Application of multifunctional polymer vesicles to preparation of medicine for treating multiple myeloma

A multiple myeloma, polymer technology, applied in the direction of antineoplastic drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of impenetrable immunogenicity, protein instability, short half-life, etc.

Active Publication Date: 2018-08-28
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 efficient therapeutic agents that have great potential for the treatment of myeloma, such as elotuzumab, a protein drug that acts extracellularly (a humanized monoclonal drug targeting CD319 on the surface of myeloma and NK cells) antibody) and daratumumab (a human IgG monoclonal antibody targeting CD38 on the surface of myeloma cells); however, the application of existing protein therapeutics, especially proteins that function in cells, is limited by many factors, including protein instability in vivo, Easy inactivation, short half-life, immunogenicity and inability to penetrate cell membrane, etc.

Method used

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  • Application of multifunctional polymer vesicles to preparation of medicine for treating multiple myeloma
  • Application of multifunctional polymer vesicles to preparation of medicine for treating multiple myeloma
  • Application of multifunctional polymer vesicles to preparation of medicine for treating multiple myeloma

Examples

Experimental program
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Embodiment 1

[0034] Example 1 Synthesis of HA-SH and PEG-P(TMC-DTC)-SP Polymers

[0035] 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

[0044] Example 2 Preparation of post-surface modified HA vesicles (HA-RCP)

[0045] 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 vesicles were prepared by solvent exchange method by mixing 50 mL of PEG5k-P (DTC2k-TMC15k) and Mal-PEG7.5k-P (DTC2k-TMC15k) in DMSO solution (10 mg / mL) was added to 950 μL 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 5 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

[0048] Example 3 Post-surface modification of HA vesicles loaded with granzyme B (HA-RCP-GrB) and reduction-triggered drug release

[0049] The loading of HA vesicles to proteins such as GrB is the same as in Example 2. Under stirring at room temperature, 50 μL 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 μL containing a certain GrB in HEPES buffer solution (pH 7.4, 5 mM), transfer to dialysis bag (MWCO 350 kDa) after the dropwise addition, dialyze in PB (pH 7.4, 5 mM) solution for 8 hours, and change dialysis 5 times during the period medium. 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 resulting vesicle solution under nitrogen protection, 37 Shake overnight at ℃, and finally use an ultrafiltration tube for ultrafiltration and centrifugation (MWCO100 kDa, 100...

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Abstract

The invention discloses the application of multifunctional polymer vesicles to the preparation of a medicine for treating multiple myeloma. Protein which acts in the cells is loaded by an improved nanometer vesicle carrier, targeted delivery of the whole tumor cells is realized, the medicine is released rapidly in tumor cells, and the efficient and low-toxicity tumor treatment aim is fulfilled. The result indicates that HA-RCP-GrB has high anti-tumor efficiency and low toxic and / or side effects in multiple myeloma LP1 subcutaneous and in-situ tumor models, the lifetime of mice suffering from in-situ myeloma is obviously prolonged, and the states of bone lesions and damage to bone trabecula are greatly improved.

Description

technical field [0001] The invention belongs to drugs for treating tumors, and in particular relates to the application of a multifunctional polymer vesicle in the preparation of drugs for treating multiple myeloma. Background technique [0002] Multiple myeloma is a systemic malignant proliferation of plasma cells, whose important features include the presence of a large number of malignant plasma cells in the bone marrow and the production of large amounts of monoclonal proteins. Clinical symptoms include anemia, hypocalcemia, impaired renal function, osteolytic injury, and peripheral neuropathy. Unlike solid tumors, in multiple myeloma, the tumor cells are spread throughout the body and are highly advanced and incurable. The treatment of myeloma has been plagued by strong toxic side effects, high recurrence rate and drug resistance for a long time. Multiple myeloma is the second most common hematologic malignancy in the United States and Europe. It is a type of disease ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K47/34A61K47/36A61P35/00
CPCA61K9/1273A61K47/34A61K47/36A61P35/00
Inventor 钟志远钟伊南孟凤华
Owner SUZHOU UNIV
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