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Branched polyHPMA copolymer-DOX conjugate, and preparation method and application thereof

A technology of hyperbranched polymers and copolymers, which can be used in pharmaceutical combinations, pharmaceutical formulations, medical preparations of non-active ingredients, etc. The effect of stable performance, good biocompatibility and simple preparation method

Active Publication Date: 2016-09-28
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis of star-shaped HPMA macromolecule-DOX polymers is not easy, and it needs to involve the synthesis of monomers, the modification of polymer functional groups, the modification of the surface of PAMAM dendrimers, and the preparation of functionalized PAMAM dendrimers. Coupling, multi-step purification, etc., the synthesis requires a multi-step process and purification, and the yield is very low
These multiple synthetic steps will prevent large-scale synthesis
In addition, cationic PAMAM dendrimers are non-biodegradable, which will also lead to potential side effects

Method used

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  • Branched polyHPMA copolymer-DOX conjugate, and preparation method and application thereof
  • Branched polyHPMA copolymer-DOX conjugate, and preparation method and application thereof
  • Branched polyHPMA copolymer-DOX conjugate, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Synthesis of functionalized chain transfer agent MA-GFLG-CTA

[0045]

[0046] Dissolve MA-GFLG-OH (1.84g, 4mmol), EDCI (764mg, 4mmol), HOBt (676mg, 5mmol) in 50mL of anhydrous DMF, then add DIPEA (3.5mL, 20mmol), under the condition of nitrogen ice bath Stir for 30min. Then N-Boc-ethylenediamine (800mg, 5mmol) was added, stirred in a nitrogen ice bath for 30min, and then stirred at room temperature for 12h. After stirring, another 250 mL of ethyl acetate (EtOAc) was added to the solution, and the water in the solution was extracted with EtOAc (50×3). The resulting new solutions were washed with saturated NaHCO 3 solution, 1M HCl solution, NaHCO 3 Washing with a saturated solution, followed by washing with a saturated HCl solution, followed by drying with anhydrous MgSO4, the solvent was removed with a rotary evaporator, and the remaining product was recrystallized in reagent EtOAc / ether (1:1) at 4°C to give a yield of 80%. (1.93 g, 3.2 mmol) of the MA...

Embodiment 2

[0048] Embodiment 2: the preparation of hyperbranched HPMA copolymer-DOX conjugate

[0049] Such as figure 2 As shown, HPMA (1.36g, 9.5mmol), MA-GG-NHNHBoc (126mg, 0.4mmol), MA-GFLGK-MA (65.6mg, 0.1mmol), MA-GFLG-CTA (29.6mg, 38.8μmol) Dissolve in 7 mL of VA044 (3.6 mg, 12.9 μmol) in a mixed solvent of deionized water / methanol (1:1, v / v).

[0050] The HPMA copolymer is precipitated in acetone / ether (2:1), this operation is repeated twice, and then the HPMA copolymer is separated by centrifugation, and the HPMA copolymer is purified twice by the method of first dissolving and then precipitating, and finally vacuum-dried to obtain Slightly pink powder. Samples further adopted (GE Healthcare) high performance liquid chromatography system combined with Superose6HR10 / 30 chromatographic column (molecular weight range of hydrophilic neutral polymer 15kDa-300kDa / 14mL separation volume), with sodium acetate buffer (pH 6.5) containing 30% acetonitrile as the The mobile phase was fu...

Embodiment 3

[0052] Embodiment 3: the characterization of nanoparticle size, morphology, Zeta potential

[0053] The resulting hyperbranched HPMA copolymer-DOX conjugate was dissolved in double-distilled water to a final concentration of 1 mg / mL, and sonicated for 30 seconds. The size of the aqueous phase and the zeta potential were measured by Zetasizer Nano ZS (Malvern Instruments, Worcestershire, UK). Subsequently, the solution containing nanoparticles was dropped on a silicon wafer of an appropriate size until the solvent evaporated completely, and the size was further confirmed by field emission scanning electron micro-scope (FE-SEM).

[0054] The results show that: the dynamic light scattering (DLS) method detects that the particle size of the aqueous phase of 1mg / mL hyperbranched HPMA copolymer-DOX conjugate nanoparticle is 102nm, and the particle size dispersion is 0.397, such as Figure 4 Shown in B. The nanoscale size and narrow particle size dispersion indicate that the prepar...

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Abstract

The invention discloses a branched polyHPMA copolymer-DOX conjugate, and the preparation method and the application thereof, and belongs to the field of biological materials. According to the invention, the branched polyHPMA copolymer-DOX conjugate is successfully prepared through one step of RAFT polymerization. DOX in the conjugate is connected with a branched polyHPMA copolymer through a pH sensitive key, and biodegradable fragments are contained in a branched polyHPMA copolymer framework. The conjugate is excellent in biocompatibility, has dual sensitive characteristics of pH sensitivity and enzyme sensitivity, and serves as an intelligent drug delivery system to form nano particles to intensively gather in tumor sites, quickly release drug under a tumor microenvironment and be degraded to be low molecular weight fragments, therefore, excellent biosecurity is ensured while the antineoplastic effect is improved, and the branched polyHPMA copolymer-DOX conjugate has a wide application scope in tumor therapy.

Description

technical field [0001] The invention belongs to the field of biological materials, and in particular relates to a hyperbranched HPMA copolymer-DOX conjugate and a preparation method and application thereof. technical background [0002] Breast tumor is the first female common malignant tumor, and its incidence is increasing year by year in our country. Seeking effective treatment has become one of the most urgent tasks at present. At present, the clinical drugs for breast tumors are mainly small-molecule anti-tumor drugs, but there are defects such as large toxic and side effects on normal tissues and organs, and low anti-tumor efficiency. The nano-drug controlled release system has the characteristics of passively targeting tumors and accumulating in tumor sites through the high permeability of solid tumors and the enhanced permeability and retention effect (EPR effect), which can effectively improve the delivery route of chemotherapy drugs and improve the anti-tumor effect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/704A61P35/00
CPCA61K31/704
Inventor 龚启勇罗奎朱红艳魏小丽
Owner SICHUAN UNIV
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