WO2023208013A1 - APPLICATION D'UN INHIBITEUR DE HIF-1α DANS LE TRAITEMENT DE L'ALOPÉCIE ANDROGÉNIQUE - Google Patents

APPLICATION D'UN INHIBITEUR DE HIF-1α DANS LE TRAITEMENT DE L'ALOPÉCIE ANDROGÉNIQUE Download PDF

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WO2023208013A1
WO2023208013A1 PCT/CN2023/090743 CN2023090743W WO2023208013A1 WO 2023208013 A1 WO2023208013 A1 WO 2023208013A1 CN 2023090743 W CN2023090743 W CN 2023090743W WO 2023208013 A1 WO2023208013 A1 WO 2023208013A1
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hif
inhibitor
hair
alopecia
androgenic alopecia
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王大鹏
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苏州翊鹏医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the invention belongs to the technical field of androgenetic alopecia treatment, and specifically relates to the application of HIF-1 ⁇ inhibitors in the treatment of androgenetic alopecia.
  • AGA Androgenic alopecia
  • the main clinical manifestations of this disease are hair loss on the forehead, top of the head (male type) or central area of the scalp (female type), which may be accompanied by There are conditions such as thin and soft hair, reduced density, or greasy scalp; under dermoscopy, the difference in hair shaft diameter is >20%, increased vellus hairs, reduced number of hairs per unit hair follicle, brown peritullary sign, yellow spot sign, etc.; the pathological characteristics are mainly hair follicles. Progressive reduction in size. Hair loss will affect many aspects of the patient's work and life, and can easily destroy the patient's self-confidence, leading to depression, anxiety and other behaviors.
  • Orentreich first proposed the term "androgenic alopecia", thus revealing the close connection between androgens and hair loss. It is currently believed that AGA is an androgen-dependent polygenic hereditary disease. This heritability increases the sensitivity of hair follicles to androgen, affects the signal transduction between the dermal papilla and hair follicle cells, leading to a series of changes such as the forehead. And/or the top susceptible hair follicles progressively shrink, the terminal hair follicles gradually transform into vellus hair follicles, the hair anagen phase progressively shortens, and the hair matrix and dermal papilla shrink at the same time, the hair also becomes shorter and thinner accordingly, leading to baldness. happened.
  • the main androgen present in the body is testosterone (testosterone, T), while dihydrotestosterone (DHT) is a more active androgen produced by the conversion of T under the catalysis of 5 ⁇ -reductase. It is similar to androgen.
  • the affinity of the androgen receptor (AR) is 5 times that of testosterone times, after testosterone or dihydrotestosterone combines with AR, it enters the nucleus and binds to the DNA receptor, thereby producing biological effects.
  • human 5 ⁇ -reductase has two isoenzymes, type I and type II. Type I is mainly distributed in sebaceous glands, chest and back skin, liver, adrenal glands and kidneys.
  • Type II is mainly distributed in the scalp and hair follicles (the outer hair root sheath is the most common). inner layer) and the tissue surrounding the hair follicle.
  • McGinley et al. found that patients with congenital type II 5 ⁇ -reductase deficiency had normal or slightly elevated serum testosterone, but reduced DHT synthesis. Homozygous patients showed pseudohermaphroditism, with reduced body hair, normal hair growth, and no AGA. occur.
  • the levels of testosterone, dihydrotestosterone, AR and 5 ⁇ -reductase in the scalp of bald areas are higher than those in non-bald areas (such as occipital scalp) or the same areas in non-bald people, thus explaining how severe AGA is.
  • minoxidil The therapeutic mechanism of minoxidil is not completely clear, and may include multiple pathways, such as opening ATP-dependent K + channels on the cell membrane, affecting the activity and stability of androgen receptor (AR), etc. Although both are currently widely used in clinical practice, neither can completely block the progression of the disease, and both have varying degrees of adverse reactions.
  • the screening method for cofactors includes the following steps: Step S1, use scalp biopsy technology to collect scalp tissue samples from normal volunteers and patients with androgenic alopecia; Step S2, detect different AR cofactors (c-Jun, NF- ⁇ B, Expression of SMAD3 and HIF-1 ⁇ ) in scalp tissue samples of normal volunteers and patients with androgenetic alopecia; Step S3, select the AR cofactors differentially expressed in step S2, and initially determine them as cofactors related to androgenetic alopecia.
  • the cofactor related to androgenic alopecia identified in the present invention is HIF-1 ⁇ .
  • the detection was performed using Western blotting.
  • a second aspect of the present invention provides the use of HIF-1 ⁇ inhibitors in the preparation of drugs for treating androgenic alopecia.
  • the HIF-1 ⁇ inhibitor can have a good effect on androgenic alopecia.
  • the HIF-1 ⁇ inhibitor can effectively inhibit the auxiliary effect of HIF-1 ⁇ on AR.
  • HIF-1 ⁇ HIF-1 ⁇ on AR is manifested by inhibiting the expression of one or more genes selected from Nmur1, Pcolce, Fbln1, Prrx1, Vim, Tnfrsf1b, and Fstl1.
  • the HIF-1 ⁇ inhibitor is selected from one or more of LW6, 2-MeOE2, PX-4782HCI, and BAY87-2243.
  • the third aspect of the present invention provides the use of a HIF-1 ⁇ detection reagent in preparing an androgenic alopecia risk prediction kit.
  • the HIF-1 ⁇ detection reagent includes antibodies for HIF-1 ⁇ Western blot detection, antibodies for immunohistochemical detection, or primers and probes for quantitative PCR.
  • the HIF-1 ⁇ detection object is the scalp tissue sample of the subject.
  • the HIF-1 ⁇ inhibitor is selected from one or more of LW6, 2-MeOE2, PX-4782HCI, and BAY87-2243.
  • the fourth aspect of the present invention provides a method for constructing a mouse model of androgenetic alopecia, which is characterized in that The method includes the step of injecting testosterone propionate into male C57BL/6 mice.
  • the frequency of injection is daily.
  • the present invention performs scalp biopsy on normal people and patients with androgenetic alopecia to screen out the differentially expressed AR cofactor HIF-1 ⁇ .
  • the risk of androgenetic alopecia can be predicted through the detection of this differentially expressed factor.
  • HIF-1 ⁇ inhibitors prevent the transcription of related genes (Nmur1, Pcolce, Fbln1, Prrx1, Vim, Tnfrsf1b, Fstl1) by effectively inhibiting HIF-1 ⁇ in the mouse model of androgenetic alopecia, causing related genes to The expression of the gene changes, and the decrease in the expression of related genes will promote hair growth in androgenetic alopecia model mice, and thus can be used as a therapeutic drug for androgenetic alopecia.
  • related genes Namur1, Pcolce, Fbln1, Prrx1, Vim, Tnfrsf1b, Fstl1
  • the drug for androgenetic alopecia prepared by using HIF-1 ⁇ inhibitors provided by the present invention has the advantages of low cost, low toxic and side effects, and significant curative effect, and provides a new strategy for the treatment of androgenetic alopecia.
  • Figure 1 shows the expression of different AR cofactors in scalp samples from patients with androgenic alopecia and normal volunteers.
  • Figure 2A shows the therapeutic effects of various HIF-1 ⁇ inhibitor drugs in the constructed mouse model of androgenic alopecia.
  • Figure 2B is a statistical diagram of the weight of new shaved hair in the constructed mouse model of androgenic alopecia.
  • Figure 3 shows the GO enrichment analysis of differentially expressed genes between skin sample cells of androgenetic alopecia model mice after treatment with the inhibitor LW6.
  • Figures 4A-4G respectively show the effects of inhibitors LW6, 2-MeOE2, PX-4782HCI, and BAY87-2243 on genes Nmur1 (Figure 4A), Pcolce ( Figure 4B), Fbln1 ( Figure 4C), Prrx1 ( Figure 4D), and Vim ( Figure 4D). 4E), Tnfrsf1b (Fig. 4F), and Fstl1 (Fig. 4G) expression levels.
  • AR androgen receptor
  • NTD N-terminal transcriptional activation domain
  • DBD DNA binding domain
  • LBD ligand binding domain
  • AR cofactor refers to a factor that modulates the transcriptional activity of the androgen receptor (AR) and thereby affects many functional properties of the AR, including ligand selectivity and/or DNA binding ability. Transcription factors.
  • AR cofactors include c-Jun, NF- ⁇ B, SMAD3 and HIF-1 ⁇ , for verification.
  • hypoxia-inducible factor is a transcription factor widely present in mammals and humans under hypoxic conditions and is a key factor in response to hypoxic stress.
  • HIF-1 ⁇ is a subunit of hypoxia inducible factor-1 (HIF-1), which is regulated by hypoxia and regulates the activity of HIF-1.
  • HIF-1 ⁇ is transferred to the nucleus and combines with HIF-1 ⁇ to form active HIF-1, which regulates the transcription of multiple genes by binding to the hypoxia response element on target genes.
  • HIF-1 ⁇ can form different signaling pathways with multiple upstream and downstream proteins to mediate hypoxic signals and regulate cells to produce a series of
  • the compensatory response to hypoxia plays an important role in the growth and development of the body as well as physiological and pathological processes, and is a focus of biomedical research.
  • HIF-1 ⁇ inhibitor refers to a compound or composition that can be used to inhibit the activity and/or expression of HIF-1 ⁇ . Including but not limited to, LW6 (CAS number: 934593-90-5), 2-MeOE2 (CAS number: 362-07-2), PX-4782HCI (CAS number: 685898-44-6), BAY87-2243 (CAS No.: 1227158-85-1) and so on.
  • AGA androgenetic alopecia
  • androgenetic alopecia is a common and frequently-occurring disease in dermatology. It is a characteristic alopecia with genetic factors involved and dependent on androgen action, which often affects The patient's body image and mental health are adversely affected.
  • the main reason for the production of AGA is that when there is too much testosterone in the skin, under the catalysis of 5-alpha reductase, testosterone can generate dihydrotestosterone. Dihydrotestosterone competes with testosterone for the androgen receptor in the hair follicle target cells.
  • dihydrotestosterone Since dihydrotestosterone is significantly more active than testosterone, dihydrotestosterone has a stronger ability to bind to androgen receptors than testosterone. Once dihydrotestosterone enters the cell nucleus, it can inhibit the growth of hair follicle cells, prompting the hair follicles to enter the resting phase in advance, leading to hair loss. Androgens can also act on sebaceous glands, activating the SREBP pathway in sebaceous gland cells, promoting the development and differentiation of immature cells in the outer layer of sebaceous gland cells into mature secretory cells, causing sebaceous gland gland hypertrophy, enhanced secretion function, and excessive sebum production. When sebaceous glands secrete excessively, excess sebum will clog or compress pores, hinder normal hair growth and even induce inflammation, causing hair to wither and fall off.
  • This example uses Western blotting to detect the expression levels of c-Jun, NF- ⁇ B, SMAD3 and HIF-1 ⁇ in scalp tissue samples from patients with androgenic alopecia and normal volunteers.
  • Scalp tissue samples were collected through scalp biopsy technology. A total of 30 scalp tissue samples from patients with androgenic alopecia and 30 normal volunteers were collected. Then use RIPA tissue/cell lysis buffer and PMSF reagent to extract the protein, and use the extracted protein for the next step of Western blotting experiment.
  • the specific steps of the Western blotting experiment are as follows: First, prepare 10% SDS separation gel and stacking gel according to the formula, mix the sample with the loading buffer, boil it in an ice bath at 100°C for 5 minutes, add equal amounts of each sample using a microsampler after ice bath and centrifugation. Lanes were electrophoretically separated and proteins were separated by SDS-PAGE, transferred to PVDF membranes (Merck Millipore, MA, USA) and incubated in 5% BSA for 1 hour.
  • c-Jun primary antibody (abcam, #ab40766), NF- ⁇ B primary antibody (abcam, #ab32536), SMAD3 primary antibody (abcam, #ab40854), HIF-1 ⁇ diluted 1:400 at 4°C.
  • the primary antibody (abcam, #ab179483) and ⁇ -actin primary antibody (abcam, #ab115777) were incubated overnight, washed three times with TBST and then incubated with goat anti-rabbit secondary antibody (abcam, #ab6721) for 1 hour. Wash 3 times with PBS buffer at room temperature, 5 min each time. Immerse the membrane in the ECL reaction solution at room temperature for 1 min. After removing the liquid, cover the film with food wrap, expose it to a line film in a dark room, develop and fix it, and observe the results.
  • the cause of hair loss is mainly due to the difference in sensitivity of local hair follicles to AR.
  • the inventor speculates that inhibiting the differential expression of AR cofactor-HIF-1 ⁇ will lead to changes in AR sensitivity and then lead to hair loss.
  • the inventors constructed a mouse model of androgenetic alopecia to explore the therapeutic effect of HIF-1 ⁇ inhibitors on androgenetic alopecia.
  • mice Male C57BL/6 mice aged 6-8 weeks and weighing 18-22g were selected for model preparation. After adaptive feeding for 1 week, they were numbered according to body weight and randomly divided according to body weight using Excel. There are 6 groups, 5 mice in each group. First, use a razor to shave the mouse hair, and then use depilatory cream to remove about 2 ⁇ 3cm 2 on its back. After depilating for 5-10 minutes, wipe the depilatory cream with warm water. The spine of the mice was used as the dividing line, and a skin area of 2 ⁇ 3 cm 2 was taken from the symmetrical part of the back as the experimental area. The drug solvent in all administration groups in the experiment was non-toxic and harmless corn oil, and the experimental animals were randomly Divided into the following groups, see Table 1 below:
  • mice in the blank group received no treatment except shaving.
  • the mice in the remaining groups were lightly anesthetized with 5% chloral hydrate and injected subcutaneously with testosterone propionate at a dose of 5 mg/kg daily to establish a mouse model of androgenic alopecia.
  • 30 days After 30 minutes of modeling treatment, the modeling group and the drug administration group were administered medication according to the above protocol. Photographs were taken every day to record the new hair of the mice. After 30 consecutive days, the mice were sacrificed and the new hair of the mice was shaved with a razor. Calculate the weight of new hair in mice.
  • Figure 2A shows the therapeutic effects of various drugs in the constructed mouse model of androgenic alopecia.
  • Figure 2B is a statistical diagram of the average weight of new hair of five shaved mice in the constructed mouse androgenic alopecia model. From Figures 2A and 2B, it can be seen that the model group experienced 30 days of hair growth. The new hair was sparse and the hair loss area was large. There was still a large bare hairless area on the back of the mouse and the average weight of the new hair was light. However, the HIF-1 ⁇ inhibitor treatment group , after 30 days of hair growth in the blank group, the new hair was dense and the area of hair loss was small. The back of the mice was visible to the naked eye with a large area of new hair and almost no exposed hairless area. The average weight of new hair was far higher than that of the modeling group.
  • HIF-1 ⁇ participates in inflammatory reactions.
  • tissue metabolic activity is enhanced due to the infiltration and high metabolic rate of inflammatory cells, resulting in an increase in oxygen demand.
  • the action of inflammatory factors causes blood vessel damage. Contraction reduces the oxygen supply to the inflammatory area, forming a hypoxic microenvironment, resulting in a large amount of HIF-1 ⁇ expression.
  • Current research shows that ILGF-1, IL-1, TNF- ⁇ , pGE2 and LPS and other pro-inflammatory cytokines can activate the transcriptional activity of HIF-1, suggesting the close relationship between HIF-1 ⁇ and the inflammatory process.
  • Example 3 Single-cell transcriptome sequencing detects cellular level gene changes in skin tissue of androgenetic alopecia mouse model
  • mice in the HIF-1 ⁇ inhibitor-LW6 treatment group peeled off and separated the skin tissue of mice in the HIF-1 ⁇ inhibitor-LW6 treatment group and the mice in the modeling group and performed single-cell transcriptome sequencing.
  • inflammation-related genes are significantly upregulated in scalp biopsy samples from patients with androgenic alopecia.
  • HIF-1 ⁇ inhibitors In order to further explore the mechanism of action of HIF-1 ⁇ inhibitors in the treatment of androgenetic alopecia, the inventors detected the transcription of inflammation-related genes (Nmur1, Pcolce, Fbln1, Prrx1, Vim, Tnfrsf1b, Fstl1) after treatment with HIF-1 ⁇ inhibitors. Condition.
  • qPCR real-time fluorescence quantitative PCR
  • the specific steps are as follows: Cut the tissue sample into 2-4 mm slices. Then transfer it to the C tube of gentleMACS, add an appropriate amount of TRIzol, tightly cover the C tube, place it upside down on the gentleMACS tissue dissociator, and continue to rotate and incubate the tissue sample for 30 minutes. After the reaction is completed, the tissue sample can be Transfer the liquid to a centrifuge tube and centrifuge at 12,000 rpm for 10 minutes. After centrifugation is completed, transfer all the aspirated supernatant to a new centrifuge tube, then add 200 mL of chloroform to it, use a vortex shaker to shake the centrifuge tube for about 15 seconds, and then place it still in the centrifuge tube.
  • HIF-1 ⁇ inhibitor LW6, 2-MeOE2, PX-4782HCI, BAY87-2243 purchased from Selleck, product numbers: #S8441, #S1233, #S7612, #S7309).
  • HIF-1 ⁇ inhibitors will lead to a decrease in the expression levels of related genes (Nmur1, Pcolce, Fbln1, Prrx1, Vim, Tnfrsf1b, Fstl1) in mouse skin samples.
  • the inventor believes that these genes are regulatory Downregulation of key genes for hair loss ultimately improved hair loss in mouse models of androgenic alopecia.

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Abstract

Une application d'un inhibiteur de HIF-1α dans la préparation d'un médicament pour le traitement de l'alopécie androgénique est divulguée dans la présente invention. L'inhibiteur de HIF-1α peut efficacement inhiber l'effet auxiliaire de HIF-1α sur AR, et inhiber l'expression de l'alopécie et de gènes associés à l'inflammation (Nmur1, Pcolce, Fbln1, Prrx1, Vim, Tnfrsf1b, Fstl1) dans un modèle murin d'alopécie androgénique, favorisant ainsi la pousse des cheveux. L'inhibiteur de HIF-1α selon la présente invention est choisi parmi un ou plusieurs composants parmi LW6, 2-MeOE2, PX-4782HCI et BAY87-2243. L'inhibiteur de HIF-1α présente les avantages de faibles coûts, de faibles effets toxiques et secondaires et d'effets curatifs considérables, et fournit une nouvelle stratégie pour le traitement de l'alopécie androgénique.
PCT/CN2023/090743 2022-04-29 2023-04-26 APPLICATION D'UN INHIBITEUR DE HIF-1α DANS LE TRAITEMENT DE L'ALOPÉCIE ANDROGÉNIQUE WO2023208013A1 (fr)

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FR2854243A1 (fr) * 2003-04-24 2004-10-29 Oreal Procede de determination d'etats pre-alopeciques et/ou d'atteintes cutanees au moyen d'un marqueur predictif: hif-1(hypoxia inducible factor-1)
CN102361853A (zh) * 2008-12-30 2012-02-22 欧洲分子生物学实验室 甲苯胺磺酰胺及其用途
CN107429284A (zh) * 2016-03-25 2017-12-01 花王株式会社 皮脂腺或毛囊选择性雄激素受体活性控制剂的评价或选择方法
CN115089711A (zh) * 2022-04-29 2022-09-23 苏州翊鹏医药科技有限公司 HIF-1α抑制剂在雄激素性脱发治疗中的应用

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