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CN-121974831-A - Tertiary amine oxidized zwitterionic lipid, lipid nano delivery particles and application thereof

CN121974831ACN 121974831 ACN121974831 ACN 121974831ACN-121974831-A

Abstract

The application relates to tertiary amine oxidized zwitterionic lipid, lipid nano delivery particles and application thereof. The present application provides tertiary amine oxidized zwitterionic lipids of suitable size and specific structure that are capable of delivering hydrophilic/hydrophobic, organic/inorganic content. The lipid nano-delivery particles are prepared based on tertiary amine oxidized zwitterionic lipid, various contents including hydrophilic drugs, hydrophobic drugs and inorganic nano-particles can be encapsulated by regulating and controlling the proportion of the tertiary amine oxidized zwitterionic lipid and the lipid without tertiary amine oxidized groups, the formed lipid nano-particles are uniform in size, stably exist in different solutions and do not agglomerate, have long blood circulation up to at least 60 hours, have high specific affinity to tumors and are accumulated in the tumors in a large amount, no obvious damage is caused to all main organs, and the bioavailability and the cancer curative effect of the contents are remarkably improved.

Inventors

  • LI RUIQUAN
  • YANG JIAN
  • SONG HAIQING

Assignees

  • 西湖大学

Dates

Publication Date
20260505
Application Date
20260127

Claims (10)

  1. 1. A tertiary amine oxidized zwitterionic lipid, which is characterized by having a chemical structure as shown in formula I: , In the formula I, R is selected from C 1 -C 6 alkyl, X and Y are respectively and independently selected from hydrophobic units with the number average molecular weight of more than or equal to 142.
  2. 2. The tertiary amine oxidized zwitterionic lipid of claim 1, wherein the tertiary amine oxidized zwitterionic lipid has a chemical structure as shown in formula II: In the formula II, R is selected from C 1 -C 6 alkyl, n=an integer of 1-3, L is a connecting group selected from ester bond, carbonate bond, amide bond, carbamate bond, urea bond or disulfide bond; R 1 and R 2 are each independently selected from the group consisting of a lipid soluble molecular residue, preferably R 1 and R 2 are each independently selected from the group consisting of a cholesterol residue, a bile acid residue, a lipid soluble vitamin residue, a steroid hormone residue, a hydrophobic signal molecule residue, more preferably R 1 and R 2 are each independently selected from the group consisting of a saturated fatty chain or an unsaturated fatty chain.
  3. 3. A tertiary amine oxidized zwitterionic lipid according to claim 2, characterized in that the tertiary amine oxidized zwitterionic lipid is selected from one of the following structures: 。
  4. 4. A lipid nanodelivery vehicle comprising a tertiary amine oxidized zwitterionic lipid, wherein the lipid nanodelivery vehicle is prepared from the tertiary amine oxidized zwitterionic lipid of any one of claims 1-3 and a lipid that does not comprise a tertiary amine oxidized group.
  5. 5. The lipid nanodelivery vehicle of claim 4, wherein the lipid free of tertiary amine oxidized zwitterionic lipid is selected from one or more of cationic lipids, anionic lipids, uncharged lipids, phospholipids, phospholipid-polyethylene glycol, vitamin E polyethylene glycol succinate or cholesterol; The mass ratio of the tertiary amine oxidized zwitterionic lipid to the lipid without tertiary amine oxidized groups is 1-20:1.
  6. 6. A lipid nano-delivery particle, characterized by comprising the lipid nano-delivery vehicle according to claim 4 or 5 and a content, wherein the mass ratio of the content to the lipid nano-delivery vehicle is 0.01-100:1.
  7. 7. The lipid nano-delivery particle of claim 6, wherein the content is selected from one of a hydrophobic drug, a hydrophilic drug, a protein, a polypeptide, DNA/RNA, an inorganic nanoparticle, an organic/inorganic hybrid nanoparticle, or a nanoscale metal-organic framework.
  8. 8. The lipid nano-delivery particle according to claim 7, wherein the hydrophobic drug is selected from one or more of sorafenib, itraconazole, lovastatin, phenytoin, dexamethasone, or ibuprofen; The hydrophilic medicine is selected from one or more of penicillin, atenolol, levodopa, metformin, 5-fluorouracil or oseltamivir; The protein is one or more selected from bevacizumab, insulin, interferon, streptokinase, blood coagulation factors or hepatitis B vaccine; The polypeptide is one or more selected from telpofungin, nesiritide, leuprorelin, polymyxin B/E or teriparatide; The DNA/RNA is selected from one or more of plasmid, mRNA or siRNA; the inorganic nano particles are selected from one or more of barium titanate, cerium oxide, ferroferric oxide, calcium phosphate or magnesium sulfate; The organic/inorganic hybrid nano particles are selected from one or more of hydroxyapatite, calcium citrate or manganese citrate; the nanoscale metal organic framework is selected from one or more of MOF-5, uiO-66 or ZIF-67.
  9. 9. The method for preparing lipid nano-delivery particles according to any one of claim 6 to 8, wherein, When the content is hydrophobic content, the lipid nano-delivery particles are prepared by dissolving or dispersing tertiary amine oxidized zwitterionic lipid, lipid without tertiary amine oxidized group and hydrophobic content in an organic solvent to obtain an organic phase, and then adding the organic phase into a stirred aqueous phase or mixing the organic phase with the aqueous phase by using a microfluidic device to obtain the nano-particles containing the hydrophobic content; When the content is hydrophilic content, the lipid nano-delivery particles are prepared by dissolving or dispersing tertiary amine oxidized zwitterionic lipid and lipid without tertiary amine oxidized groups in an organic solvent to obtain an organic phase, adding the organic phase into a stirred aqueous phase containing the hydrophilic content or mixing the organic phase with the aqueous phase containing the hydrophilic content by using a microfluidic device to obtain the nano-particles containing the hydrophilic content; The volume ratio of the organic phase to the water phase is 1:2-20.
  10. 10. The use of the lipid nano-delivery particles according to any one of claims 6-8, wherein the lipid nano-delivery particles are formulated as one or more of intravenous injection, intraperitoneal injection, intramuscular injection, intratumoral injection, intradermal injection or subcutaneous injection.

Description

Tertiary amine oxidized zwitterionic lipid, lipid nano delivery particles and application thereof Technical Field The invention belongs to the technical field of biological medicine, and particularly relates to tertiary amine oxidized zwitterionic lipid, lipid nano delivery particles and application thereof. Background Lipid nanodelivery systems are an important platform in the field of modern drug delivery, and their great clinical potential is evident by successful application in new coronal mRNA vaccines. Traditional liposome drugs, such as Doxil (doxorubicin liposome) and Onivyde (irinotecan liposome), have been widely used for the treatment of diseases such as cancer. Such formulations can improve their pharmacokinetic behavior to some extent by encapsulating the drug, reducing early leakage and rapid clearance. However, conventional liposomes composed of conventional phospholipids still have significant limitations. Studies have shown that their accumulation in target tissues is inefficient, and that tumor tissue permeability is poor, leading to limited therapeutic efficacy (Zhou et al, biomaterials, 2020, 240, 119902). The traditional liposome surface is easy to generate nonspecific protein adsorption, is rapidly identified and cleared by an immune system, and is difficult to realize high-efficiency delivery. To overcome these challenges, the design of new lipid materials has become an important issue. In recent years, tertiary amine-oxidized group-modified materials have exhibited unique advantages. Researches show that the material can form a strong hydration layer, effectively resist the nonspecific adsorption of proteins, and endow the nano-carrier with long-acting circulation capacity (Chen et al Nature Biomedical Engineering, 2021, 5, 1019). More importantly, the tertiary amine oxidized structure has high affinity with cell membrane phospholipids, so that the tertiary amine oxidized structure not only can promote the efficient internalization of the carrier by cells, but also can target a golgi apparatus and actively trigger a transcellular transport path, thereby remarkably enhancing the tissue penetration and tumor deep accumulation capacity. However, these existing nano-delivery systems carrying tertiary amine-oxidized groups (nitrogen atom linked to two short saturated fatty chains or in one heterocycle) still have less than ideal performance in tumor-specific selection and are easily aggregated in major organs such as liver, spleen and intestinal tract, which do not exhibit significant advantages over conventional liposomes. Therefore, a novel tertiary amine oxidized group functionalized lipid-based nano delivery system with high tumor selectivity is developed, and has important clinical transformation value for improving the delivery efficiency and bioavailability of contents and enhancing curative effect. Disclosure of Invention Based on the problem that the nano delivery system carrying tertiary amine oxidized radicals in the prior art is easy to gather in main organs such as liver, spleen and intestinal tract, the invention provides novel tertiary amine oxidized zwitterionic lipid, lipid nano delivery particles and application thereof. The tertiary amine oxidized zwitterionic lipid provided by the invention can be hybridized with one or more auxiliary lipids for wrapping various hydrophilic/hydrophobic organic/inorganic contents to form nano particles, the obtained nano particles are uniform in size, stably exist in different solutions and do not agglomerate, can escape from a mononuclear phagocyte system to be phagocytized in vivo, realize long circulation, have excellent biocompatibility, and can be specifically aggregated in the tumor and be retained in other main organs. The aim of the invention can be achieved by the following technical scheme: In a first aspect, the present invention provides a tertiary amine oxidized zwitterionic lipid, the chemical structure of which is shown in formula I: , In the formula I, R is selected from C 1-C6 alkyl, X and Y are respectively and independently selected from hydrophobic units with the number average molecular weight of more than or equal to 142. In formula I, the nitrogen atom is attached to both a short chain alkyl group (i.e., R structure) and two larger hydrophobic units. In some embodiments of the invention, X and Y in the structure of formula I independently comprise a linkage and a residue of a fat-soluble molecule. In some embodiments of the invention, the tertiary amine oxidized zwitterionic lipid has a chemical structure as shown in formula II: In formula II, R is selected from C 1-C6 alkyl, n=an integer from 1 to 3, L is a linking group including, but not limited to, an ester bond, carbonate bond, amide bond, urethane bond, urea bond, disulfide bond, R 1 and R 2 are each independently selected from fat-soluble molecular residues. Further preferably, in the structure of formula II, R 1 and R 2 are each independently selected from