Multifunctional poly(malic acid) carried drug for targeting treatment of tumors

A technology of polymalic acid and anti-tumor drugs, which can be used in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., and can solve problems such as the limitation of micelle stability

Inactive Publication Date: 2014-04-23
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, limited by the stability of micelles, it is still a challenge whether the membrane-penetrating peptide can be safely protected before reaching the target site.

Method used

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  • Multifunctional poly(malic acid) carried drug for targeting treatment of tumors
  • Multifunctional poly(malic acid) carried drug for targeting treatment of tumors
  • Multifunctional poly(malic acid) carried drug for targeting treatment of tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: TAT-PEG 2 -PMLA(DOX)-Hz-PEG 6 -Establishment of FA drug loading system

[0040] (1) Aldehyde polyethylene glycol-folate (CHO-PEG 6 -FA) Preparation

[0041] Weigh 44 mg of folic acid (FA) and dissolve it in an appropriate amount of DMSO, and add 22 mg (Boc) in turn 2 O, 20 mg triethylamine, reacted at room temperature in the dark for 4 h to obtain Boc-protected FA; then sequentially added 170 mg HO-PEG 6 -CHO (M n : 6000), 19 mg EDC·HCl, 10 mg DMAP, protected from light at room temperature, stirred overnight; the reaction solution was dialyzed with DMSO for 24 h, deionized water for 48 h, and freeze-dried to obtain CHO-PEG-FA(Boc); CHO-PEG-FA(Boc) was dissolved in 10 mL of anhydrous CH 2 Cl 2 5 mL TFA was added dropwise, stirred at room temperature for 4 h, and CH was removed by rotary evaporation. 2 Cl 2 and TFA to give FA-PEG-CHO.

[0042]

[0043] (2) Polymalic acid (PMLA-NH 2 ) preparation

[0044] Weigh 80 mg PMLA, dissolve 88 mg NHS in 20...

Embodiment 2

[0054] Embodiment 2: TAT-PMLA (CPT-NH 2 )-Hz-PEG 6 Establishment of drug loading system

[0055] Weigh a slightly excess amount of polymalic acid (PMLA; Mn: 5,000) 30 mg and dissolve it in an appropriate amount of DMF, add EDC?HCl 100 mg, 2 ml 5% hydrazine hydrate, and stir overnight at room temperature. Add 200mg OHC-PEG 6 -OH (Mn: 6,000) was stirred at room temperature for 10 h. After the end, dialyze with deionized water for 48h to remove unreacted substrate and solvent, and freeze-dry to obtain the product PMLA-Hz-PEG 6 -OH.

[0056] The PMLA-Hz-PEG 6 -OH was dissolved in an appropriate amount of DMF, EDC?HCl and TEA were added, and stirred in an ice-water bath. The DMF solution of appropriate amount of TAT is added dropwise in this system, then adds 50mg aminocamptothecin (CPT-NH 2 ), reacted at 0°C for 2 hours, then transferred to room temperature for 24 hours, dialyzed in deionized water for 24 hours, and freeze-dried to obtain yellow powder TAT-PMLA (CPT-NH 2 )...

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PUM

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Abstract

The invention discloses a poly(malic acid) carried drug, which is prepared by fixing drug on poly(malic acid) carriers. The drug incudes antitumor drug and derivatives thereof, wherein the antitumor drug contains amino groups or can be introduced with amino groups. The poly(malic acid) carriers are connected with cell-penetrating peptides, and targeting groups Ligand or targeting groups modified with flexible chains are connected to the poly(malic acid) carriers through breakable bonds. Structural characteristics of the poly(malic acid) carriers are utilized sufficiently, activated molecules with different biological characteristics are connected to the poly(malic acid) carriers sequentially, and a polymer drug system with characteristics of targeting and high-efficiency endocytosis drug-delivery for tumor treatment is established by the shielding-deshielding effect. The polymer drug system realizes active targeting to tumor portions by binding of specificities of ligand-receptor and antibody-antigen.

Description

technical field [0001] The invention relates to a tumor-targeting multifunctional polymalic acid carrier drug. Background technique [0002] Chemotherapy is one of the main means of comprehensive treatment of malignant tumors. Antineoplastic drugs usually have extremely high biotoxicity and less bioselectivity. While killing tumor cells, they also kill normal tissue cells. Due to non-specific toxicity, lack of tumor selectivity, and multidrug resistance of tumors, most anticancer drugs are not as effective as expected, and their side effects on normal tissues are the main problem that plagues chemotherapy. [0003] Biocompatible and biodegradable polymer materials can be used as carriers of small molecule drugs to selectively release drugs at the lesion site, greatly improve the bioavailability of drugs, and effectively reduce the toxic side effects and dosage of drugs ; Introducing targeting molecules into polymers can also actively target drugs to lesion sites. At prese...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/48A61K45/00A61P35/00C08G81/00C08G63/91C08G65/48
Inventor 吴红李飞李伟陶阳春乔友备范黎
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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