CN107158399A - Amphiphilic nano medicine and its preparation method and application - Google Patents

Abstract

The present invention relates to a kind of amphiphilic nano-medicine and its preparation method and application. By connecting hydrophilic groups into the structure of hydrophobic drugs, the nano-medicines with good hydrophilicity can be improved. Taking Sorafenib as an example, The modified sorafenib has good hydrophilic properties. This method provides a new idea for the modification of hydrophobic drugs. It does not reduce the curative effect at the same time, in order to improve the utilization of the drug and reduce the side effects. Targeted therapy for tumors is of great significance.

Description

Amphiphilic nano-medicine and its preparation method and application

technical field

The invention belongs to the field of medicinal chemistry, relates to amphiphilic nano-medicine, and also relates to a preparation method and application of the amphiphilic nano-medicine.

Background technique

With the improvement of people's living standards, health problems have become increasingly prominent. Cancer is one of the major diseases that currently affect human health and threaten human life. Therefore, the World Health Organization and the health departments of various countries regard conquering cancer as a top priority. At present, there are three main methods to treat cancer: one is surgical treatment, which is also the oldest cancer treatment method, that is, surgical resection is used to remove cancerous tissue and prevent the spread of cancer cells. The second is to use chemotherapy or radiotherapy, and the third is drug treatment. The method of surgical resection is relatively traumatic to the human body, leading to a decline in the patient's immunity and resistance to disease. Moreover, surgical resection is a local treatment, and more are only applicable to early cancers. At the same time, surgical treatment also has this certain risk, and postoperative recurrence or metastasis is prone to occur. Radiotherapy kills not only cancer cells but also other normal cells, causing patients to have systemic symptoms. And drug therapy, especially targeted drug therapy, can kill cancer cells efficiently, and greatly reduce the side effects on the patient's body, so that the overall effect of the patient has been greatly improved. The drug in our study, sorafenib, is a targeted therapy drug, which is different from chemotherapy drugs, and it can effectively inhibit tumor cell proliferation and tumor angiogenesis, rather than cytotoxic effect. It has potential broad-spectrum anti-tumor effect. Treatment of inoperable or distantly metastatic liver tumor cells; treatment of inoperable kidney tumor cells; treatment of locally recurrent or metastatic, progressively differentiated thyroid patients who are no longer responding to radioactive iodine therapy. Sorafenib has no cytotoxic effect, can stabilize the disease, and prolong the disease progression-free survival of patients. Sorafenib is also the first and only effective drug in the world that has been medically proven to significantly prolong the survival time of patients with liver cancer. And it is this series of advantages that promote the development and application of Sorafenib. Its application in the treatment of patients with inoperable advanced liver cancer is of great significance.

Sorafenib inhibits tumor cell proliferation and tumor angiogenesis by inhibiting the activity of Raf-1 and B-Raf serine and threonine kinases, thereby inhibiting the RAS/RAF/MEK/ERK signaling pathway and inhibiting tumor growth. Cell proliferation; Sorafenib inhibits tumor angiogenesis. Tumor growth depends on the formation of new blood vessels, and VEGFR and PDGFR are the most important regulators that promote angiogenesis. Sorafenib has an inhibitory effect on the tyrosine kinase activity of these two receptors, therefore, it blocks the formation of tumor neovascularization and cuts off the nutrient supply of tumor cells, and indirectly inhibits the growth of tumor cells.

Sorafenib is a new drug successfully developed on the basis of further clarification of the molecular biological mechanism of tumorigenesis, and has a unique multi-target anti-tumor effect. It has no cytotoxic effect, can stabilize the condition, and prolong the disease progression-free survival period of patients. It's late. The success achieved in the treatment of kidney cancer has brought new inspiration to the research and development of targeted drugs. In Europe, its treatment of liver cancer has been approved as the second indication, and it has also received positive opinions in the United States. How to formulate the best program to improve its curative effect is an important issue we face in today's research.

Sorafenib has strong hydrophobicity and low bioavailability, so improving its water solubility is an urgent problem we need to solve. The successful development of sorafenib tosylate has brought good news to patients with advanced liver cancer. The existing dosage form is Sorafenib Tosylate Tablets, and the recommended dosage is 400 mg once, twice a day. Although the dosage has been reduced, unavoidable adverse events still occur. Multiple clinical studies have shown that common adverse reactions of sorafenib include diarrhea, fatigue, hand-foot syndrome, hypertension, rash, and vomiting. Most of them are mild to moderate, and can be relieved after dose reduction and symptomatic treatment. The main grade 3/4 adverse reactions include fatigue, hand-foot syndrome and diarrhea. Reduction, interruption or withdrawal of sorafenib treatment may affect the efficacy of the drug. Therefore, early and effective control of adverse reactions, while maintaining sorafenib treatment, is particularly important for improving clinical efficacy, improving patients' quality of life and drug compliance. Reducing the toxic and side effects of sorafenib, improving bioavailability, and increasing the water solubility of the drug are still problems to be solved.

Contents of the invention

In view of this, one of the purposes of the present invention is to provide a kind of amphiphilic nano-medicine; the second purpose of the present invention is to provide the preparation method of amphiphilic nano-medicine, and the third purpose of the present invention is to provide the amphiphilic nano-medicine Applications.

To achieve the above object, the present invention provides the following technical solutions:

1. An amphiphilic nano-drug, whose structure is ABLD, wherein A is a hydrophilic group selected from Or PEG200～10000; B is n is a positive integer ranging from 1 to 10; L is a cleavable group selected from D is a hydrophobic drug selected from Doxorubicin, camptothecin, gemcitabine, irinotecan, paclitaxel, or triptolide.

In the present invention, the PEG200-10000 is linear PEG200-10000, branched-chain PEG200-10000 or 3-8 arm PEG200-10000.

In the present invention, the cleavable group is

In the present invention, the hydrophobic drug is selected from

In the present invention, its structure is in the form of T-A-B-L-D, wherein T is a targeting group selected from galactose, LHRH, lactose or folic acid.

Preferably, its structure is shown in formula II:

The a, b and c are hydrogen,

2. The preparation method of the amphiphilic nano-medicine, comprising the steps of:

(1) Connect the cleavable disulfide bond to the amino-functionalized PEG through Michael addition reaction to prepare terminal-functionalized and amphiphilic PEG molecules;

(2) reacting the amphiphilic PEG molecules described in step (1) with the hydrogen on the amide group of the hydrophobic drug, thereby obtaining the amphiphilic nano drug.

Preferably, the hydrophobic drug is selected from Doxorubicin, camptothecin, gemcitabine, irinotecan, paclitaxel, or triptolide.

3. The application of the amphiphilic nano-medicine in the preparation of drugs for treating tumors.

Preferably, the amphiphilic nanomedicine is sorafenib amphiphilic nanomedicine, and the tumor is liver cancer.

The beneficial effect of the present invention lies in that among many tumor therapeutic drugs, the drug has strong hydrophobicity, low bioavailability, and large toxic and side effects. The invention of Sorafenib utilizes the special structure of amphiphilic molecules, which not only improves the water solubility of hydrophobic drugs, but also enables the newly obtained molecules to form nanoparticles in water solubility, thereby improving the passive targeting of drugs , enhance the efficacy and reduce possible side effects. The new drug molecule designed by the invention has good water solubility, definite structure, easy repetition and characterization, and good therapeutic effect.

Description of drawings

In order to make the purpose, technical scheme and beneficial effect of the present invention clearer, the present invention provides the following drawings for illustration:

Figure 1 is the hydrogen spectrum of SCNS.

Figure 2 is the particle size of SCNS in aqueous solution.

Fig. 3 is the result of SCNS and sorafenib anti-hepatoma cell (HepG2) (A: Sorafenib; B: SCNS).

detailed description

The preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

Example 1

The cleavable disulfide bond was connected to the amino-functionalized PEG through Michael addition reaction to prepare a terminal-functionalized and amphiphilic PEG molecule (compound I). The specific route is as follows:

Then compound I is reacted with Sorafenib a part amide hydrogen to obtain the final compound SCNS, the specific route is as follows:

The results of the SCNS hydrogen spectrum of the compound are shown in Figure 1. The results showed that: after Michael addition reaction, Sorafenib was successfully connected to PEG.

Example 2

The water solubility of the SCNS synthesized in Example 1 was compared with that of Sorafenib, and the results are shown in Table 1.

Table 1. Comparison of water solubility of SCNS and Sorafenib

The results showed that Sorafenib was almost completely insoluble in water, while the improved compound SCNS had good water solubility.

Example 3

The morphology of SCNS in aqueous solution was measured for particle size, and the results are shown in Figure 2. Experimental results show that the obtained compound forms nanoparticles of about 200nm in water solubility, which is beneficial for entering cells and intravenous administration.

Example 4

SCNS and Sorafenib were used for the MTT experiment of liver cancer cells (HepG2), the specific method is as follows:

1. Take a 96-well plate and add 100 μL of culture medium to each well. After the cell suspension is prepared, mix gently, and then add 10ul of cell suspension to the wells with culture medium. After mixing, put in 5% CO ₂ and incubate at 37°C for 24 hours.

2. After 24 hours, add the corresponding amount of drug according to a certain concentration gradient, 5% CO ₂ , and cultivate in a 37° C. incubator for 48 hours.

3. After 48 hours, aspirate the culture medium, add 20 μL of MTT solution (the final concentration of MTT is 5 mg/ml, use PBS as solvent) to each well, incubate in 5% CO ₂ , 37° C. incubator for 4 hours.

4. Add 100 μL DMSO to each well, and you can see the precipitation of purple formazan. Mix the solvent and formazan thoroughly, and detect the absorbance with a microplate reader to obtain the cell survival status.

The results are shown in Figure 3. The results showed that as the concentration of SCNS gradually increased, the survival rate of liver cancer cells decreased, and the trend was basically consistent with that of Sorafenib, indicating that the SCNS prepared by the present invention also has a good anti-liver cancer effect.

Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that it can be described in terms of form and Various changes may be made in the details without departing from the scope of the invention defined by the claims.

Claims (10)

1. a kind of amphiphilic nano medicine, it is characterised in that：Its structure is A-B-L-D, and wherein A is hydrophilic radical, is selected fromOr PEG200~10000；B is N is 1~10 positive integer；L for can cleavable groups, be selected from D is hydrophobic drug, It is selected fromAdriamycin, camptothecine, gemcitabine, Irinotecan, Japanese yew Alcohol or triptolide.

2. amphiphilic nano medicine according to claim 1, it is characterised in that：PEG200~10000 are straight chain PEG200~10000, side chain PEG200~10000 or 3-8 arms PEG200~10000.

3. amphiphilic nano medicine according to claim 1, it is characterised in that：It is described can cleavable groups be

4. amphiphilic nano medicine according to claim 1, it is characterised in that：The hydrophobic drug is selected from

5. amphiphilic nano medicine according to claim 1 or claim 2, it is characterised in that：Its structure is T-A-B-L-D forms, its Middle T is targeting group, selected from galactolipin, LHRH, lactose or folic acid.

6. amphiphilic nano medicine described in claim 1 or 2, it is characterised in that its structure is as shown in formula II：

Described a, b and c be hydrogen,

7. the preparation method of any one of the claim 1~6 amphiphilic nano medicine, it is characterised in that comprise the following steps：

(1) disulfide bond that can be broken is connected on the PEG of amino functional by Michael addition reaction, prepares end work( It can change and with amphipathic PEG molecules；

(2) hydrogen on the amide groups of step (1) amphipathic the PEG molecules and hydrophobic drug is reacted, so as to obtain Amphiphilic nano medicine.

8. the preparation method of amphiphilic nano medicine according to claim 7, it is characterised in that：The hydrophobic drug is selected fromAdriamycin, camptothecine, gemcitabine, Irinotecan, taxol or Triptolide.

9. the preparation of any one of the claim 1~6 amphiphilic nano medicine and its application in treatment tumour.

10. application according to claim 9, it is characterised in that：The amphiphilic nano medicine is that Sorafenib is amphipathic Nano medication, the tumour is liver cancer.