HA-mediated targeted double-drug-loading cationic liposome coating and preparation method thereof

A cationic liposome, dual drug-loading technology, applied in the directions of liposome delivery, pharmaceutical formulations, and non-active ingredients medical preparations, etc. The effect of reducing efflux and good therapeutic effect

Inactive Publication Date: 2021-06-22
SUZHOU AIHE PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the traditional combination therapy, that is, drug cocktail therapy, has certain limitations in clinical practice due to the incoordination of drug distribution after administration
Additionally, differences in solubility, potency, pharmacokinetics, and bioavailability between drugs make dosing schedules for HAART extremely challenging

Method used

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  • HA-mediated targeted double-drug-loading cationic liposome coating and preparation method thereof
  • HA-mediated targeted double-drug-loading cationic liposome coating and preparation method thereof
  • HA-mediated targeted double-drug-loading cationic liposome coating and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] A method for preparing a HA-mediated targeted dual drug-loaded cationic liposome coating mainly includes the following steps: S1, preparing polylysine polymer macromolecule PLL;

[0050] Such as figure 1 As shown, the reaction formula for the preparation of polylysine polymer macromolecule PLL, the specific steps include the following: a, b, c;

[0051] a. Dissolve the formula Lys(Z) (5 g, 17.85 mmol) in 65 ml of anhydrous tetrahydrofuran, stir for 30 min, add phosgene (2.12 g, 7.15 mmol), and react at 50° C. for 3 h under nitrogen gas. Add a large amount of pre-cooled n-hexane and stir for 10 min, and filter with suction to obtain the compound Lys(Z)-NCA. 1H NMR (400MHz, DMSO-d6): δ9.11(1H, α-NH), 7.34(5H, Ph), 5.00(2H, -CH2Ph), 4.42(1H, -CH), 2.98(2H, -CH2 ), 1.69(2H, -CH2), 1.4(2H, -CH2), 1.28(2H, -CH2).FT-IR (cm-1): 943 (O=C-O-C=O stretching vibration absorption band NCA), 1688 (C=O in the Cbz group), 1774, 1812 (C=O in the NCA), 1250 (C-O in the Cbz group).

[...

Embodiment 2

[0061] (1) Determination of two kinds of nanoparticles morphology and particle size:

[0062] The morphology of multifunctional liposomes was observed by transmission electron microscopy (TEM). Particle size, zeta potential and polydispersity (PDI) were determined by a Malvern Zetasizer 3000 system.

[0063] (2) Determination of drug encapsulation efficiency:

[0064] The two liposomes were added to water separately, and an equal volume of methanol was added. Subsequently, the solution was sonicated for 20 minutes, and the supernatant was obtained after centrifugation at 10000 rpm for 10 minutes. The amount of PTX and SOR was measured by HPLC C18 column (250 mm x 4.6 mm, 5 μm) combined with a flow rate of 1 mL / min and absorption wavelengths of 227 and 266 nm. The mobile phase of PTX is methanol:water (75:25, v / v), while the mobile phase of SOR is a mixture of acetonitrile and disodium phosphate (buffer pH=4, phosphoric acid 55:45, v / v).

[0065] (3) The calculation formula...

Embodiment 3

[0071] Performance test of the cationic liposome coated with hyaluronic acid of the present invention

[0072] (1) In vitro drug release study

[0073] The in vitro release of PTX and SOR from liposomes was studied by dialysis. Such as Figure 8 Shown are the release results of HA-TPD-CL-PTX / SOR liposomes, the left picture does not contain HAase, and the right picture contains HAase;

[0074] 1 mL of HA-TPD-CL-PTX / SOR was loaded into a dialysis bag (MWCO: 3.5 μkDa), then placed in 30 mL of LPBS at pH 7.4 or 5.0, containing 1% Tween80, with or without HAase 2 mg / mL. The samples were kept at 37°C and shaken at 100 rpm. At desired time intervals, remove 1 mL of release medium and replenish with an equal volume of fresh medium. The amount of drug released in the sample was detected by HPLC, and the cumulative release amount was calculated.

[0075] (2) Stability of liposomes

[0076] Such as Figure 9 Shown is HA-TPD-CL-PTX / SOR liposome particle size in distilled water, sur...

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Abstract

The invention discloses an HA (hyaluronic acid)-mediated targeted double-drug-loading cationic liposome coating, which is a cationic liposome coating co-modified by HA (hyaluronic acid), TPGS (tocopheryl phosphate synthase) and polylysine-deoxycholic acid (PLL-DA), and is used for co-delivering PTX (paclitaxel) and SOR (sorafenib) so as to treat multidrug resistance cancers. And the liposome coating adopts a lipid membrane hydration-ultrasonic method to prepare the drug-loaded TPD-CL-PTX / SOR liposome of the HA coating. The multifunctional liposome (HA-TPD-CL-PTX / SOR) can be preferentially gathered at a tumor part through a passive targeting effect and a CD44 mediated active targeting effect after intravenous injection. PTX and SOR are released from tumor cells and have a synergistic anti-tumor effect. Besides, TPGS can further interfere with the mitochondrial function and prevent energy supply of a P-gp efflux pump so as to reduce efflux of PTX or SOR to the maximum extent, so that drugs with high treatment concentration are maintained in cancer cells, multi-drug resistance is effectively reversed, and the method is promising.

Description

technical field [0001] The invention relates to the technical field of drug-loaded liposomes, in particular to an HA-mediated targeting double-loaded cationic liposome coating. Background technique [0002] Cancer remains a major threat to human health. Over the past 30 years, conventional chemotherapy has not made significant progress as the mainstay of cancer treatment. One of the well-known challenges is the lack of selective accumulation in cancer cells, leading to considerable toxic side effects in normal tissues. Another reason is the emergence of multidrug resistance (MDR), which occurs in more than 50% and is a major obstacle to successful chemotherapy. A well-studied mechanism of multidrug resistance in cancer cells is P-glycoprotein (P-gp), an overexpressed membrane protein that belongs to the group of ATP-binding cassette (ABC) transporters. It can effectively pump anticancer drugs out of cancer cells against the concentration gradient, thereby reducing the dru...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K47/34A61K31/337A61K31/44A61K9/51A61K47/36A61P35/00
CPCA61K9/1277A61K9/1271A61K31/337A61K31/44A61K9/5161A61P35/00A61K2300/00
Inventor 王雪源杜晓
Owner SUZHOU AIHE PHARM TECH CO LTD
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