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An active targeting liposome delivery system for tumors in situ and lymphatic metastases

A carrier system and lymphatic transfer technology, which can be used in liposome delivery, anti-tumor drugs, medical preparations with inactive ingredients, etc., and can solve problems such as affecting the effect of targeted therapy, tissue damage, and necrosis.

Inactive Publication Date: 2011-12-07
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the following problems generally exist in the specific implementation of liposomes in the process of targeting the lymphatic system: ①After liposomes are injected into the interstitial space, the lymphatic absorption is not complete, and some of them are retained in the interstitial space of the injection site, and the retained amount is about 100% of the total administered dose. 10-40%, repeated injections of liposomes containing anti-tumor drugs will cause local tissue damage or even necrosis; ②Liposomes entering the lymphatic system will accumulate in normal lymph nodes due to mechanical retention or macrophage phagocytosis, which will easily cause normal lymph nodes Tissue damage; ③The accumulation of liposomes in lymph nodes is a passive process, which has no selectivity for normal lymph nodes and tumor metastatic lymph nodes, and may even be metastasized by tumors when liposomes cannot be retained or phagocytized due to the structural damage of lymph nodes caused by tumor metastasis The amount of liposome uptake by lymph nodes is lower than that of normal lymph nodes, which affects the effect of targeted therapy
The results show that this treatment method has a good effect on the treatment of early stage tumors and can effectively inhibit tumor metastasis, but it is basically ineffective for tumors that have undergone lymphatic hyperplasia or metastases
There is no report on the use of LyP-1 for modifying liposomes, nor the use of LyP-1 in tumors in situ and lymphatic metastases

Method used

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  • An active targeting liposome delivery system for tumors in situ and lymphatic metastases
  • An active targeting liposome delivery system for tumors in situ and lymphatic metastases
  • An active targeting liposome delivery system for tumors in situ and lymphatic metastases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Synthesis, purification and characterization of LyP-1-FAM and LyP-1-PEG-DSPE

[0045] 1. Synthesis, purification and characterization of LyP-1-FAM

[0046] Weigh 0.4167g of Boc-Cys(Mbzl)-PAM resin (degree of substitution: 0.6mmol / g) in a peptide bottle, swell the resin with DMF (N,N-dimethylformamide), and drain it after 20 minutes . Add TFA (trifluoroacetic acid) about twice the volume of the resin to stir the reaction, remove the TFA, then add TFA and operate in the same way once to remove the Boc protecting group. Activation of Boc-Gly with HBTU (benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate) in DMF and DIEA (N, N-diisopropylethylamine), After the resin was washed with DMF, Boc-Gly activation solution was added, and the reaction was shaken. After the reaction was completed, the reaction solution was removed, and the resin was washed with DMF. Subsequently, the remaining amino acids were sequentially connected according to the LyP-1 sequence by...

Embodiment 2

[0055] Construction of animal models of orthotopic tumors and lymphatic metastatic tumors

[0056] Nude mice were subcutaneously inoculated with MDA-MB-435 tumor cells in both hind footpads or single hind footpad, at a concentration of 1×106 cells / footpad. They were raised at the SPF level, and the lymph nodes and major organs at all levels were taken for pathological examination 3 and 6 weeks after inoculation to determine the time of lymphatic metastasis of the tumor and provide reference for tumor staging.

Embodiment 3

[0058] In vivo and in vitro targeting verification of LyP-1

[0059] 1. In vitro tumor cell targeting verification of LyP-1

[0060] Take the monolayer cultured MDA-MB-435 cells in the logarithmic growth phase, digest the monolayer cultured cells with 0.25% trypsin and 0.025% disodium edetate, and prepare with DMEM culture medium containing 10% fetal bovine serum Single cell suspension, 1×10 per well 5 Cells were inoculated in a 24-well culture plate with a volume of 1 ml per well, and the culture plate was moved into a carbon dioxide incubator, and cultured overnight at 37°C, 5% carbon dioxide and saturated humidity conditions, so that the cells adhered to the wall. On the next day, a series of FAM and LyP-1-FAM solutions with different concentrations were prepared with DMEM medium containing 1% fetal bovine serum. Aspirate the culture medium in the culture plate, add a series of solutions of FAM and LyP-1-FAM, incubate at 37°C for 4 hours, and discard the supernatant. The...

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Abstract

The invention belongs to the field of pharmaceutical preparations, and relates to an active targeting liposome carrier system for in situ tumors and lymphatic metastatic tumors. The carrier system is composed of polypeptides and liposomes whose amino acid sequence is CGNKRTRGC sequence of LyP-1. Wherein the LyP-1 sequence polypeptide is connected by two cysteines through a disulfide bond to form a ring structure. The liposome carrier system can passively drain the liposome into the lymphatic system through subcutaneous interstitial injection or intramuscular injection, and target the tumor metastasis lymph node through the mediated effect of LyP-1. The system can also be administered directly via intravenous injection, targeting tumors in situ and lymphatic metastases through tumor EPR effects and LyP-1-mediated effects. The liposome carrier system of the present invention can be used for targeted delivery of drugs for the diagnosis or treatment of tumors in situ and lymphatic metastases.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to an active targeting liposome carrier system for in situ tumors and lymphatic metastatic tumors, in particular to an active targeting liposome carrier system modified by a polypeptide containing LyP-1 (amino acid sequence is CGNKRTRGC) sequence Liposome carrier system, preparation method and medical application thereof. Background technique [0002] With the deterioration of the living environment of human beings, there are more and more factors that induce cancer, and the incidence of cancer is showing an obvious upward trend. Cancer has become a major disease that threatens human health and life. Lymphatic metastasis is an important way of solid tumor metastasis, and it is also an important cause of tumor death in patients. Lymphatic metastasis generally occurs in the early or middle stages of tumors. If it is not controlled in time, it may cause tumor cells to flow ba...

Claims

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Application Information

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IPC IPC(8): A61K47/42A61K47/24A61K47/28A61K47/34A61K49/14A61K9/127A61P35/00A61P35/04
Inventor 陆伟跃闫志强王飞顾炳孟庆刚占昌友谢操
Owner FUDAN UNIV
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