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Novel polypeptide modified tumor targeted liposome of targeted integrin receptor

A technology of integrin receptors and targeting liposomes, which is applied in liposome delivery, hybrid peptides, anti-tumor drugs, etc., can solve the problems of non-tissue specificity, achieve few influencing factors, simple process, The effect of increased intake

Inactive Publication Date: 2013-12-04
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, CPP also has certain defects, that is, it does not have tissue specificity. Some studies have realized its long-term circulation in the body through PEGylation of CPP, and achieved passive tumor targeting through the EPR effect of tumor tissue. A means to achieve highly effective active targeting

Method used

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  • Novel polypeptide modified tumor targeted liposome of targeted integrin receptor
  • Novel polypeptide modified tumor targeted liposome of targeted integrin receptor
  • Novel polypeptide modified tumor targeted liposome of targeted integrin receptor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1 R 8 - Preparation of Ring (RGD)

[0058] (1) Take 1g of 2-CL-Trt Resin resin and place it in a solid-phase reactor, add 15ml of dichloromethane (DCM) to swell for 30min, and then drain the DCM;

[0059] (2) Weigh 0.9 g of arginine protected by fluorenylmethoxycarbonyl (Fmoc) at the N-terminal, add it to the swollen resin, add N,N-diisopropylethylamine (DIEA), dimethylamide ( DMF), DCM nitrogen bubbling reaction at room temperature for 2.5 hours, drain the reaction solution after the reaction, add 20ml of ethyl acetate to wash, then add 20% hexahydropyridine / DMF solution to remove the Fmoc protecting group, add ethyl acetate after removing the protecting group 20ml wash;

[0060] (3) Weigh 0.67 g of glycine protected by fluorenylmethoxycarbonyl (Fmoc) at the N-terminal, add it to the reactor, and then add benzotriazole-N,N,N',N'-tetramethyluronium hexafluoro Phosphate ester (HBTU), DIEA, react at room temperature for 2 hours with nitrogen gas bubbling, add 2...

Embodiment 2

[0067] Example 2. DSPE-PEG 2000 -R 8 - Preparation of Ring (RGD)

[0068] In a 25ml round bottom flask, add 10ml of chloroform, then add 15.0mg (5.1umol) of DSPE-PEG2000-Mal, 3ul (17.9mmol) of triethylamine, and then dissolve 15.0mg (7.7umol) of R8-ring (RGD) in Add 5ml of methanol to a round-bottomed flask, and react in the dark for 24 hours at room temperature. The reaction solution is spin-dried under reduced pressure to obtain the initial product, which is dissolved in chloroform, filtered, and then spin-dried under reduced pressure to obtain DSPE-PEG2000-R8-ring (RGD) 23.1 mg (94.3%), as a colorless oily compound.

[0069]Based on the method of this example, when PEG is selected from 200-50000, CPP is selected from TAT, VP22, RX (X=3, 4, 5, 6, 7, 8, 9, 10, 11, 12), Penetratin, Transpotan Etc., each specific DSPE-PEG-CPP-ring (RGD) can be prepared analogously.

[0070]

Embodiment 3

[0071] Example 3. Preparation of TAT-ring (RGD) modified liposomes

[0072] Integrin receptor-targeted liposomes were prepared from phospholipids, cholesterol, DSPE-PEG2000, and DSPE-PEG2000-TAT-ring (RGD). Weigh 1.4 mg of phospholipids, 0.4 mg of cholesterol, 0.3 mg of DSPE-PEG2000, and 0.2 mg of DSPE-PEG2000-TAT-ring (RGD), dissolve them in an appropriate amount of chloroform, and remove the chloroform by rotary evaporation under reduced pressure in a water bath at 37°C to form a uniform For the lipid film, add 1ml PBS buffer solution to hydrate for 1h, and the probe is sonicated (10s, 10s, 15 times). Sequentially extrude through 400nm, 200nm and 100nm polycarbonate membranes to obtain TAT-ring (RGD) modified liposomes.

[0073]

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Abstract

The invention provides a novel polypeptide modified tumor targeted liposome of a targeted integrin receptor. The novel polypeptide is mainly formed by covalent linkage of ring-shaped RGD and cell penetrating peptides, and not only has the selective targeting capability of an integrin receptor, but also can achieve mediated endocytosis; the liposome mainly comprises phospholipid, cholesterol, lipid-polyethyleneglycol and lipid-polyethyleneglycol-novel polypeptide ligand chimeric substance, and is a very potential tumor targeted treatment carrier.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical preparations, in particular to a tumor-targeted liposome drug delivery system, which combines a cyclic arginine-glycine-aspartic acid (RGD) sequence with a cell-penetrating peptide ( CPP) to obtain a new type of polypeptide that has both integrin receptor targeting and high-efficiency mediation into cells, and modified on the surface of liposomes to obtain a tumor-targeting liposome. [0002] Background technique [0003] As a commonly used drug carrier, liposome has good biocompatibility, can increase drug efficacy, reduce drug toxicity, and is easy to carry out ligand modification on the surface. It can be used as a delivery carrier for various therapeutic drugs. After modifying the surface of liposomes with hydrophilic polyethylene glycol (PEG), long-circulating liposomes can be prepared, which can significantly enhance their circulation time in vivo, and passively accumulate to tumor t...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K47/42A61K47/34C07K19/00A61P35/00
Inventor 何勤刘亚圆唐洁
Owner SICHUAN UNIV
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