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Polysialic acid lipid grafted derivatives and applications thereof

A technology of polysialic acid and derivatives, which is applied in the field of preparation and modification of microparticle preparations, can solve the problems that PEGylated macromolecules are not easy to be taken up by tumor cells, hinder the interaction between drugs and tumor cells, and block uptake by cells, so as to achieve targeted High stability, high yield, and controllable degree of polymerization

Active Publication Date: 2017-04-05
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The protective effect of PEG on the carrier depends on the properties of the protective layer formed by the polymer on the surface of the modified substance. However, the study found that this protective layer brings the following three problems: ① Cell uptake is blocked, that is, surface hydration caused by PEG modification The layer will hinder the interaction between the drug and tumor cells to a certain extent, making it difficult for the drug to enter the appropriate intracellular compartment, resulting in PEGylated macromolecules being difficult to be taken up by tumor cells; ② Accelerated blood clearance, PEGylated liposomes, When PEGylated carriers such as micelles and PEGylated nanoparticles are injected repeatedly, the body will be induced to produce antibodies in the first injection, resulting in the rapid removal of PEGylated carriers from the blood in the second injection and a large amount of accumulation in the liver and spleen. Known as "accelerated blood clearance (ABC)"
However, in order to obtain a satisfactory reaction yield, it needs to be carried out at a higher temperature for a certain period of time, which is not conducive to the stability of drugs such as modified proteins and polypeptides (such as interferon α-2b)

Method used

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  • Polysialic acid lipid grafted derivatives and applications thereof
  • Polysialic acid lipid grafted derivatives and applications thereof
  • Polysialic acid lipid grafted derivatives and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Embodiment 1: the synthesis of octadecyl dimethyl betaine BS18 and PSA

[0071] Dissolve BS18 (39.4mg, 0.01mmoL) in 4mL of FA, add EDC / NHS, and activate for 90min. At this time, the system is clear. PSA dissolved in 5mL of FA - Na + (60mg, 0.02mmoLSA monomer) was added to the reaction system, stirred at room temperature for 48h, the reaction solution was clear and slightly yellow.

[0072] Post-treatment: After diluting the substance in the dialysis bag (molecular weight cut-off 1000Da) to 40mL, the dialysis medium is ethanol-water (V / V, 1:2) system, with a volume of 2250mL for dialysis, dialysis at 60°C, and dialysis for 3 times within 4 hours Medium, after overnight dialysis, change the dialysis medium twice in the next 8 hours, and then overnight, a total of 48 hours, the material in the dialysis bag is clarified throughout the process. Part of the water-ethanol was spun out in a vacuum, and freeze-dried to obtain a white flocculent substance, which was the synthet...

Embodiment 2 18

[0081] Embodiment 2. octadecanoic acid (OSA) and PSA synthesis

[0082] 3g H-type cation exchange resin, add 15mL containing 5g TBAB aqueous solution, stir at room temperature for 2h, pass the stirred suspension through the column, wash with deionized water, and mix the obtained cation exchange resin with PSA - Na + (200mg, 0.65mmoL) deionized aqueous solution was mixed and stirred overnight at room temperature. Take out the stirred liquid, centrifuge, collect the centrifuged liquid and freeze-dry, and the obtained substance is PSA - TBA + , with a solubility of 4mg PSA - TBA + / 1mL DMF.

[0083] Use IFS-55 Fourier transform infrared spectrometer (Bruker company, Switzerland) to obtain product PSA - TBA + Infrared analysis is carried out, and the test spectrum is shown in the accompanying drawing: Attached Figure 6 for PSA - TBA + . In the IR spectrum, while relative to PSA, it is at 2918.1, 2849.8cm -1 The stretching vibration peak of the alkyl chain is strengthe...

Embodiment 3

[0092] The mensuration of embodiment 3.PSA derivative critical micelle concentration (CMC)

[0093] Since the molecular structure of PSA-BS18 has hydrophilic groups and lipophilic groups, as a polymer block, it can spontaneously form micelles in water, and its critical micelle concentration can be determined by fluorescent probe method.

[0094] Precisely pipette 0.1mL with a concentration of 1×10 -5 Several parts of M-pyrene working solution were placed in the vials, blown dry with nitrogen gas, accurately weighed several parts of PSA-BS18, put them in the above-mentioned vials, and added 10 mL of pure water respectively to obtain the concentration of the pyrene working solution as 10 -7 M (the saturated solubility of pyrene in water is 7×10 -7 M), water bath ultrasonic 30min, place overnight, promptly obtain concentration and be respectively 5 * 10 -4 , 1×10 -3 , 3×10 -3 , 5×10 -3 , 1×10 -2 , 3×10 -2 , 5×10 -2 , 1×10 -1 , 5×10 -1 , 1,5g / L PSA-BS18 solution. The aq...

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Abstract

The invention belongs to the field of medicine preparations, and particularly relates to polysialic acid lipid grafted derivatives, a preparing method thereof and applications of the derivatives, particularly applications for preparation and modification of microparticle preparations. Sialic acid units in the polysialic acid are connected through alpha-2,8-glucosidic bonds, and lipid segments and hydroxy in the sialic acid units are connected through ester bonds. A structural formula is shown in the description, wherein SA is a sialic acid unit, x is the number of the lipid segments grafted in the polysialic acid molecule, m is the number of the sialic acid units in the polysialic acid molecule, the m is not more than 100 and not less than 1, the x is not more than 30 and not less than 1, x / m is 5-30%, R-CO- is derived from R-COOH, and the R-COOH is a lipid compound containing carboxyl. Immunogenicity of microparticle preparations prepared or modified by the compounds is extremely low and the microparticle preparations have excellent in-vivo pharmacokinetic properties.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a lipid graft derivative of polysialic acid, its synthesis method and application, especially for the preparation and modification of microparticle preparations. Background technique [0002] In the development history of drug delivery system (drug delivery system, DDS), the PEGylation (PEGylation, also known as PEGylation) technology of carriers and drug molecules is a milestone. PEGylation can reduce the recognition of the modified carrier / molecule by the mononuclear phagocyte system (MPS), prolong the blood circulation time, and realize the tumor growth by using the enhanced permeability and retention effect (EPR effect) for short. Site targeting. The protective effect of PEG on the carrier depends on the properties of the protective layer formed by the polymer on the surface of the modified substance. However, the study found that this protective layer ...

Claims

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Application Information

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IPC IPC(8): C08B37/00A61K9/107A61K47/36A61K9/127A61K9/14A61P35/00A61P35/04
Inventor 邓意辉张婷周松雷骆翔王旭玲刘洋刘欣荣宋艳志林湘云
Owner SHENYANG PHARMA UNIVERSITY
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