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A class of heterozygous tumor-targeting nanomicelles and uses thereof

A tumor targeting and nanomicelle technology, applied in the application field of tumor targeted therapy, can solve the problems of normal tissue or organ damage, insufficient drug concentration, leakage, etc., and achieve the effect of good safety and stability improvement.

Active Publication Date: 2019-09-20
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The research on nanomicelle drug delivery system is in the ascendant, but there are still some deficiencies, among which the typical problems are: i) Some micellar drug delivery systems are not stable enough in the circulatory system, and there are phenomena such as sudden release, leakage and early enzymatic hydrolysis, resulting in Insufficient drug concentration reaching the lesion site and causing damage to normal tissues or organs; ii) Insufficient drug active targeting
Endter et al. used RT-PCR to analyze multiple types of lung cancer cells and found that the expression of PepT1 on all tested cell membranes was positive, suggesting that high expression of PpeT1 on tumor cell membranes may be a common phenomenon

Method used

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  • A class of heterozygous tumor-targeting nanomicelles and uses thereof
  • A class of heterozygous tumor-targeting nanomicelles and uses thereof
  • A class of heterozygous tumor-targeting nanomicelles and uses thereof

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Experimental program
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preparation example Construction

[0029] The preparation method of polymer 1 of the present invention and polymer 2 is shown in reaction formula (I), (II):

[0030]

[0031] Reaction formula (I)

[0032]

[0033] in,

[0034] Reaction formula (II)

[0035] The synthetic method of polymer 1 comprises the following steps:

[0036] Step 1: reacting the azide-protected PEG with the Boc-protected L-valine-L-valine dipeptide in the presence of a condensing agent to obtain a dipeptide-modified PEG intermediate 1;

[0037] Step 2: intermediate 1 is reduced by catalytic hydrogenation to obtain intermediate 2;

[0038] Step 3: Ring-opening polymerization of intermediate 2 with 10-40 equivalents of L-alanine-N-carboxyl-internal anhydride or 2,4-dinitrophenyl protected histidine internal anhydride to obtain intermediate 3 or 4;

[0039] Step 4: Deprotection of intermediates 3 and 4 to obtain polymer 1.

[0040] The synthetic method of polymer 2 comprises the following steps:

[0041] Step 1: Reaction of azido...

Embodiment 1

[0045] Embodiment 1. Preparation of Intermediate 1

[0046]

[0047] At 25°C, Boc-L-Val-L-Val dipeptide (1.2mmol), HO-PEG-N 3 (1mmol), DCC (1mmol) and DMAP (0.1mmol) were added to a 100mL single-necked bottle, and 100mL CH 2 Cl 2 Stir to dissolve, N 2 protection, reacted for 24h, and the reaction solution gradually became turbid. After stopping the reaction, filter, and the filtrate was washed with 5% HCl aqueous solution (50mL×3), and the organic layer was anhydrous Na 2 SO 4 Drying, suction filtration, filtrate concentration, column chromatography (CH 2 Cl 2 :CH 3 OH=10:1) A white waxy solid was obtained with a yield of 56%.

[0048] IR(KBr,cm -1 ):3418(NH,s); 2887(CH 2 CH 2 ,vs); 2105(N 3 , s); 1720, 1669, 1624 (C=O, s); 1112 (CH 2 -O-CH 2 ,vs)

[0049] 1 HNMR (300MHz, CDCl 3 ,δ): 5.25 (NH-CO), 3.99-4.55 (NH-CO); 4.57, 3.97 (NH-C H -CO); 3.64(O-C H 2 C H 2 -O); 2.25, 2.13 (C H (CH 3 ) 2 ); 1.45(C(C H 3 ) 3 );0.93(CH(C H 3 ) 2 )

Embodiment 2

[0050] Embodiment 2. Preparation of Intermediate 2

[0051]

[0052] Intermediate 1 (0.23 mmol) was dissolved in 10 mL CH 2 Cl 2 , then add 20mL of ethanol and 0.05g of 10% Pd / C, hydrogenate at 40°C until the reaction is complete, filter with suction, concentrate the filtrate to 3mL, add dropwise to 50mL of diethyl ether with vigorous stirring, cool and stand in an ice-water bath for 30min, and filter with suction , and dried to obtain a white solid with a yield of 90%.

[0053] IR(KBr,cm -1 ):3412(NH,NH 2 ,s); 2887(CH 2 CH 2 , vs); 1739, 1708, 1676 (C=O, s); 1112 (CH 2 -O-CH 2 ,vs)

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Abstract

The invention discloses a hybrid subtype tumor targeted nano-micelle and a purpose thereof. The micelle is obtained through mixing and self assembly of a polymer 1 and a polymer 2, wherein the hydrophilic ends of the polymer 1 and the polymer 2 are respectively L-valine-L-valine dipeptide and raloxifene-modified polyethyleneglycol embedding sections; the hydrophobic end is polymer histidine or polymer lactamine. The micelle belongs to a kind of nano-micelle based on PepT1 and ER as the target, and can coat hydrophobic anti-tumor medicine; in-vitro study shows that the stability of the micelle is obviously superior to non-hybrid micelle; meanwhile, the type of nano-micelle medication system can be selectively taken by PepT1 and ER high-expression tumor cells; the tumor cells shows selective cell toxicity, and can be applied to preparation of tumor targeted treatment medicine.

Description

technical field [0001] The present invention relates to a class of heterozygous tumor targeting nanomicelles based on peptide transporter 1 (PepT1) and estrogen receptor (ER) targeting, and its application in the field of tumor targeting therapy. Background technique [0002] Cancer is a serious threat to human health. According to data from the Ministry of Health of my country, cancer has become the second leading cause of death after cardiovascular disease. By 2020, the number of new cases in my country will exceed 3 million each year. Corresponding to the ravages of cancer, the current clinical treatment methods are unsatisfactory. Surgery and chemotherapy are the main weapons for cancer patients to fight against the disease. Unfortunately, currently clinically used chemotherapy drugs such as adriamycin, cisplatin, oxaliplatin, paclitaxel, camptothecin, 5-fluorouracil, etc. have no therapeutic effect. Satisfactory, its main defect is poor selectivity, and has more seriou...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/107A61K31/4535A61K31/704A61K47/34A61K47/64A61K47/60A61P35/00
Inventor 房雷
Owner SOUTHEAST UNIV
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