Preparation method of rgd and peg co-modified pamam dendrimer loaded with arsenic trioxide drug delivery system

A technology of arsenic trioxide and dendrimers, which is applied in the direction of pharmaceutical formulas, medical preparations containing active ingredients, etc., can solve the lack of specificity of distribution in the body, intracranial central tissue adverse reactions, ATO Poor fat solubility and other problems to achieve the effect of improving pharmacokinetic characteristics, increasing bioavailability, and reducing toxicity

CN106667963BActive Publication Date: 2020-09-29ZHEJIANG CHINESE MEDICAL UNIVERSITY
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
Publication Date
2020-09-29

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Abstract

The invention discloses a preparation method of an RGD (Arg-Gly-Asp) and PEG (Polyethylene Glycol) co-modified PAMAM (Polyamide-Amne Dendrimer) arsenic trioxide-loaded medicine delivery system. The preparation method comprises the following steps: enabling a sulfydryl group of an RGD cyclopeptide to react with a maleimide group of MAL-PEG-NHS, thus generating RGD-PEG-NHS; then reacting with a surface amino group of PAMAM, thus generating RGD-PEG-PAMAM; enabling the RGD-PEG-PAMAM to react with mPEG-NHS, thus preparing RGD-PEG-PAMAM-mPEG; enabling an arsenic trioxide solution to react with the RGD-PEG-PAMAM-mPEG, thus preparing the RGD and PEG co-modified PAMAM arsenic trioxide-loaded medicine delivery system. According to the preparation method disclosed by the invention, highly toxic traditional Chinese medicine-arsenic trioxide is firstly loaded in PAMAM; compared with an original medicine, a certain slow release action can be reflected, and the problems that ATO is poor in fat solubility, the blood-brain barrier penetration is difficult, body distribution is lack of specificity, and the like are solved; RGD is used for modifying the PAMAM, so that cellular uptake of tumor cells on the PAMAM is further increased; mPEG is used for modifying residual amino groups on the PAMAM, so that the cytotoxicity of a carrier can be further reduced.
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Description

technical field

[0001] The invention relates to the technical field of biomedicine, in particular to a preparation method of a PAMAM dendrimer loaded with arsenic trioxide drug delivery system co-modified by RGD and PEG. Background technique

[0002] Arsenic trioxide (ATO) is the effective active ingredient of the traditional Chinese medicine arsenic, and it is mainly used clinically for the treatment of acute promyelocytic leukemia. Some scholars have found that ATO can also inhibit the growth and induce apoptosis of a variety of solid tumor cells, and has broad-spectrum anticancer properties. However, due to the lack of specificity in the distribution of ATO in the body, it often produces serious adverse reactions to other normal tissues when the effective concentration is reached; in addition, ATO has a short half-life and is eliminated rapidly after administration, thus limiting its application in solid tumors.

[0003] Polyamide-amine dendrimers (PAMAM) are a class of ...

Examples

Embodiment 1

[0043] (1) Preparation of arsenic solution:

[0044] Weigh a certain amount of arsenic trioxide, add concentrated hydrochloric acid drop by drop to it until it is completely dissolved, then adjust the pH to 7.4 with concentrated sodium hydroxide solution to make arsenic salt mother liquor with a concentration of about 1 mg / mL.

[0045] (2) Preparation of RGDyC-PEG-PAMAM:

[0046] Weigh 4.68mg RGDyC, dissolve in 2mL acetic acid-sodium acetate buffer (pH 6.0), add 27.32mgMAL-PEG to it 3500 -NHS, vortexed for 30s, quickly added to 2 mL of borax-sodium hydroxide buffer (pH 9.2) containing 5.0 mg of PAMAM G5, and reacted overnight at room temperature. The pH of the system was adjusted to 7.0 by buffer, and 5 μL of β-mercaptoethanol was added to react for 1 h to terminate the unreacted maleimide groups. Use a Millipore ultrafiltration centrifuge tube with a cut-off molecular weight of 10,000 to perform ultrapure water ultrafiltration and centrifugation, and freeze-dry to obtain 15...