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Atherosclerotic plaque-targeting platelet membrane coated rapamycin bionic nano particles and application thereof

A technology of atherosclerosis and rapamycin, applied in the field of medicine, can solve the problems of endangering unstable plaques and counteracting anti-plaque efficacy

Inactive Publication Date: 2018-05-18
ZHONGSHAN HOSPITAL FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are certain limitations in device-mediated drug delivery: (1) Space limitations: only enough drugs can be ensured for the plaques in the stent and balloon adhering parts, while the remaining coronary plaques and systemic organ arterial plaques are free. cover
What is even more embarrassing is that plaque vulnerability has more clinical prognostic value than the degree of vascular stenosis. At present, interventional interventions are based on the severity of stenosis, and it is impossible to estimate the more harmful unstable plaques with mild to moderate stenosis.
(2) Time limitation: it can only be implemented during interventional therapy, the drug release of the stent is fast, and lasts for several hours to several weeks, while AS is essentially a chronic inflammatory disease that requires long-term medication
(3) Although balloon expansion and stent release have the therapeutic effect of mechanical support, a new round of atheromatous plaque growth will undoubtedly be initiated due to vascular dissection injury and foreign body reaction, which offsets the anti-plaque efficacy of the drug to a certain extent
At present, there are no related studies and related patent applications on the use of cell membrane-coated biomimetic nanoparticles to carry rapamycin for targeted treatment of atherosclerotic plaques

Method used

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  • Atherosclerotic plaque-targeting platelet membrane coated rapamycin bionic nano particles and application thereof
  • Atherosclerotic plaque-targeting platelet membrane coated rapamycin bionic nano particles and application thereof
  • Atherosclerotic plaque-targeting platelet membrane coated rapamycin bionic nano particles and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1: Synthesis of biomimetic nanoparticles of rapamycin coated with platelet membrane

[0043] Synthesis schematic see figure 1 . 800 μg of rapamycin and 20 mg of PLGA were dissolved in 1 ml of acetone, injected into 2 ml of water, and PLGA nanoparticles loaded with rapamycin were prepared by nanoparticle precipitation method under vacuum. After the human platelet-rich plasma was anticoagulated with EDTA, it was centrifuged at 100g for 20min to remove the remaining blood cells. Add EDTA and prostacyclin to the supernatant to inhibit platelet activation, centrifuge at 800 g for 20 min, discard the supernatant, and resuspend the platelets in PBS containing EDTA and protease inhibitors. 3×10 9 Platelets were used to coat 1 mg PLGA nanoparticles. Platelets Platelet membranes were prepared using the repeated freeze-thaw method. After the platelets were quick-frozen with liquid nitrogen, they were dissolved at room temperature and repeated three times, centrifuged ...

Embodiment 2

[0045] Example 2: PNP simulates platelet adhesion function in vitro

[0046] The adhesion function of platelets was simulated by combining PNP with collagen, fibrin, vWF, etc. under static and dynamic conditions in vitro.

[0047] Binding of PNP to collagen and fibrin in a static state: After adding collagen or fibrin to a 96-well plate, add DiD-labeled PNP, incubate at 37°C for 5 minutes, wash with PBS, dissolve the bound PNP with DMSO, and measure with a microplate reader its fluorescence intensity. As shown in 4A and B, PNP has a strong binding force to collagen and fibrin, which are 8.3 times and 9.6 times that of uncoated platelet membrane nanoparticles (NP), respectively, and there is a significant difference between the two.

[0048] The combination of PNP with collagen, fibrin and vWF in a dynamic state: use glass slides to prepare collagen and fibrin, place them in a parallel plate flow chamber, DiD-labeled PNP flows through the parallel plate flow chamber at 500S-1,...

Embodiment 3

[0050] Example 3: PNP binds to atherosclerotic plaque in vitro

[0051] In Vitro Binding Ability of PNP to Mouse Atherosclerotic Plaques: ApoE - / - After mice were fed with a high-fat diet for 8 weeks, the aorta was removed and co-incubated with DiD-labeled PNP for imaging of isolated organs, such as Figure 4 F and G, the fluorescence intensity of the PNP group was significantly higher than that of the control group NP, and it was mainly distributed in the area rich in plaques (the branch of the brachiocephalic trunk and the subclavian artery). strong binding.

[0052] The in vitro binding ability of PNP and human carotid atherosclerotic plaque: After the human carotid plaque was taken out, it was co-incubated with DiD-labeled PNP, and after OCT embedding, it was frozen and sectioned, and laser confocal microscope observation showed that the PNP group had more Red fluorescence (PNP) adhered, while no obvious red fluorescence was seen in the NP group (such as Figure 4 H sho...

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Abstract

The invention relates to a new dosage form of rapamycin, atherosclerotic plaque-targeting platelet membrane coated rapamycin bionic nano particles. The invention also provides a preparation method andapplication of the new dosage form. The invention has the following advantages: the invention provides atherosclerotic plaque-targeting platelet membrane coated rapamycin bionic nano particles (RAP-PNP), wherein a nano carrier entraps rapamycin, and the surface of the nano carrier is coated with a platelet membrane; the attachment protein on the platelet membrane simulates the natural homing ability of platelet for atherosclerotic plaque, and performs targeted delivery of the rapamycin to part of the atherosclerotic plaque; then, the drug concentration in the plaque is increased, macrophage autophagy is activated, the plaque development is inhibited while the plaque is stabilized, the curative effect of rapamycin against atherosclerosis is improved, and systemic adverse reactions are reduced.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular, a platelet membrane-coated biomimetic nanoparticle of rapamycin targeting atherosclerotic plaques and its application in the preparation of medicines for treating atherosclerotic diseases . Background technique [0002] Atherosclerosis (AS) is a chronic inflammatory and metabolic disease, which is the pathophysiological basis and main cause of various cardiovascular and cerebrovascular diseases, and has high disability and mortality rates. Over the past few years, breakthroughs have been made in the treatment of AS, and the wide application of antiplatelets, statins and interventional therapy (PCI) has greatly promoted the prognosis of AS patients. However, reversing and stabilizing plaque is still the most difficult basic and clinical problem at present, and it is necessary to develop more effective means and drugs to treat atherosclerotic diseases. [0003] Rapamycin (RAP), a...

Claims

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Application Information

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IPC IPC(8): A61K9/51A61K31/436A61K47/46A61K47/34A61P9/10
CPCA61K9/5146A61K9/5176A61K31/436
Inventor 葛均波钱菊英黄浙勇庞志清宋亚楠程蕾蕾
Owner ZHONGSHAN HOSPITAL FUDAN UNIV
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