pH-sensitive polymer micelles for drug delivery

A polymer glue and drug technology, which can be used in drug combinations, inactive components of polymer compounds, anti-tumor drugs, etc., can solve problems such as limiting drug absorption, increasing drug transmembrane absorption, and tumor cell drug resistance.

Active Publication Date: 2019-01-01
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, related studies have also found that TAT peptide is easily degraded by certain enzymes in body fluids (such as pancreatic enzymes, etc.), which significantly reduces its cell membrane penetration ability (Torchilin et al., Drug Deliv, 2011, 18, 377–384.; Brock et al., J Biol Chem, 2004, 279, 12625–12635.)
[0005] There have been many studies on the application of polymer block copolymer micelles and TAT peptides to deliver anti-tumor drugs, but there are still few studies on the combined application of pH-sensitive polymer micelles and TAT peptides, and there is also a lack of An anti-tumor drug micelle composition that can selectively exert the transmembrane effect of TAT peptide, increase drug transmembrane absorption, and protect TAT peptide to prevent enzymatic degradation
This limits the absorption of drugs by tumor cells, and the intracellular drug concentration is lower than the effective therapeutic dose, which in turn leads to the emergence of drug resistance, recurrence and metastasis of tumor cells

Method used

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  • pH-sensitive polymer micelles for drug delivery
  • pH-sensitive polymer micelles for drug delivery
  • pH-sensitive polymer micelles for drug delivery

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0172] Example 1: PLA 2K -NH 2 Synthesis

[0173] Put 10g of lactide in a 250mL reaction flask, add 150mL of anhydrous toluene, heat and stir to 100°C to dissolve the lactide. Weigh 0.71 g of 3-(tert-butyloxycarbonylamino)-1-propanol, and dissolve it in an appropriate amount of anhydrous toluene. Weigh 0.1g stannous octoate (Sn(Oct) 2 ), and dissolved in an appropriate amount of anhydrous toluene. Under the condition of nitrogen protection, the above two mixed solutions were added into the lactide-toluene solution, under nitrogen protection, stirred at 100°C, and reacted for 10 hours. After 10 hours, the toluene was removed under reduced pressure, the product was dissolved in anhydrous dichloromethane, precipitated in anhydrous methanol, and the flocculent precipitate obtained by centrifugation was vacuum-dried, and the obtained white colloidal solid was PLA-NH-Boc. Yield about 65%.

[0174] Dissolve 1 g of PLA-NH-Boc obtained above in 12 mL of anhydrous dichlorometha...

Embodiment 2

[0175] Embodiment 2: the synthesis of BLG-NCA

[0176] Put 10 g of glutamic acid-γ-benzyl ester (BLG) in a 100 mL reaction flask, add 30 mL of anhydrous tetrahydrofuran, and stir at 50°C. Weigh 6g of triphosgene (BTC), add it into the reaction bottle, and stir at 50°C for about 3 hours. The reaction solution was poured into 150 mL of anhydrous n-hexane, refrigerated at -20°C for 48 hours, and filtered to obtain the crude BLG-NCA. The crude BLG-NCA was recrystallized three times from anhydrous ethyl acetate and anhydrous n-hexane, and dried under reduced pressure to obtain white needle crystals as the final product BLG-NCA. The yield is about 87%.

Embodiment 3

[0177] Example 3: PGA 6K -b-PLA 2K Synthesis

[0178] Step 1: Place 3 g of the BLG-NCA obtained in Example 2 into a 250 mL reaction flask and dry under reduced pressure for 2 hours, add 150 mL of anhydrous DMF under nitrogen protection, and then add triethylamine (the amount is 0.075 mole times the amount of BLG-NCA ). Take by weighing 0.15g embodiment 1 gained PLA 2K -NH 2 , added to the reaction flask under the protection of nitrogen, and stirred at room temperature for 72 hours. The reaction solution was poured into excess anhydrous ether for precipitation, filtered, and dried under reduced pressure to obtain PBGA-b-PLA as a pale yellow solid. The yield of step 1 was 92%.

[0179] Step 2: Dissolve 1 g of PBGA-b-PLA obtained in the above steps in 10 mL of dichloroacetic acid, add 5 mL of HBr (33%), stir at room temperature for 2 hours, then drop the reaction solution into excess -20°C ether to settle, wash, Filtration, the obtained white solid was dissolved in DMF,...

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Abstract

The invention discloses a pH sensitive polymer micelle for delivering medicaments. In particular, the invention discloses a polymer micelle composition which contains a polyglutamic acid-polylactic acid block copolymer expressed by a formula of PGAm-PLAn, wherein m and n express the polymerization degrees of a polyglutamic acid chain and a polylactic acid chain respectively; and the polymer micelle composition also contains TAT peptide covalently connected polyethylene glycol-distearoyl phosphoethanolamine (TAT-PEG-DSPE), polyethylene glycol-distearoyl phosphoethanolamine (PEG-DSPE) and optional medicinal carriers and antitumor medicaments. The invention also relates to a preparation method of the polymer micelle composition and an application of the polyglutamic acid-polylactic acid block copolymer in preparation of the polymer micelle composition. The polymer micelle disclosed by the invention has pH sensitivity, thereby being capable of prolonging the retention time of the medicaments at tumor parts, giving play to a membrane penetrating function of TAT peptide in a targeting manner, increasing trans-membrane absorption of the medicaments, being capable of protecting the TAT peptide at the same time and preventing enzyme degradation. Moreover, the polymer micelle composition provided by the invention is excellent in drug loading performance.

Description

technical field [0001] The patent of the present invention relates to an anti-tumor drug preparation administered by intravenous injection and its preparation method, which is composed of three amphiphilic polymer block copolymers and an anti-tumor drug, which can be selectively accumulated in tumor lesion sites , prolong the residence time of tumor lesions, increase the absorption of drugs by tumor cells, promote tumor cell apoptosis, and reduce the toxic and side effects of anti-tumor drugs on other normal tissues and organs. Background technique [0002] Polymer block copolymer micelles can improve the targeting of anti-tumor drug delivery. Chinese patent CN101160354mB shows that making anti-tumor drugs into polymer drug micelles can increase tumor site accumulation, prolong residence time, and reduce drug Toxic and side effects on normal tissues and organs, and named this phenomenon as EPR (enhanced permeability and retention, enhanced permeability and retention) effect....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/107A61K47/34A61K47/42A61K45/00A61P35/00C08G69/44
Inventor 高钟镐王启明
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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