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CN-122005503-A - Ultrasonic response apoptosis bionic targeting nano-carrier delivery material and preparation method thereof

CN122005503ACN 122005503 ACN122005503 ACN 122005503ACN-122005503-A

Abstract

The invention belongs to the technical field of nano-drugs, and particularly relates to an ultrasound-responsive apoptosis bionic targeting nano-carrier delivery material and a preparation method thereof. The invention takes beta-cyclodextrin Polymer (PCD) as a core skeleton, modifies Phosphorylserine (PS) through a phosphate bond to enhance targeting capability, takes main subject-object interaction to encapsulate Perfluorohexane (PFH) as an ultrasonic response core under low temperature condition, and takes liposome (soybean lecithin and cholesterol) to carry out outer coating, thereby remarkably improving the in vivo stability and circulation half-life of the system, realizing breakthrough of the PCD-PS system from local administration to systemic administration for the first time, having excellent ultrasonic responsiveness, being capable of being accurately triggered and releasing contents at a targeting position, simultaneously endowing the system with active targeting by the design of apoptosis-like cells, ensuring the stability of in vivo circulation by a double coating structure, and realizing the synergistic effects of stable circulation, active targeting and ultrasonic triggering.

Inventors

  • ZENG RONG
  • GAO ZHENHUI

Assignees

  • 暨南大学

Dates

Publication Date
20260512
Application Date
20260309

Claims (10)

  1. 1. An ultrasound responsive apoptosis biomimetic targeting nanocarrier delivery material, comprising: A phosphoserine-modified beta-cyclodextrin polymer core, wherein the phosphoserine is modified on the beta-cyclodextrin polymer backbone by a phosphate bond; Perfluorohexane entrapped within the hydrophobic cavity of the beta-cyclodextrin polymer by host guest interaction; And the liposome is coated on the outer layer of the core.
  2. 2. The ultrasound responsive apoptosis biomimetic targeting nanocarrier delivery material of claim 1, wherein said liposome is comprised of soy lecithin and cholesterol.
  3. 3. The ultrasound responsive apoptosis biomimetic targeting nanocarrier delivery material of claim 2, wherein the mass ratio of soy lecithin to cholesterol is 5:4.
  4. 4. A method for preparing the ultrasound-responsive apoptosis bionic targeting nanocarrier delivery material according to any of claims 1 to 3, comprising the steps of: (1) Preparing a phosphorylserine-modified beta-cyclodextrin polymer; (2) Mixing the phosphorylserine modified beta-cyclodextrin polymer and perfluorohexane in a phosphate buffer solution according to a mass ratio of 5:2 at a temperature of 0-4 ℃ to form a complex suspension; (3) Dissolving soybean lecithin and cholesterol in an organic solvent, and removing the solvent to form a lipid film; (4) And (3) adding the composite suspension prepared in the step (2) into the lipid film, and performing hydration, ultrasonic treatment and film extrusion to obtain the ultrasonic response apoptosis bionic targeting nano-carrier delivery material.
  5. 5. The method of claim 4, wherein the step (1) of synthesizing the β -cyclodextrin polymer comprises: Dissolving beta-cyclodextrin in sodium hydroxide aqueous solution, adding epichlorohydrin, reacting at 30+/-2 ℃ for 24-48 h, adding acetone after the reaction is finished to precipitate a polymer, and washing, dialyzing and freeze-drying to obtain the beta-cyclodextrin.
  6. 6. The method of claim 5, wherein the method of synthesizing the phosphoserine modified β -cyclodextrin polymer of step (1) comprises: The FMOC-L-serine methyl ester, the phosphorus-containing cross-linking agent and the beta-cyclodextrin polymer are sequentially reacted in an organic solvent, and the preparation method is obtained after oxidation, deprotection, filtration, dialysis and freeze drying.
  7. 7. The method of claim 6, wherein the phosphorus-containing cross-linking agent is bis (diisopropylamino) (2-cyanoethoxy) phosphine; the organic solvent is N, N-dimethylformamide.
  8. 8. The process according to claim 4, wherein the organic solvent in the step (3) is methylene chloride.
  9. 9. The method of claim 4, wherein in step (4), the hydration is carried out under stirring at 37 ℃ and 400 rpm for 30: 30 min.
  10. 10. The method according to claim 4, wherein in the step (4), the ultrasonic treatment is performed by using an ultrasonic cell disruption apparatus, the working frequency is 20 kHz, the power is 100W, and the batch operation mode is adopted, each ultrasonic treatment is suspended by 2 min by 1 min, and the accumulated treatment time is 10 min.

Description

Ultrasonic response apoptosis bionic targeting nano-carrier delivery material and preparation method thereof Technical Field The invention belongs to the technical field of nano-drugs, and particularly relates to an ultrasound-responsive apoptosis bionic targeting nano-carrier delivery material and a preparation method thereof. Background The elimination of apoptotic cells is an important process for the body to maintain homeostasis. When apoptosis occurs, phosphoserine (Phosphorylserine, PS) inside the cell membrane is everted outside the membrane and recognized by specific receptors (such as Tim-4, TAM receptor family, etc.) on the surface of phagocytes such as macrophages. By utilizing the biological characteristic of PS, the PS is modified on the surface of the nano-carrier, so that the carrier can simulate apoptotic cells, and the active targeting of anti-inflammatory tissues is realized. Perfluorohexane (PFH) is a low boiling point liquid perfluorocarbon. When entrapped in a confined space (e.g., a liposome), the input of external energy (e.g., ultrasound) can trigger a sharp gas-liquid phase change or promote dissociation from the cavity, which makes it well suited as a physical switch to disrupt the structure of the carrier and release the contents. However, PFH has two technical bottlenecks in practical application, namely poor physical stability, easy escape in the process of storage and in-vivo circulation due to the easy volatility, and insufficient targeting capability, and the traditional PFH preparation mainly depends on passive targeting (such as EPR effect), has limited specific enrichment efficiency in pathological tissues (especially in inflammatory areas), and is difficult to meet the requirement of accurate diagnosis and treatment. Cyclodextrin polymers (Cyclodextrin Polymer, PCD) are a three-dimensional network of macromolecules formed by cross-linking polymerization of beta-cyclodextrin units. Each cyclodextrin unit has a hydrophobic cavity, so that effective entrapment and stabilization of PFH molecules can be realized through interaction with a host-guest of the PFH molecules, and the problem of volatility of the PFH is overcome to a certain extent. There are significant limitations to existing attempts to modify PS onto PCD (i.e., PCD-PS systems) in that such systems are typically administered only by local injection and cannot utilize the blood circulation system to achieve treatment of deep lesions distant from the site of administration. The liposome (Liposome) is a vesicle structure formed by phospholipid bilayer, has good biocompatibility and encapsulation capacity, and can obviously improve the in vivo stability and circulation half-life of the carrier. The internal structure is stabilized under the protection of the liposome shell, and the volatile PFH is doubly locked by the cavity of the PCD and the bilayer membrane of the liposome. Therefore, the PCD-PS/PFH is wrapped by the liposome, the nano-carrier system realizes the crossing from 'local passive diffusion' to 'whole body active targeting+ultrasonic triggering response', and has important clinical value and application prospect in the treatment of inflammation-related diseases. Disclosure of Invention The invention aims at solving the existing problems and provides an ultrasonic response apoptosis bionic targeting nano-carrier delivery material and a preparation method thereof. The invention is realized by the following technical scheme: A first object of the present invention is to provide an ultrasound responsive apoptosis biomimetic targeting nanocarrier delivery material comprising: A phosphoserine-modified beta-cyclodextrin polymer core, wherein the phosphoserine is modified on the beta-cyclodextrin polymer backbone by a phosphate bond; Perfluorohexane entrapped within the hydrophobic cavity of the beta-cyclodextrin polymer by host guest interaction; And the liposome is coated on the outer layer of the core. Further, the liposome is composed of soybean lecithin and cholesterol. Further, the mass ratio of the soybean lecithin to the cholesterol is 5:4. The second object of the present invention is to provide a method for preparing the ultrasound-responsive apoptosis bionic targeting nanocarrier delivery material according to any one of claims 1 to 3, comprising the following steps: (1) Preparing a phosphorylserine-modified beta-cyclodextrin polymer; (2) Mixing the phosphorylserine modified beta-cyclodextrin polymer and perfluorohexane in a phosphate buffer solution according to a mass ratio of 5:2 at a temperature of 0-4 ℃ to form a complex suspension; (3) Dissolving soybean lecithin and cholesterol in an organic solvent, and removing the solvent to form a lipid film; (4) And (3) adding the composite suspension prepared in the step (2) into the lipid film, and performing hydration, ultrasonic treatment and film extrusion to obtain the ultrasonic response apoptosis bionic targeting nano-carrier delivery material. Fu