Search

CN-122005594-A - Pharmaceutical composition containing PROTAC small molecules and siRNA molecules and application thereof

CN122005594ACN 122005594 ACN122005594 ACN 122005594ACN-122005594-A

Abstract

The invention provides a pharmaceutical composition containing PROTAC small molecules and siRNA molecules and application thereof, belonging to the technical field of alopecia medicine preparation. The invention provides a composition comprising siRNA targeting NFKBIZ genes and functional small molecules (protein degradation targeting chimeric molecules or fish peptide LAGF molecules) with targeting Androgen Receptor (AR), wherein nanoparticles prepared by using a soybean lecithin nanoliposome delivery system can effectively overcome the difficulty in delivering the composition to keratinocytes, promote efficient skin delivery, remove excessive ROS, inhibit inflammatory reaction in hair follicles, provide an effective multi-target strategy for AGA treatment, effectively regulate the expression of AR proteins, regulate signal paths related to hair growth, and finally realize multi-mode cooperative treatment on AGA, thereby enhancing the treatment effect on alopecia.

Inventors

  • ZHANG CHUAN
  • ZHOU YANAN
  • ZHU YIDONG
  • LI LIANG
  • LI XIN

Assignees

  • 上海交通大学
  • 齐鲁制药有限公司

Dates

Publication Date
20260512
Application Date
20251229

Claims (10)

  1. 1. A composition comprising an siRNA targeting the human NFKBIZ gene and a functional small molecule targeting a degrading androgen receptor protein; The nucleotide sequence of the siRNA targeting the human NFKBIZ gene is shown as SEQ ID NO. 1, and the nucleotide sequence of the siRNA targeting the murine NFKBIZ gene is shown as SEQ ID NO. 3.
  2. 2. The composition of claim 1, wherein the functional small molecule targeted to degrade androgen receptor proteins comprises a protein degradation targeting chimera or fish-derived peptide LAGF molecule targeted to androgen receptor; The composition includes a first combination of the NFKBIZ gene targeting siRNA and an androgen receptor targeting protein degradation targeting chimeric molecule and/or a second combination of the NFKBIZ gene targeting siRNA and a fish-derived peptide LAGF molecule.
  3. 3. The composition of claim 2, wherein in the first combination, the molar ratio of the siRNA targeting the NFKBIZ gene to the androgen receptor targeting protein degradation targeting chimeric molecule is 1:3-20.
  4. 4. The composition according to claim 2, wherein in the second combination, the mass ratio of the molar amount of the siRNA targeting the NFKBIZ gene to the molecular amount of the fish peptide LAGF is 1 μmol/3-8 mg.
  5. 5. The method of preparing the composition of any one of claims 1 to 4, comprising mixing and shaking the dissolved NFKBIZ gene targeting siRNA with a functional small molecule of an androgen receptor targeting protein.
  6. 6. A nanoparticle for treating alopecia, comprising a liposome and the composition of any one of claims 1 to 4 or siRNA targeting NFKBIZ gene coated in the liposome; The nucleotide sequence of the siRNA targeting the human NFKBIZ gene is shown as SEQ ID NO. 1, and the nucleotide sequence of the siRNA targeting the murine NFKBIZ gene is shown as SEQ ID NO. 3.
  7. 7. The nanoparticle for treating alopecia of claim 6, wherein the liposome is prepared by mixing soybean lecithin and deoxycholate sodium; The mass ratio of the soybean lecithin to the sodium deoxycholate is 9-11:1.
  8. 8. A method for preparing the nanoparticle for treating alopecia according to claim 6 or 7, comprising the steps of: Dissolving soybean lecithin and sodium deoxycholate to prepare a film coating; Adding an siRNA targeting the NFKBIZ gene or the composition of any one of claims 1-4 to the film coating, forming a liposome suspension by hydration; repeatedly freezing and thawing the liposome suspension until the film breaks, and extruding the nano particles.
  9. 9. A medicament for treating alopecia, characterized in that the active ingredient comprises siRNA targeting NFKBIZ gene, the composition according to any one of claims 1 to 4, the nanoparticle for treating alopecia according to claim 6 or 7 or the nanoparticle prepared by the preparation method according to claim 8; The nucleotide sequence of the siRNA targeting the human NFKBIZ gene is shown as SEQ ID NO. 1, and the nucleotide sequence of the siRNA targeting the murine NFKBIZ gene is shown as SEQ ID NO. 3.
  10. 10. The siRNA targeting the NFKBIZ gene, the composition according to any one of claims 2-4, the nanoparticle for treating alopecia according to claim 6 or 7 or the application of the nanoparticle prepared by the preparation method according to claim 8 in preparation of medicines for treating androgenetic alopecia, wherein the nucleotide sequence of the siRNA targeting the human NFKBIZ gene is shown as SEQ ID NO. 1, and the nucleotide sequence of the siRNA targeting the murine NFKBIZ gene is shown as SEQ ID NO. 3.

Description

Pharmaceutical composition containing PROTAC small molecules and siRNA molecules and application thereof Technical Field The application belongs to the technical field of alopecia medicine preparation, and particularly relates to a pharmaceutical composition containing PROTAC functional small molecules and siRNA molecules and application thereof. Background Androgenetic alopecia (AGA) is gradually showing a tendency to younger as a global, cross-race and sex-independent disease. However, there is still a lack of effective treatments. Androgen Receptor (AR) binding to androgens, excess Reactive Oxygen Species (ROS), and hypovascularization of the microenvironment surrounding the hair follicle are key factors leading to the occurrence of AGA. According to the problem of alopecia, two main treatments are currently available, namely minoxidil vasodilator and AR-related pathway regulator, which have side effects and disadvantages. Disclosure of Invention The invention provides a composition composed of siRNA capable of effectively treating androgenetic alopecia and functional small molecules of targeted degradation androgen receptor, wherein the siRNA molecules can effectively inhibit inflammation by targeting NFKBIZ genes, and the functional small molecules can relieve pathological driving factors of androgenetic alopecia by targeted degradation androgen receptor, and finally achieve the aim of efficiently treating alopecia by synergism. The invention provides a composition comprising siRNA targeting human NFKBIZ gene and functional small molecules targeting androgen receptor protein degradation; The nucleotide sequence of the siRNA targeting the human NFKBIZ gene is shown as SEQ ID NO. 1, and the nucleotide sequence of the siRNA targeting the murine NFKBIZ gene is shown as SEQ ID NO. 3. Preferably, the functional small molecule targeting the androgen receptor protein comprises a protein degradation targeting chimera targeting the androgen receptor or a fish-derived peptide LAGF molecule; The composition includes a first combination of the NFKBIZ gene targeting siRNA and an androgen receptor targeting protein degradation targeting chimeric molecule and/or a second combination of the NFKBIZ gene targeting siRNA and a fish-derived peptide LAGF molecule. Preferably, in the first combination, the molar ratio of the siRNA targeting the NFKBIZ gene to the protein degradation targeting chimeric molecule targeting the androgen receptor is 1:3-20. Preferably, in the second combination, the mass ratio of the mol of siRNA targeting the NFKBIZ gene to the molecular weight of fish peptide LAGF is 1 mu mol and 3-8 mg. The invention provides a preparation method of the composition, which comprises the steps of mixing and oscillating dissolved siRNA targeting NFKBIZ genes and functional small molecules of androgen receptor targeting proteins. The present invention provides a nanoparticle for treating alopecia, comprising a liposome and the composition or siRNA targeting NFKBIZ gene coated in the liposome; The nucleotide sequence of the siRNA targeting the human NFKBIZ gene is shown as SEQ ID NO. 1, and the nucleotide sequence of the siRNA targeting the murine NFKBIZ gene is shown as SEQ ID NO. 3. Preferably, the liposome is prepared by mixing soybean lecithin and sodium deoxycholate; The mass ratio of the soybean lecithin to the sodium deoxycholate is 9-11:1. The invention provides a preparation method of nano particles for treating alopecia, which comprises the following steps: Dissolving soybean lecithin and sodium deoxycholate to prepare a film coating; adding siRNA targeting NFKBIZ gene or said composition to said film coating, forming a liposome suspension by hydration; repeatedly freezing and thawing the liposome suspension until the film breaks, and extruding the nano particles. The invention provides a medicament for treating alopecia, which comprises siRNA targeting NFKBIZ genes, the composition, nano particles for treating alopecia or nano particles prepared by the preparation method; The nucleotide sequence of the siRNA targeting the human NFKBIZ gene is shown as SEQ ID NO. 1, and the nucleotide sequence of the siRNA targeting the murine NFKBIZ gene is shown as SEQ ID NO. 3. The invention provides an siRNA targeting NFKBIZ gene, the composition, the nano particle for treating alopecia or the application of the nano particle prepared by the preparation method in preparation of a medicament for treating androgenetic alopecia, wherein the nucleotide sequence of the siRNA targeting human NFKBIZ gene is shown as SEQ ID NO. 1, and the nucleotide sequence of the siRNA targeting murine NFKBIZ gene is shown as SEQ ID NO. 3. The invention provides a composition containing siRNA targeting NFKBIZ genes and functional small molecules targeting androgen receptor degradation, wherein the nucleotide sequence of the siRNA targeting human NFKBIZ genes is shown as SEQ ID NO. 1, and the nucleotide sequence of the siRNA targeting murine