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Folic acid receptor-mediated in-tumor environment-sensitive doxorubicin albumin nanoparticle and preparation method

A technology of albumin nanoparticles and folic acid receptors, which can be used in antitumor drugs, medical preparations with inactive ingredients, and medical preparations containing active ingredients, etc., and can solve the problems of poor selectivity and incomplete drug release from nanoparticles. , to achieve the effect of reducing toxic side effects, stable transportation, and prolonging circulation time

Active Publication Date: 2019-03-12
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aiming at the problems of poor selectivity of existing chemotherapeutic drugs and incomplete release of traditional nanoparticle drugs, the present invention provides a drug with strong active targeting ability, high drug loading and embedding rate, complete drug release, and effective Folate receptor-mediated pH and reduction double-sensitive doxorubicin albumin nanoparticles for reducing toxic and side effects of drugs and preparation method thereof

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  • Folic acid receptor-mediated in-tumor environment-sensitive doxorubicin albumin nanoparticle and preparation method
  • Folic acid receptor-mediated in-tumor environment-sensitive doxorubicin albumin nanoparticle and preparation method
  • Folic acid receptor-mediated in-tumor environment-sensitive doxorubicin albumin nanoparticle and preparation method

Examples

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Embodiment 1

[0037] This embodiment provides a folate receptor-mediated pH and reduction dual-sensitive doxorubicin albumin nanoparticles. See attached figure 1 , is a schematic diagram of the preparation process of folic acid receptor-mediated pH and reduction double-sensitive doxorubicin albumin nanoparticles, through aminocarboxyl condensation reaction and one-pot amide reaction, folic acid is grafted on the surface of bovine serum albumin successively and histamine, and then open the disulfide bond of the folic acid-albumin-histamine modifier through GSH, mix with the doxorubicin solution, and finally the disulfide bond spontaneously cross-links to form nanoparticles.

[0038] The specific preparation method of the present embodiment comprises the following steps:

[0039] 1. Synthesis of folic acid-albumin modifier:

[0040] Dissolve 88 mg folate acid (FA) in 4 mL dimethyl sulfoxide (DMSO), sonicate for 10 min, and add 58 mg 1-(3-dimethylaminopropyl)-3-ethyl carbon under stirring D...

Embodiment 2

[0050] This example investigates the particle size change of DOX / FBH-NPs prepared in Example 1 under the conditions of different pH and GSH concentration.

[0051] Filter the DOX / FBH-NPs with a 0.22 μM filter membrane, and sonicate for 5-10 minutes. The DOX / FBH-NPs solution was incubated in the following environments: phosphate buffered saline (PBS) at pH 7.4, PBS at pH 5.3, PBS at pH 7.4 and 10mM GSH, and the volume ratio of PBS to nanoparticle solution was 5: 1. The incubation time is 2 hours, the incubation temperature is 37°C, and then placed in a cuvette, put into the sample pool, and the particle size change is measured by a Malvern particle size analyzer. For the results, see the attached Image 6 ,Depend on Image 6 It can be seen that the particle size of DOX / FBH-NPs increases in PBS at pH 5.3, but the disulfide bonds of nanoparticles are opened under the condition of high concentration of GSH, and the particle size is disordered. This result proves that DOX / FBH-NPs...

Embodiment 3

[0053] In this example, the drug-loading behavior of DOX / FBH-NPs prepared in Example 1 was investigated.

[0054] Establish DOX standard curve equation 1: Accurately weigh an appropriate amount of DOX, use water as solvent, and dilute to the following concentrations: 100 μg / mL, 80 μg / mL, 40 μg / mL, 20 μg / mL, 10 μg / mL, 5 μg / mL, 2.5 μg / mL, 1.25 μg / mL, 0.625 μg / mL. The absorbance was measured with a multifunctional microplate reader. Do a linear regression with the DOX concentration on the absorbance value to obtain the standard curve equation: y=240.46x-11.213 (r 2 =0.9991).

[0055] The drug loading and encapsulation efficiency of DOX / FBH-NPs were calculated by formula (1) and formula (2), respectively.

[0056] The formula (1) for calculating the drug loading of DOX / FBH-NPs: the amount of drug loaded / the weight of the carrier; The difference in the amount of DOX in the serum.

[0057] The encapsulation efficiency calculation formula (2) of DOX / FBH-NPs: entrapped drug amoun...

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Abstract

The invention discloses a folic acid receptor-mediated in-tumor environment-sensitive doxorubicin albumin nanoparticle and a preparation method. An amino group and a carboxyl group are condensed and subjected to acylation reaction, and folic acid is linked to albumin; after a one-pot amide reaction, histamine is mixed with a folic acid-albumin solution to obtain a folic acid-targeted and pH-sensitive folic acid-albumin-histamine modifier; glutathione is used for opening a disulfide bond in the folic acid-albumin-histamine, and mixed with doxorubicin at alkaline pH to achieve spontaneous cross-linking of the intermolecular disulfide bond and to obtain the folic acid receptor-mediated pH-and-glutathione-sensitive albumin doxorubicin nanoparticle. The nanoparticle provided by the invention has an approximate spherical shape and strong uniformity, the particle size of about 70 nm, a small dispersion coefficient, good stability, and high drug loading and embedding rate of doxorubicin; underthe double stimulation of pH and glutathione, a drug can be quickly released, and the important application value is achieved in targeted drug delivery to tumors.

Description

technical field [0001] The invention relates to a folic acid receptor-mediated pH and reduction dual-sensitive albumin nano drug loading system and a preparation method thereof, belonging to the technical field of anti-tumor targeted drugs. Background technique [0002] Tumor has increasingly become a major killer that affects human health. A major problem with traditional chemotherapy drugs is the lack of targeting, which has great side effects on the body, and the amount of drugs that actually reach tumor cells and play a role is very small. Therefore, It is very important to design an effective and highly targeted drug delivery system. [0003] Due to their particle size and good surface properties, nanoparticles are easy to stay and accumulate in tumor tissues, so they are widely used in targeted drug delivery systems. Albumin is a good carrier for drug delivery in recent years, with many advantages and broad application prospects. In March 2016, the US FDA approved th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/54A61K47/64A61K47/69A61K31/704A61P35/00
CPCA61K47/545A61K47/643A61K47/6925A61P35/00A61K31/704
Inventor 张学农王丹丹陈维良
Owner SUZHOU UNIV
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