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CN-121987574-A - PH/ROS dual-response double-drug load nano material based on andrographolide, and preparation and application thereof

CN121987574ACN 121987574 ACN121987574 ACN 121987574ACN-121987574-A

Abstract

The invention discloses an andrographolide-based pH/ROS dual-response dual-drug loaded nanomaterial and preparation and application thereof. The material consists of amphiphilic polymer (PEG-fan-shaped lysine-formylphenylboric acid) and hydrophobic drugs A and B. Drug A is covalently bound to the polymer via a borate ester linkage to form a prodrug, and drug B is physically entrapped in the hydrophobic core of the nanoparticle. The acid and high Reactive Oxygen Species (ROS) microenvironment of inflammatory lesions are utilized to trigger the cleavage of Schiff base bonds and boric acid ester bonds in a molecular chain, induce the disassembly of nano particles and cooperatively release double drugs. The enrichment degree and the bioavailability of the medicine at the lung inflammation position are obviously improved through passive targeting, the high-efficiency inhibition of inflammatory factor storm is realized, and a new scheme is provided for the accurate delivery of the hydrophobic anti-inflammatory medicine.

Inventors

  • HE YIYAN
  • ZHOU YIN
  • CHEN YANMING
  • MAO HONGLI
  • CUI YUWEN

Assignees

  • 南京工业大学

Dates

Publication Date
20260508
Application Date
20260205

Claims (10)

  1. 1. The andrographolide-based pH/ROS dual-response double-drug load nanomaterial is characterized by comprising an amphiphilic polymer, a hydrophobic drug A and a hydrophobic drug B; The amphiphilic polymer is polyethylene glycol-fan-shaped lysine-formylphenylboric acid, wherein polyethylene glycol is condensed with carboxyl of the fan-shaped lysine through terminal amino groups of the polyethylene glycol, and the terminal amino groups of the fan-shaped lysine react with aldehyde groups of the formylphenylboric acid to form Schiff base bonds; The hydrophobic drug A contains a1, 2 or 1,3 diol structure, and is covalently bound with phenylboronic acid groups in the amphiphilic polymer through formed boric acid ester bonds to form an amphiphilic prodrug; The nano material is formed by self-assembling the amphiphilic prodrug, the amphiphilic polymer and the hydrophobic drug B through hydrophilic and hydrophobic effects.
  2. 2. The nanomaterial of claim 1, wherein the polyethylene glycol is single-side amino-terminated, has a weight average molecular weight of 2000-10000 Da, wherein the algebraic number of the fan-shaped lysine is 1-4 generations, and the formylphenylboronic acid is one of o-formylphenylboronic acid, m-formylphenylboronic acid or p-formylphenylboronic acid.
  3. 3. The nanomaterial of claim 1, wherein the degree of modification of formylphenylboronic acid in the amphiphilic polymer is 5-80%.
  4. 4. The nanomaterial of claim 1, wherein the hydrophobic drug a is a hydrophobic drug containing a1, 2-diol or 1, 3-diol structure.
  5. 5. The nanomaterial of claim 4, wherein the hydrophobic drug a is selected from one or both of andrographolide and quercetin.
  6. 6. The nanomaterial of claim 1, wherein the molar ratio of the hydrophobic drug a to formylphenylboronic acid in the amphiphilic polymer is 1:1 to 3:1.
  7. 7. The nanomaterial of claim 1, wherein the hydrophobic drug B is a hydrophobic drug having an anti-inflammatory effect, and is selected from at least one of andrographolide, quercetin, dexamethasone, diclofenac, tranilast, indomethacin, tanshinone, and β -myrcene.
  8. 8. A method for preparing a nanomaterial according to any one of claims 1 to 7, comprising the steps of dissolving an amphiphilic polymer, an amphiphilic prodrug and a hydrophobic drug B in an organic solvent, dropping the mixture into an aqueous solution under ultrasonic conditions for self-assembly, and removing the free hydrophobic drug B and the organic solvent by dialysis to obtain the nanomaterial.
  9. 9. The method of claim 8, wherein the nanomaterial comprises a dual drug loading of 5% -35%.
  10. 10. Use of the nanomaterial according to any of claims 1-7 for the preparation of a medicament for the treatment of pneumonia.

Description

PH/ROS dual-response double-drug load nano material based on andrographolide, and preparation and application thereof Technical Field The invention relates to the technical field of biomedical materials, in particular to an andrographolide-based pH/ROS dual-response dual-drug loaded nanomaterial and preparation and application thereof. Background Pulmonary inflammation is a central pathological feature of a variety of respiratory diseases (e.g., acute lung injury ALI, acute respiratory distress syndrome ARDS). In severe conditions, an outbreak of inflammatory factor Storm (Cytokine Storm) can lead to a transient surge of pro-inflammatory factors (e.g., TNF-alpha, IL-6, etc.), causing severe tissue damage and even systemic multiple organ failure. Although hydrophobic anti-inflammatory drugs such as Andrographolide (ANDRO) and dexamethasone (Dex) have remarkable curative effects, the drugs are limited by extremely low bioavailability and lack of targeting, effective treatment concentration is difficult to achieve at focus positions, and serious toxic and side effects are easy to generate after systemic administration. Currently, delivery of drugs using nanocarriers has become an important issue. The inflammation focus is accompanied by acidic microenvironment (pH drop) and high oxidative stress (ROS surge), and the intelligent response type nano-carrier developed based on the characteristics has great potential. However, the existing single-response vector often has the problems of incomplete release, insufficient response sensitivity, poor biocompatibility of the vector and the like. In particular, how to construct a system that can form prodrugs by both physical entrapment and covalent conjugation, and that can achieve layered, high-efficiency release using both schiff base linkages (pH response) and borate linkages (pH/ROS dual response) remains a great challenge in this area. At present, a few researches report that sector lysine is taken as a structural core, and the self structural characteristics of andrographolide are combined to construct the multi-bond linkage and double-response synergistic nano delivery system. Therefore, the development of the high-efficiency nano material which can precisely target the lung inflammation area, sensitively respond to the focus microenvironment and realize the double-medicine synergistic release has important clinical significance for solving the problems of treating pneumonia and inhibiting inflammatory factor storm. Disclosure of Invention The invention aims to provide an andrographolide-based pH/ROS dual-response dual-drug loaded nanomaterial as well as a preparation method and application thereof. The nano material consists of amphiphilic polymer (polyethylene glycol-sector lysine-formylphenylboric acid) and two hydrophobic drugs. The hydrophobic drug A is formed into covalent boric acid ester bonds through condensation of diol sites in a molecular structure and phenylboric acid groups in a polymer, so that the amphiphilic prodrug is constructed, the prodrug enters a nano-inner core in a self-assembly way by virtue of a hydrophobic driving force, and the hydrophobic drug B is cooperatively embedded into a hydrophobic center formed by the amphiphilic polymer and the prodrug in a physical entrapment way. The obtained nano particles can accurately identify and respond to the low pH and high ROS microenvironment of the focus part, and structural degradation and disassembly occur. Another object of the present invention is to provide an application of the above nanomaterial in preparing a medicament for treating inflammatory diseases. By utilizing the characteristic acidity and oxidative stress of the lesion site, the nano material is driven to responsively break and accurately release the load, the physical package medicine is quickly released, the covalent medicine is released according to the requirement through breaking the chemical bond, the ROS level in the microenvironment is cooperatively regulated and controlled, and the targeted anti-inflammatory treatment effect is achieved. The technical purpose is realized by the following scheme: The preparation method of the andrographolide-based pH/ROS dual-response dual-drug loaded nanomaterial provided by the invention comprises the following steps: (1) The preparation of amphiphilic polymer (PEG-GnK-FPBA) includes the steps of coupling unilaterally amino-terminated polyethylene glycol with carboxyl-terminated sector lysine through amidation reaction, removing BOC protecting group under acidic condition to expose amino, mixing with formylphenylboric acid in neutral environment, and utilizing the condensation reaction of amino and formyl to construct Schiff base bond with pH response characteristic to obtain target polymer. (2) And (3) preparing the amphiphilic prodrug, namely, co-dissolving the amphiphilic polymer obtained in the step (1) and a hydrophobic drug A in an organic solvent, and condensing a typical 1, 2