CN-121971391-A - Embolic agent with open porous structure for slowly releasing triptolide

Abstract

The invention relates to the technical field of medical treatment, in particular to an embolic agent of slow-release triptolide with an open porous structure. The embolic agent is an open pore PBVHx microsphere loaded with triptolide, and is marked as TP@OPMs, the TP@OPMs have a porous structure with open pores on the surface and interconnected pores, PBVHx contains 90 mol% of 3-hydroxybutyric acid, 3 mol% of 3-hydroxyvaleric acid and 7 mol% of 3-hydroxycaproic acid, and the molecular weight is 46 kDa. The invention provides an embolic agent with an open porous structure for slowly releasing triptolide, which is prepared by adopting an improved double emulsion method (G/O/W) based on a novel non-lactic polymer PBVHx and adopting a novel open-pore microsphere (TP@OPMs) loaded with Triptolide (TP) for chemoembolization treatment.

Inventors

• WEI DAIXU
• MA XUE

Assignees

• 成都大学

Dates

Publication Date

20260505

Application Date

20260126

Claims (8)

1. 1. An embolic agent with an open porous structure for slowly releasing triptolide is characterized in that the embolic agent is an open pore PBVHx microsphere loaded with triptolide and is marked as TP@OPMs; the TP@OPMs have a porous structure with open surfaces and interconnected internal pores.
2. 2. An embolic agent with an open porous structure, slow release triptolide according to claim 1, wherein PBVHx comprises 90% mol% 3-hydroxybutyric acid, 3 mol% 3-hydroxyvaleric acid and 7% mol% 3-hydroxyhexanoic acid, with a molecular weight of 46 kDa.
3. 3. A process for preparing tp@opms according to any one of claims 1-2, characterized by the steps of: A. PBVHx is dissolved in dichloromethane together with TP; B. mixing ammonium bicarbonate aqueous solution with the solution obtained in the step A, and homogenizing and emulsifying to form G/O colostrum; C. pouring the G/O colostrum into a polyvinyl alcohol water solution, and stirring and volatilizing dichloromethane to form G/O/W double emulsion; D. And (3) centrifuging, washing and freeze-drying to obtain TP@OPMs.
4. 4. A process according to claim 3, wherein the mass ratio of PBVHx to TP is 25:1.
5. 5. A method according to claim 3, wherein the aqueous ammonium bicarbonate solution has a mass-to-volume concentration of 20%.
6. 6. A method according to claim 3, wherein the aqueous polyvinyl alcohol solution has a mass-to-volume concentration of 1%.
7. 7. Use of said tp@opms prepared according to claim 3 for the preparation of a chemoembolic formulation for the treatment of hepatocellular carcinoma.
8. 8. Use of said tp@opms prepared according to claim 3 for the preparation of a vascular embolic device for inducing ischemic necrosis of tumors.

Description

Embolic agent with open porous structure for slowly releasing triptolide Technical Field The invention relates to the technical field of medical treatment, in particular to an embolic agent of slow-release triptolide with an open porous structure. Background Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide, and has become an important research focus in the fields of human health and public health because of its high morbidity and mortality. Surgical excision of tumors is a major strategy for cancer treatment, but complications such as tumor recurrence, metastasis, bleeding and the like may occur after surgery, resulting in poor prognosis and even treatment failure. Chemotherapy is still one of the preferred regimens for hepatocellular carcinoma treatment, but its serious side effects limit clinical efficacy. Thus, there is an urgent need to develop new, efficient, safe anti-liver cancer drugs and to build optimized Transcatheter Arterial Chemoembolization (TACE) systems. These advances are critical to the clinical treatment of non-resectable hepatocellular carcinoma and can provide significant survival benefits to patients. With the continued intensive research into biocompatible materials and oncology, innovative and effective drug delivery technologies are widely explored to improve cancer therapeutic effects. At present, more and more active ingredients of traditional Chinese medicines are researched and focused. Triptolide (TP) is a diterpenoid compound extracted from tripterygium wilfordii, and has been attracting attention because of its broad-spectrum antitumor properties. Its mechanism of action includes inhibition of TNF/NF- κb/BCL2 signaling pathway, p53 mediated apoptosis, and regulation of c-Myc/miRNA cluster/target gene axis. Compared with traditional anti-liver cancer drugs (such as doxorubicin, sorafenib and cisplatin), the TP has more remarkable curative effect on hepatocellular carcinoma. However, the potential hepatotoxicity of TP severely limits its clinical application, and TP has poor pharmacokinetic properties as a hydrophobic drug. In order to solve the problem, TP is embedded in hydrophobic bio-polyester or hydrogel to realize the controlled drug release, so that the dosage of TP can be reduced, the anti-tumor curative effect can be improved, and the TP becomes a key strategy for reducing side effects. The hydrogel has good fluidity and biodegradability, and is often used as a drug release type embolic agent to reduce toxicity of hydrophilic drugs and maintain sustained anticancer effects. However, TP is not stably dispersed in hydrogels as a typical hydrophobic drug. In recent years, biodegradable drug-loaded embolic microspheres prepared by taking polylactic acid (PLA) and derivatives thereof (such as polylactic acid-glycolic acid copolymer, PLGA) as raw materials become a research hotspot in the fields of drug delivery and embolic therapy. Based on 20 different composition optimized formulas, PLGA microspheres with average particle diameter of 42.36 μm, drug content of 7.96%, drug encapsulation rate of 80.16% and initial release rate of 14.48% were prepared, and the microspheres can realize TP sustained release for 4 weeks in vitro. Also, wu et al prepared PLGA nanoparticles functionalized with methoxypolyethylene glycol-5-S-hexadecyl (mPEG-S-S-C) and soy lecithin for co-delivery of Doxorubicin (DOX) with TP. By means of self-assembly, these hydrophobic compounds were successfully loaded into PLGA nanoparticles, showing a remarkable synergy both in vitro and in vivo studies, and TP was able to promote the uptake of DOX by KB cells (human luminal squamous cell carcinoma cell line). The PLGA nano particles (TPL@mPLGA) for simulating tumor cell membranes, which are prepared by Li et al, are used for loading TP to treat hepatocellular carcinoma, the particle size of the nano particles is 195.5+/-7.5 nm, zeta potential is-21.5+/-0.2 mV, drug loading rate is 2.94%, and the nano particles have good stability, reduce the toxicity of TP while enhancing anti-tumor effect, and provide a promising scheme for treating hepatocellular carcinoma Despite the wide range of applications of PLGA or PLA microspheres in tissue engineering and drug delivery systems, lactic acid released by these polymers may pose a potential risk to the tissue. Lactic acid accumulation can lead to acidification of the tumor microenvironment, potentially promoting tumor invasion and metastasis. In addition, accumulation of lactic acid may also inhibit immune responses, allowing tumors to evade immune surveillance, further driving cancer progression. Polyhydroxyalkanoates (PHAs) are a class of biopolymer compounds synthesized by microorganisms, have biodegradability, and are widely used in the fields of tissue engineering and drug delivery. Unlike strongly acidic lactic acid released by PLGA and PLA (pk=3.8), 3-hydroxybutyric acid (3 HB) released by PHA is more acidic (pk=4.5). I