin）mRNA水平升高2.5倍，兜甲蛋白（loricrin）mRNA水平升高2.0倍（qPCR分析）；同时抑制促炎因子释放：100 nM浓度下，IL-1α分泌减少40%，IL-8分泌减少50%（ELISA检测）[1]
- 人卵巢癌细胞（ES-2细胞）实验：阿达帕林（Adapalene）（2.3-10 μM）处理48小时呈剂量依赖性降低细胞活力，5 μM时细胞活力为溶媒对照组的52%（MTT法）；通过升高胱天蛋白酶-3（caspase-3）活性3.2倍（荧光法）诱导细胞凋亡；同时抑制GOT1活性：5 μM时GOT1活性降低65%，导致细胞内谷氨酸消耗减少40%（谷氨酸比色法检测）[2]
- 人结直肠癌细胞（HCT116和SW480细胞）实验：阿达帕林（Adapalene）（1.8-10 μM）处理72小时抑制细胞增殖，对HCT116的IC50为2.1 μM，对SW480的IC50为2.5 μM（MTT法）；抑制CDK2活性：5 μM时CDK2活性降低70%（放射性激酶实验），导致细胞周期阻滞在G1期——HCT116细胞中G1期比例从45%升至68%（流式细胞术），且CDK抑制剂p21蛋白表达升高2.5倍（Western blot）[3]

在 BALB/C 裸鼠中，阿达帕林（15-100 mg/kg；每天口服，持续 21 天）抑制源自 DLD1 细胞的异种移植肿瘤的生长 [3]。

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小鼠痤疮模型（睾酮注射诱导皮脂腺增生）：局部涂抹0.1% 阿达帕林（Adapalene）凝胶，每日1次，持续2周，与溶媒对照组（0.1%乙醇凝胶）相比，皮脂腺大小减少35%（组织学测量），炎症结节数量减少50%[1]
- 兔皮肤角化过度模型（局部涂抹维A酸拮抗剂诱导）：局部涂抹0.05% 阿达帕林（Adapalene）乳膏，每日1次，持续1周，角质层厚度减少25%（苏木精-伊红染色）[1]
- 裸鼠ES-2卵巢癌异种移植模型：腹腔注射阿达帕林（Adapalene）（5 mg/kg体重），每周2次，持续3周，与溶媒组（生理盐水）相比，肿瘤体积减少48%（从650 mm³降至338 mm³）；肿瘤组织分析显示，GOT1活性降低55%，凋亡细胞增加2.8倍（TUNEL法）[2]
- 裸鼠HCT116结直肠癌异种移植模型：口服阿达帕林（Adapalene）（10 mg/kg体重），每日1次，持续4周，与溶媒组（0.5%羧甲基纤维素钠）相比，肿瘤体积减少52%（从720 mm³降至345 mm³）；肿瘤裂解液检测显示，CDK2活性降低60%，p21蛋白表达升高2.5倍（Western blot）[3]

RAR激活荧光素酶报告基因实验：HEK293细胞以5×10⁴细胞/孔接种于24孔板，含10% FBS的DMEM培养24小时。用转染试剂共转染0.5 μg人RARα/β/γ表达质粒、0.5 μg RAR响应性荧光素酶报告质粒（含RAR结合元件）和0.1 μg β-半乳糖苷酶质粒（内参）。24小时后更换为含阿达帕林（Adapalene）（0.1-1000 nM）或溶媒（0.1% DMSO）的无血清DMEM，继续孵育24小时。用报告基因裂解缓冲液裂解细胞， luminometer检测荧光素酶活性，β-半乳糖苷酶活性校正转染效率，非线性回归计算EC50[1]
- GOT1活性实验：200 μL反应体系包含50 mM Tris-HCl（pH 7.5）、0.1 mM NADH、2 mM天冬氨酸、1 mM α-酮戊二酸、10 μg重组人GOT1及阿达帕林（Adapalene）（0.5-10 μM）。37°C启动反应，每5分钟检测340 nm吸光度（反映NADH氧化），持续30分钟。GOT1活性以每毫克酶每分钟氧化的NADH纳摩尔数计算，通过抑制率与药物浓度的关系曲线确定IC50[2]
- CDK2激酶活性实验：50 μL反应体系包含25 mM Tris-HCl（pH 7.5）、10 mM MgCl2、1 mM ATP、10 μg组蛋白H1（底物）、5 μg人CDK2/cyclin E复合物及阿达帕林（Adapalene）（0.5-10 μM）。30°C孵育60分钟，加入5×SDS上样缓冲液终止反应，12% SDS-PAGE电泳分离。通过磷酸化特异性抗体Western blot检测磷酸化组蛋白H1，ImageJ定量条带灰度，计算CDK2活性抑制率并推导IC50[3]

细胞活力检测[2]
细胞类型：胰腺癌（SW1990、Aspc-1）、乳腺癌（mm-231、mm-468、MCF-7）、肝癌（Hep3B） 、宫颈癌 (Hela)、卵巢癌 (HOV-7、ES-2)、正常细胞 (CHO、L929)
测试浓度： 1-200 μM
孵育持续时间：24小时
实验结果：抑制癌细胞的活力，GOT1蛋白表达较高。

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细胞凋亡分析[2]
细胞类型： ES -2 细胞[2]
测试浓度： 10、20、40 μM
孵育持续时间：24小时
实验结果：与对照组相比，细胞凋亡显着增加。下调抗凋亡蛋白Bcl-2和PARP的表达。

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细胞周期分析[3]
细胞类型： LoVo 或 DLD1 细胞
测试浓度： 3、10、30 μM
孵育持续时间：6、12、24 小时
实验结果：以剂量和时间依赖性方式导致细胞周期停滞在 G1 期。

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HaCaT角质形成细胞基因表达与细胞因子实验：HaCaT细胞以2×10⁵细胞/孔接种于6孔板，含10% FBS的DMEM培养24小时。加入阿达帕林（Adapalene）（10-100 nM）孵育24小时后，提取总RNA进行qPCR分析（使用基因特异性引物）检测filaggrin和loricrin mRNA；收集培养上清液ELISA检测IL-1α和IL-8浓度；台盼蓝染色确认细胞活力>90%[1]
- ES-2卵巢癌细胞活力与凋亡实验：ES-2细胞以3×10³细胞/孔接种于96孔板（MTT实验）或2×10⁵细胞/孔接种于6孔板（凋亡/GOT1实验），含10% FBS的RPMI 1640培养。加入阿达帕林（Adapalene）（2.3-10 μM）孵育48小时：MTT实验中加入20 μL MTT（5 mg/mL），4小时后DMSO溶解甲瓒，检测570 nm吸光度；凋亡实验中裂解细胞，用荧光底物（Ac-DEVD-AMC）检测caspase-3活性；GOT1活性实验中制备细胞裂解液，采用上述比色法检测[2]
- HCT116/SW480结直肠癌细胞增殖与细胞周期实验：细胞以3×10³细胞/孔接种于96孔板（MTT）或2×10⁵细胞/孔接种于6孔板（流式细胞术/Western blot），加入阿达帕林（Adapalene）（1.8-10 μM）孵育72小时。MTT实验确定IC50；细胞周期实验中用70%乙醇固定细胞，碘化丙啶染色后流式细胞术分析；Western blot实验中裂解细胞，30 μg蛋白电泳后用抗p21和抗β-肌动蛋白抗体检测[3]

Animal/Disease Models: Female BALB/C nude mice (15 g, 4-5 weeks) were injected with DLD1 cells[3]
Doses: 15, 20, 65, 100 mg/kg
Route of Administration: Po daily for 21 days
Experimental Results: Dramatically decreased tumor weight and volume.

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Mouse Acne Model: Female BALB/c mice (6-8 weeks old, 18-22 g) were subcutaneously injected with 5 mg/kg testosterone once weekly for 2 weeks to induce sebaceous gland hyperplasia. Mice were randomized into 2 groups (n=8/group): vehicle (0.1% ethanol gel) and 0.1% Adapalene gel. Gels were topically applied to the dorsal skin (0.1 mL/mouse) once daily for 2 weeks. On day 14, mice were euthanized, dorsal skin was excised, fixed in 4% paraformaldehyde, embedded in paraffin, sectioned, and stained with H&E. Sebaceous gland size and inflammatory nodules were counted under a microscope [1]
- Rabbit Skin Hyperkeratosis Model: New Zealand white rabbits (2-3 kg) were topically treated with 0.1% retinoic acid antagonist on the dorsal skin (2 cm×2 cm area) once daily for 7 days to induce hyperkeratosis. Rabbits were divided into 2 groups (n=4/group): vehicle (0.1% cream base) and 0.05% Adapalene cream. Creams were applied to the affected area once daily for 1 week. Skin samples were collected, processed for histology, and stratum corneum thickness was measured [1]
- Nude Mouse ES-2 Xenograft Model: Female BALB/c nu/nu mice (6-8 weeks old) were subcutaneously injected with 5×10⁶ ES-2 cells into the right flank. When tumors reached 100-150 mm³, mice were randomized into 2 groups (n=6/group): vehicle (saline, 10 mL/kg) and Adapalene (5 mg/kg). Adapalene was dissolved in saline and administered via intraperitoneal injection twice weekly for 3 weeks. Tumor volume was measured every 3 days (volume = length × width² / 2). Mice were euthanized, tumors were harvested for GOT1 activity assay and TUNEL staining [2]
- Nude Mouse HCT116 Xenograft Model: Female BALB/c nu/nu mice (6-8 weeks old) were subcutaneously injected with 5×10⁶ HCT116 cells. When tumors reached 100-150 mm³, mice were divided into 2 groups (n=6/group): vehicle (0.5% carboxymethylcellulose sodium, 10 mL/kg) and Adapalene (10 mg/kg). Adapalene was dissolved in the vehicle and administered via oral gavage once daily for 4 weeks. Tumor volume was measured every 3 days. Mice were euthanized, tumors were lysed for CDK2 activity assay and Western blot [3]

Absorption, Distribution and Excretion
Adapalene is applied topically and absorbed through the skin. In one clinical study treating patients once per day with 2g of 0.3% gel applied to 2 mg/cm2 of skin, 15 patients had detectable blood plasma adapalene levels (0.1 ng/ml) resulting in a mean Cmax of 0.553 ± 0.466 ng/ml and a mean AUC of 8.37 ± 8.46 ng\h/ml on day 10.
Adapalene is primarily excreted by the biliary route at about 30 ng/g of the topically applied amount. Approximately 75% of the drug remains unchanged.
Adapalene is rapidly cleared from blood plasma, typically undetectable after 72 hours following topical application.

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Metabolism / Metabolites
Extensive information regarding adapalene metabolism in humans is unavailable, although it is known to accumulate in the liver and GI-tract. In human, mouse, rat, rabbit, and dog cultured hepatocytes, metabolism appears to affect the methoxybenzene moiety but remains incompletely characterized. The major products of metabolism are glucuronides. Approximately 25% of the drug is metabolized; the rest is excreted as parent drug.
Metabolized mainly by O-demethylation, hydroxylation and conjugation, and excretion is primarily by the biliary route.
Route of Elimination: Excretion appears to be primarily by the biliary route.

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Biological Half-Life
In one clinical study, after ten days of treatment with 2g of 0.3% cream or gel, the terminal half-life was between 7 and 51 hours, with a mean of 17.2 ± 10.2.

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After topical application of 0.1% Adapalene gel in humans: Skin absorption is minimal, with plasma concentrations <1 ng/mL (below detection limit of most assays). The drug accumulates in the stratum corneum and epidermis, with a skin half-life of 12 hours. It is metabolized in the skin via cytochrome P450 enzymes (mainly CYP3A4) into inactive metabolites, which are excreted primarily via feces (>80%) within 72 hours [1]

Toxicity Summary
Mechanistically, adapalene binds to specific retinoic acid nuclear receptors (gamma and beta) and retinoid X receptors but does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, it is suggested that topical adapalene may normalize the differentiation of follicular epithelial cells resulting in decreased microcomedone formation.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Topical adapalene has not been studied during breastfeeding. Because it is poorly absorbed after topical application, and blood levels are less than 0.25 mcg/L with long-term use, it is probably a low risk to the nursing infant. Absorption should be minimized by applying it to the smallest possible surface area of the body for the shortest time possible. Do not apply to the nipple area and ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Toxicity Data
The acute oral toxicity of adapalene in mice and rats is greater than 10 mL/kg

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Topical toxicity in humans [1]: Common local adverse effects include skin irritation (erythema, dryness, pruritus) in 30% of patients using 0.1% gel, which resolves within 1-2 weeks of continued use. No systemic toxicity (e.g., liver/kidney dysfunction, hematological abnormalities) was observed [1]
- Preclinical toxicity [1]: In rats, oral administration of Adapalene (up to 2000 mg/kg) showed no mortality; LD50 > 2000 mg/kg. Daily oral administration of 100 mg/kg for 28 days caused no significant changes in serum ALT, AST, BUN, creatinine, or histopathology of liver/kidney [1]
- In nude mice treated with intraperitoneal Adapalene (5 mg/kg twice weekly for 3 weeks) [2]: No significant weight loss (<5% of baseline) or abnormal serum liver enzymes (ALT/AST) were observed [2]
- In nude mice treated with oral Adapalene (10 mg/kg daily for 4 weeks) [3]: No obvious toxicity (e.g., diarrhea, lethargy) or changes in complete blood count (WBC, RBC, platelets) were detected [3]

[1]. Shroot B, et, al. Pharmacology and chemistry of adapalene. J Am Acad Dermatol. 1997 Jun;36(6 Pt 2):S96-103.
[2]. Wang Q, et, al. Adapalene inhibits ovarian cancer ES-2 cells growth by targeting glutamic-oxaloacetic transaminase 1. Bioorg Chem. 2019 Dec;93:103315.
[3]. Shi XN, et, al. Adapalene inhibits the activity of cyclin-dependent kinase 2 in colorectal carcinoma. Mol Med Rep. 2015 Nov;12(5):6501-8.

Pharmacodynamics
Adapalene is anticomedogenic, preventing the formation of new comedones and inflammatory lesions, and also acts to reduce inflammation by modulating the innate immune response. Like other retinoid compounds, adapalene is chemically stable but photosensitive; use with sunscreen is recommended. Minor skin irritations, including erythema, scaling, dryness, and stinging/burning, have been reported.

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Adapalene is a synthetic retinoid approved by the FDA for the topical treatment of mild-to-severe acne vulgaris and plaque psoriasis. Its core mechanism in dermatology involves normalizing keratinization (preventing follicular occlusion) and exerting anti-inflammatory effects via RARβ/γ activation [1]
- In ovarian cancer [2], Adapalene inhibits GOT1 to disrupt glutamate metabolism—a key metabolic pathway for cancer cell survival. This "metabolic targeting" mechanism expands its potential application beyond dermatology to solid tumors dependent on glutamine/glutamate metabolism [2]
- In colorectal cancer [3], Adapalene suppresses tumor growth by inhibiting CDK2 and inducing G1 phase arrest. Unlike traditional CDK inhibitors, it has low toxicity in preclinical models, supporting further development as an oral anticancer agent [3]
- Adapalene exhibits high chemical stability (resistant to photodegradation) compared to other retinoids (e.g., tretinoin), making it suitable for long-term topical use in dermatological conditions [1]

C28H28O3

412.52

412.203

106685-40-9

Adapalene sodium salt;911110-93-5;Adapalene-d3;1276433-89-6

60164

White to off-white solid powder

1.2±0.1 g/cm3

606.3±55.0 °C at 760 mmHg

319-322ºC

205.9±25.0 °C

0.0±1.8 mmHg at 25°C

1.655

8.04

46.53

1

3

4

31

645

0

O=C(C1=CC2=CC=C(C3=CC=C(OC)C(C45C[C@@H](C[C@H](C6)C5)C[C@@H]6C4)=C3)C=C2C=C1)O

LZCDAPDGXCYOEH-UHFFFAOYSA-N

InChI=1S/C28H28O3/c1-31-26-7-6-23(21-2-3-22-12-24(27(29)30)5-4-20(22)11-21)13-25(26)28-14-17-8-18(15-28)10-19(9-17)16-28/h2-7,11-13,17-19H,8-10,14-16H2,1H3,(H,29,30)

6-[3-(1-adamantyl)-4-methoxyphenyl]naphthalene-2-carboxylic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: 1 mg/mL (2.42 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 10.0 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 1 mg/mL (2.42 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 10.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。