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Preparation method and application of intelligent bone targeted delivery medicine capable of efficiently entering cells

A technology for drug delivery and bone targeting, applied in the field of medical treatment, can solve problems such as weak growth of bone metastases, increase drug toxicity and side effects, and affect anti-tumor effects, achieve good bone targeting, and reduce systemic toxicity. , the effect of increasing efficiency

Pending Publication Date: 2022-07-08
FOURTH MILITARY MEDICAL UNIVERSITY
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Problems solved by technology

[0002] Lung cancer is one of the main causes of malignant tumor-related deaths worldwide, and its incidence is increasing year by year in many countries. In patients with advanced lung cancer, bone is a common site of metastasis. Currently, chemotherapy is the clinical first choice for bone metastasis of lung cancer. However, due to the characteristics of high bone hardness and low drug permeability, it is difficult to effectively deliver chemotherapy drugs to bone metastases according to traditional drug administration methods, which seriously affects its anti-tumor effect and easily increases the side effects of drugs. Therefore, the development of a safe and effective drug delivery system that can specifically deliver drugs to bone metastases is of great significance for the treatment of lung cancer bone metastases
[0003] Although the current drug delivery system for bone metastases has improved bone targeting, a large number of chemotherapy drugs are distributed in the bone tissue, and the drug or delivery system cannot be separated from the bone tissue and then effectively transported into tumor cells to play a therapeutic role. Its inhibitory effect on the growth of bone metastases is not strong

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  • Preparation method and application of intelligent bone targeted delivery medicine capable of efficiently entering cells
  • Preparation method and application of intelligent bone targeted delivery medicine capable of efficiently entering cells
  • Preparation method and application of intelligent bone targeted delivery medicine capable of efficiently entering cells

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preparation example Construction

[0050] see Figure 1-2 , the preparation method of the intelligent bone targeted delivery drug that can efficiently enter cells, comprising the following steps:

[0051] S1: Synthesis of bone-targeting hydrophilic material PEG-ALN;

[0052] S101: with polyethylene glycol (NH 2 -PEG (2000) -COOH), cis-aconitic anhydride and alendronate sodium (ALN) as raw materials to prepare a series of bone-targeting hydrophilic materials PEG-ALN modified with different amounts of cis-aconitic anhydride;

[0053] S102: using dialysis and freeze-drying methods to separate and purify the reaction product, and use spectroscopy to identify the structure of the reaction product;

[0054] S2: Synthesis of lung cancer cell targeting material cRGD-PAMAM;

[0055] S201: Using G5-generation PAMAM, succinic anhydride and cRGDyk as raw materials to prepare cRGD-PAMAM, a high-efficiency cellular targeting material;

[0056] S202: adopting the method of dialysis and freeze-drying to separate and solid...

Embodiment 1

[0078] DTX@cRGD-PAMMA-PEG-ALN was lyophilized to obtain a white loose solid, and the polymer material was determined by 1H NMR. The results are as follows: image 3 It can be seen from the figure that the characteristic peak of PEG is 3.64ppm [-(CH 2 O)n-], the characteristic peak of ALN is 2.97ppm [-NH-CH 2 -CH 2 -CH 2 -C(OH)P 2 -]. The acid-sensitive bond formed by CA has a characteristic peak at 1.8ppm [-COCH=C(COOH)-]. PAMAM at 2.2 ppm [-HNCH 2 CH 2 CO-], 2.7ppm[-CONHCH 2 CH 2 NH-], 3.2ppm[-CONHCH 2 CH 2 NH 2 ] and 3.3ppm[-NHCH 2 CH 2 There are several peaks at NHCO-]. cRGDyk at 8.0ppm[-C 6 H 5 There is a peak at OH], and the polymer material is determined by IR, and the results are as follows Figure 4 shown, of which 1737cm -1 The characteristic peak at is the stretching vibration of ester bond C=O, 1618cm -1 The characteristic peak at 1655cm comes from the stretching vibration of the amide bond C=O, and the 1655cm -1 The absorption peak of ALN is pro...

Embodiment 2

[0080] The particle size of DTX@cRGD-PAMMA-PEG-ALN is about 150 nm, Figure 5 From the PDI value, it can be observed that the particle size distribution of the delivery system is uniform and the Zeta potential is moderate, which can effectively avoid aggregation between the drug-loaded nanosystems and ensure the stability of the drug-loaded nanosystems. cRGD-PAMMA-PEG-ALN has a relatively high performance. High drug loading and encapsulation efficiency, the morphology of DTX@cRGD-PAMMA-PEG-ALN was further observed by TEM, from Figure 5 It can be seen in B that the drug-loaded carrier is spherical and has good dispersibility. The particle sizes of the drug-loaded nanosystems measured by TEM are all smaller than those measured by DLS, because the particle size of the nanoparticle hydrated fluid measured by DLS is.

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Abstract

The invention discloses a preparation method and application of an intelligent bone targeted delivery drug capable of efficiently entering cells. The preparation method comprises the following steps: S1, synthesizing a bone targeted hydrophilic material PEG-ALN; the preparation method comprises the following steps: S101, preparing a series of different amounts of cis-aconitic anhydride modified bone-targeting hydrophilic materials PEG-ALN by taking polyethylene glycol (NH2-PEG (2000)-COOH), cis-aconitic anhydride and alendronate sodium as raw materials; s102, separating and purifying the reaction product by adopting dialysis and freeze-drying methods, and identifying the structure of the reaction product by adopting a spectroscopy means; s2, synthesizing a lung cancer cell targeting material cRGD-PAMAM (Polyamidoamine); s201, the G5 generation PAMAM, succinic anhydride and cRGD are used as raw materials for preparing the efficient cell entering targeting material cRGD-PAMAM. The cRGDyk has specific adsorbability on an alpha v beta 3 integrin receptor overexpressed by tumor cells, the efficiency of the nano delivery platform taken by the tumor cells after reaching a bone tumor part is improved, PEG-ALN groups broken under the influence of an acidic tumor environment cause failure of a charge shielding layer on the surface of PAMAM and exposure of a large amount of positive charges, and the tumor cells can be efficiently delivered to the bone tumor part. Therefore, the cell entry efficiency of the drug carrier is greatly enhanced.

Description

technical field [0001] The present invention relates to the field of medical treatment, in particular to a preparation method and application of intelligent bone targeted drug delivery capable of efficiently entering cells. Background technique [0002] Lung cancer is one of the main causes of cancer-related death worldwide, and its incidence is increasing year by year in many countries. In patients with advanced lung cancer, bone is a common site of metastasis. Currently, chemotherapy is the clinical first choice for bone metastasis of lung cancer. However, due to the characteristics of high bone hardness and low drug permeability, it is difficult to effectively deliver chemotherapeutic drugs to the site of bone metastases by traditional drug delivery methods, which seriously affects its anti-tumor effect and easily increases the toxic and side effects of drugs. Therefore, the development of a safe and effective drug delivery system that can specifically deliver drugs to bo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/14A61K31/337A61K47/34A61K47/54A61K47/62A61P19/08A61P35/00B82Y5/00
CPCA61K9/146A61K31/337A61K47/545A61K47/548A61K47/62A61K47/34A61P19/08A61P35/00B82Y5/00
Inventor 叶威良韩江帆秦向阳周四元曹琼袁晓峰
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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