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Application of reversible crosslinked asymmetric vesicles in preparation of medicines for treating acute leukemia

An acute leukemia and asymmetric technology is applied in the application field of reversible cross-linked asymmetric vesicles in the preparation of drugs for the treatment of acute leukemia, and can solve the problems of protein instability, easy inactivation, short half-life, etc.

Active Publication Date: 2018-06-22
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therapeutic proteins are a class of safe and highly effective therapeutic agents, which have great potential for the treatment of myeloma; however, the application of existing protein therapeutics, especially proteins that function in cells, is limited by many factors, including protein in vivo Unstable, easily inactivated, short half-life, immunogenic and unable to penetrate the cell membrane, etc.

Method used

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  • Application of reversible crosslinked asymmetric vesicles in preparation of medicines for treating acute leukemia
  • Application of reversible crosslinked asymmetric vesicles in preparation of medicines for treating acute leukemia
  • Application of reversible crosslinked asymmetric vesicles in preparation of medicines for treating acute leukemia

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Example 1 Synthesis of HA-SH and PEG-P(TMC-DTC)-SP Polymers

[0034] HA-SH (molecular weight about 17000Da) is obtained from HA through two-step reaction. First, sodium borohydrocyanide (126 mg, 2.0 mmol) was added to a boric acid buffer solution (pH 8.5, 50 mM, 10.0 mL), the entire reaction solution was stirred at 40°C for 5 days. Then dithiothreitol (DTT, 0.15 g, 1.0 mmol) was added to the reaction solution under nitrogen atmosphere, and the reaction was stirred at room temperature for 24 hours. HA-SH was isolated by dialysis in deionized water (MWCO 3500) and freeze-drying under nitrogen protection. Yield: 84%. The conversion rate of HA-SH can be measured to be about 98% by the ELLMAN reagent method. The H NMR spectrum shows that in addition to the signal peaks of HA (δ 1.86, 3.28-4.02, 4.21-4.75), there are new signal peaks at δ 2.68-2.98, which are formed after the aldehyde group at the HA terminal reacts with cystamine The methylene proton peak next to the se...

Embodiment 2

[0043] Example 2 Preparation of post-surface modified HA vesicles (HA-RCP)

[0044] Modified self-crosslinked vesicles after preparation of surface HA for active targeting protein drug delivery. Compared with pre-modified vesicles, HA post-modified vesicles can ensure that HA targeting molecules are fully exposed outside the vesicles to fully interact with CD44 on the surface of tumor cells, and can also ensure that the structure and size of the vesicles remain unchanged. Blank vesicle RCP was prepared by solvent exchange method by mixing 50 μL of PEG5k-P (DTC2k-TMC15k) and Mal-PEG7.5k-P (DTC2k-TMC15k) in DMSO solution (10 mg / mL) was added to 950 L HEPES buffer solution (pH 7.4), and then dialyzed in PB (pH 7.4, 5 mM) for 8 hours, and the dialysis medium was changed 6 times. Then add 1.2-fold excess of HA-SH (17 kDa) relative to the Mal group under nitrogen, shake at 37°C overnight, and finally use an ultrafiltration tube for ultrafiltration and centrifugation (MWCO 100 kDa,...

Embodiment 3

[0047] Example 3 Post-surface modification of HA vesicles loaded with granzyme B (HA-RCP-GrB) and reduction-triggered drug release

[0048] The loading of HA vesicles to proteins such as GrB is the same as in Example 2. Under stirring at room temperature, 50 L of a DMSO solution (10 mg / mL) of PEG5k-P (DTC2k-TMC15k) and Mal-PEG7.5k-P (DTC2k-TMC15k) mixed in a specific ratio was added to 950 L containing a certain GrB in HEPES buffer solution (pH 7.4, 5 mM), transfer to dialysis bag (MWCO350 kDa) after the dropwise addition, and dialyze in PB (pH 7.4, 5 mM) solution for 8 hours, during which the dialysis medium was changed 5 times . The method of modifying GrB-loaded vesicles with HA-SH is the same as that of blank vesicles: add a specific amount of HA-SH (17 kDa) 1.2 times the amount of the Mal group to the obtained vesicle solution under nitrogen protection, 37 Shake overnight at ℃, and finally use an ultrafiltration tube for ultrafiltration and centrifugation (MWCO 100kDa, ...

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Abstract

The invention discloses application of reversible crosslinked asymmetric vesicles in preparation of medicines for treating acute leukemia. An improved nano-vesicle carrier is used for loading proteinacting in cells, so that the targeted delivery of tumor cells in a whole body is realized, the medicines are rapidly released in the tumor cells, and the aim of treating the tumors with high efficiency and low toxicity is further achieved. The result prove that HA-RCP-GrB has high anti-tumor efficiency and low toxic and side effects in a human acute myeloid leukemia AML-2 subcutaneous tumor model,so that the survival time of a model mouse is significantly improved.

Description

technical field [0001] The invention belongs to drugs for treating tumors, and in particular relates to the application of reversible cross-linked asymmetric vesicles in the preparation of drugs for treating acute leukemia. Background technique [0002] Acute myeloid leukemia (AML) is the most common type of leukemia, characterized by clonal enrichment and proliferation of immature myeloid cells in the bone marrow, resulting in inhibition of differentiation, enrichment of immature cells at different stages, and loss of normal hematopoietic elements. reduce [Ferrara F., et al. Lancet 2013, 381 (9865), 484-495.]. AML occurs in all age groups; its clinical presentation is variable and nonspecific, but is usually attributable to leukocyte infiltration in the bone marrow and consequent cytopenia, manifested by anemia (fatigue and dyspnea on exertion), hypertropic Neutropenia (susceptibility to infection) and thrombocytopenia (susceptibility to bleeding), these symptoms usually ...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K47/34A61K47/69A61K47/61A61K38/48A61P35/02
CPCA61K9/1273A61K38/482A61K47/34C12Y304/21079
Inventor 孟凤华钟伊南钟志远
Owner SUZHOU UNIV
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