Method for synthesizing multifunctional active targeted hyaluronic acid-polylactic acid carrier and preparing anti-tumor medicinal micelle of multifunctional active targeted hyaluronic acid-polylactic acid carrier

An anti-tumor drug, hyaluronic acid technology, applied in the field of polymer chemistry and pharmaceutical preparations, can solve the problems of clinical application difficulties, poor biocompatibility of octadecanecarboxylic acid, etc., achieve active targeting of long tumors, avoid Effects of phagocytosis and excretion by the kidneys and prolongation of circulation time

Active Publication Date: 2014-09-24
CHINA PHARM UNIV
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Problems solved by technology

Chinese patent 201010228961 authorizes a preparation method of hyaluronic acid-C18 micelles. Dissolve HA-C18 and paclitaxel in DMSO, mix evenly with magnetic stirring, and use dialysis to remove organic solvents and free paclitaxel. The particle size is 236.6nm. The drug loading is 9.57%. Compared with polyester, octadecanoic acid has poor biocompatibility, and it will be difficult to apply in clinical practice in the future.

Method used

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  • Method for synthesizing multifunctional active targeted hyaluronic acid-polylactic acid carrier and preparing anti-tumor medicinal micelle of multifunctional active targeted hyaluronic acid-polylactic acid carrier
  • Method for synthesizing multifunctional active targeted hyaluronic acid-polylactic acid carrier and preparing anti-tumor medicinal micelle of multifunctional active targeted hyaluronic acid-polylactic acid carrier
  • Method for synthesizing multifunctional active targeted hyaluronic acid-polylactic acid carrier and preparing anti-tumor medicinal micelle of multifunctional active targeted hyaluronic acid-polylactic acid carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1 Synthesis and activation of polylactic acid (PLA)

[0039] Synthesis of polylactic acid (PLA): Using the ring-opening polymerization method, add 10 g D, L-lactide (69.4 mmol) into a single-necked round-bottomed flask, the temperature of the oil bath is 120 ° C, and after the lactide is melted, add the catalyst 1.8 mL Sn(Oct) 2 (5 mmol). The air in the container was purged with nitrogen gas, and the temperature was gradually raised to 160°C, and the polymerization reaction was carried out for 6 hours. Add an appropriate amount of ethyl acetate to dissolve, add ethanol to precipitate, filter with suction, wash with deionized water, and dry in vacuo to obtain a pale yellow PLA solid with a yield of 80.2%. The results of ring-opening polymerization reaction temperature and time on the molecular weight of polylactic acid are shown in Table 1.

[0040] The polylactic acid reaction formula is as follows:

[0041]

[0042] The molecular weight of PLA was det...

Embodiment 2

[0048] Example 2 Synthesis of hyaluronic acid-polylactic acid (HA-PLA)

[0049] (1) Terminal Amination Synthesis of Hyaluronic Acid

[0050] Amination of hyaluronic acid (Mn: 7800): adopt reductive amination reaction, dissolve 150mg N,N-diethylethylenediamine (1.3mmol) with pH9.5 phosphate buffer, weigh 9.5g hyaluronic acid ( HA 7800 ) and 100 mL of purified water to dissolve (1.2 mmol) was dropped into the above solution, and magnetically stirred for 4 h. Add 0.04 g of sodium cyanoborohydride (0.6 mmol), control the temperature at 8-20 ° C for 1 h, and react at room temperature for 12 h. Put the reactant into a dialysis bag (molecular weight cut-off is 8000-10000), and then dialyze with PBS buffer solution for two days. Freeze-dried and freeze-dried to obtain terminal amination-hyaluronic acid (HA-NH 2 ), yield 85.91%.

[0051] (2)HA 7800 -PLA 3500 Synthesis

[0052] Weigh 8.2g of HA-NH 2 (1.1mmol), add PBS (pH9.5) buffer solution 100mL, ultrasonically dissolve, add ...

Embodiment 3

[0055] Example 3 Structural characterization and property determination of hyaluronic acid-polylactic acid

[0056] (1) Specific steps for structural characterization

[0057] Infrared spectrum (FT-IR) characterization: take appropriate amount of PLA, HA and HA-PLA, mix with KBr, grind into powder, press into thin slices, use NICO LET-5700 Fourier transform infrared spectrometer to measure and analyze. The analysis from the FT-IR light diagram of HA-PLA is as follows: The characteristic absorption peak of HA is 3424.5cm -1 (υasOH and υasNH), 2892.8cm-1 (υC-H), 1628.7cm -1 (υasC-O); PLA characteristic absorption peak is 1758.1cm -1 (υC=O), 2995.8cm -1 (υasCH3), 1455.6cm -1 (δasCH3); 2892.8cm -1 The intensity of the peak increases, and through the analysis of the above results, it is confirmed that PLA is covalently linked to HA with a newly generated amide bond, and the synthetic product is determined to be a hyaluronic acid-polylactic acid (HA-PLA) block copolymer.

[00...

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Abstract

The invention belongs to the fields of polymer chemistry and medicinal preparations, and particularly relates to a method for synthesizing an active targeted hyaluronic acid-polylactic acid carrier, a method for preparing an anti-tumor medicinal micelle of the active targeted hyaluronic acid-polylactic acid carrier and an application thereof. By adopting a novel self-assembly technology, amphipathic PEG (polyethylene glycol) block polyester copolymer and tumor targeted ligand hyaluronic acid-polylactic acid copolymer are self-assembled by means of the electrostatic interaction to form a multifunctional composite micelle; the solubility of insoluble tumor medicaments and the drug loading capacity and encapsulation efficiency of water-soluble anti-tumor medicines can be remarkably improved by virtue of the anti-cancer drug-loaded micelle and composite micelle composition, the medicines can be biodegraded in a body, phagocytosis of a reticuloendothelial system (RES) and excretion of a kidney can be avoided. The active targeted hyaluronic acid-polylactic acid carrier has a long-circulating effect, the multifunctional composition has a prominent advantage of tumor active targeting effect, and parameters of pharmacodynamics in vitro and in vivo of the micelle are remarkably superior to those of common anti-tumor injections. Clinically acceptable administration means of the micelle includes injection administration or mucosal administration, and preparations of the micelle can be injection, transfusion, injection lyophilized powder injections or dry powder inhalation.

Description

technical field [0001] The invention belongs to the fields of polymer chemistry and pharmaceutical preparations. It specifically relates to the synthesis of active-targeting hyaluronic acid-polylactic acid carrier and the preparation method and application of anti-tumor drug micelles; the invention also relates to a new self-assembly method with active-targeting biodegradable carrier and amphiphilic block copolymer carrier. technology. Background technique [0002] Cancer is a common disease that seriously endangers people's health and life. There are 12 million new cases every year in the world, and the death rate is high. In my country, the number of cases exceeds 2.2 million every year. It is the leading cause of disease death among Chinese residents. According to the report of the National Ministry of Health Information Center, in recent years, the main cancer types that have harmed the people of our country are gastric cancer (21.76%), liver cancer (17.83%), lung cance...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/36A61K9/107A61P35/00C08G81/02
Inventor 李娟王广基陈芳张经纬周芳
Owner CHINA PHARM UNIV
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