ph and oxidation-reduction dual-sensitive layer cross-linking nanoparticle as well as preparation method and application thereof

A nanoparticle, sensitive technology, applied in the fields of polymer chemistry and biomedical engineering, can solve the problems of fast clearance rate, poor targeting, poor controlled release effect, etc., to achieve improved enrichment and retention, low toxicity, and biocompatibility good sex effect

Active Publication Date: 2014-12-24

天津渤化讯创科技有限公司

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AI-Extracted Technical Summary

Problems solved by technology

It aims to improve the targeted delivery efficiency of nanocarriers through the synergistic effect of targeting groups, hydrophilic segments, disulfide bond reversible cross-linked shells, and pH-sensitive hydrophobic cores, and...

Method used

Utilize laser particle size analyzer and transmission electron microscope to detect the particle diameter and the shape of double sensitive type layer cross-linked blank nanoparticle and drug-loaded nanoparticle, measurement result is as shown in Figure 3, the double sensitive type layer prepared in the present embodiment The particle diameters of cross-linked drug-loaded nanoparticles II-1 and blank nanoparticles II-1b were 153nm and 142nm, respectively, with narrow particle size distribution and obvious core-shell structure.

[0081] The evaluation results of the release behavior are shown in FIG. 5A. The introduction of the layered cross-linked shell can effectively reduce the release of the drug under normal physiological conditions, and the release rate decreases with the increase of the cross-linked density. Even under acidic conditions, the layer-crosslinked shell can inhibit drug release to a certain ex...

Abstract

The invention relates to a pH and oxidation-reduction dual-sensitive layer cross-linking nanoparticle as well as a preparation method and an application thereof. A hydrophilic layer which at least contains PCB (Polycarboxylate Betaine) or PEG (Polyethylene Glycol) is positioned on the surface of the nanoparticle, a hydrophobic nuclei which at least contains a pH-sensitive polymer unit is positioned in the nanoparticle, and an S-S (Disulfide Bond) cross-linking layer which is formed through cross-linking reaction between PDS (Polymethacrylamide Ehtylpyridine Disulfide) units is positioned between the hydrophilic layer and the hydrophobic nuclei. A tumor targeted group can be modified on the hydrophilic layer positioned on the surface of the pH and oxidation-reduction dual-sensitive layer cross-linking nanoparticle, and the gathering of the nanoparticle on a tumor tissue and the endocytosis of the nanoparticle on the tumor cell are accelerated through the specific targeted effect of the nanoparticle on a tumor cell. The pH and oxidation-reduction dual-sensitive layer cross-linking nanoparticle disclosed by the invention has the advantages of good biocompatibility and low toxicity. According to the pH and oxidation-reduction dual-sensitive layer cross-linking nanoparticle, a cross-linked structure is dissociated under the action of glutathione inside the tumor cell, so that the release of a medicine is promoted. The preparation method disclosed by the invention is simple, convenient, good in stability and conveniently operated and popularized.

Application Domain

Macromolecular non-active ingredientsAntineoplastic agents +2

Technology Topic

MethacrylamideTumor target +13

Image

Examples

Experimental program(11)

Example Embodiment

[0047] figure 1 It is a schematic diagram of the double sensitive layer cross-linked nanoparticles of the embodiment of the present invention. From figure 1 It can be seen that the double sensitive layer cross-linked nanoparticles of the present invention have a three-layer structure, the outer layer is RGD with tumor targeting function and zwitterionic polymer PCB, and the interlayer is a shell layer cross-linked by disulfide bonds, which is hydrophobic. The drug is loaded in the inner core through hydrophobic interaction with the hydrophobic segment PDPA. Example 1 (I-1)

[0048] The preparation method of triblock RGD-PCB-b-PDS-b-PDPA polymer includes the following steps:

[0049] (a) Preparation of PCB(tBU)-b-PDS-b-PDPA polymer

[0050] Add the reversible addition-fragmentation chain transfer polymerization (RAFT) chain transfer agent trithiododecyl-2-isopropanoate (CTAm) (36.5mg, 0.1mM) and zwitterionic monomers in the shlenk reaction tube in sequence Betaine tert-butyl carboxylate methyl methacrylate (CB-tBU) (816mg, 2.5mM), initiator (AIBN) (1.64mg, 0.01mM) and 3mL solvent dimethylformamide (DMF), vacuum /After three cycles of nitrogen gas, the reaction tube was sealed and reacted in an oil bath at 68~72℃ for 24h; after the reaction system was cooled to room temperature, the monomer containing active disulfide bond, methacrylamide ethyl pyridine disulfide ( DS) (127mg, 1.0mM), supplemented with AIBN (1.64mg, 0.01mM), after three cycles of vacuum/nitrogen, the reaction tube is sealed, and the reaction is continued for 24h in an oil bath at 68~72℃; finally, the reaction After the system is cooled to room temperature, add diisopropylaminoethyl methacrylate (DPA) (640mg, 2.5mM) and supplement the initiator AIBN (1.64mg, 0.01mM). After three cycles of vacuum/nitrogen, airtight The reaction tube, continue to react for 24h in an oil bath at 68~72℃; after the reaction, add DMF to dissolve it, put it into a dialysis bag, dialyze with deionized water for 72h, replace the dialysate every 12h, and freeze-dry to obtain PCB(tBU )-b-PDS-b-PDPA triblock polymer, the structural formula is shown in formula 1-1:

[0051] ……….Formula 1-1

[0052] (b) Preparation of RGD-PCB(tBU)-b-PDS-b-PDPA polymer

[0053] The obtained PCB(tBU)-b-PDS-b-PDPA (0.01mM) polymer was dissolved in 5mL purified DMSO, and NHS(0.2mM) and (EDC.HCl)(0.1mM) were added in sequence at room temperature. After the activation reaction for 2h, add 0.2mM mercaptoethanol to quench the unreacted EDC.HCl, add RGD (0.01mM), continue the reaction at room temperature for 24h; after the reaction, put it into a dialysis bag and dialyzed with deionized water for 72h , Replace the dialysate every 12h; freeze-dry to obtain RGD-PCB(tBU)-b-PDS-b-PDPA triblock polymer, the structural formula is shown in formula 1-2:

[0054] ……….Formula 1-2

[0055] (c) Preparation of RGD-PCB-b-PDS-b-PDPA polymer

[0056] The RGD-PCB(tBU)-b-PDS-b-PDPA triblock polymer was dissolved in 3mL of trifluoroacetic acid (TFA) and reacted at room temperature for 2h to hydrolyze the tert-butyl ester on the PCB (tBU) segment. After the reaction, the TFA was spun out with a rotary evaporator, dissolved in DMSO, dialyzed with deionized water for 72 hours, and the dialysate was replaced every 12 hours. Freeze-drying obtains RGD-PCB-b-PDS-b-PDPA triblock polymer, the structure is shown in formula 1-3:

[0057] ……….Formula 1-3

[0058] Using nuclear magnetic resonance spectroscopy to characterize RGD-PCB(tBU)-b-PDS-b-PDPA and RGD-PCB-b-PDS-b-PDPA polymers, the results are as follows figure 2 Shown. The characteristic peaks of the polymer obtained in this example were analyzed, and the result showed that the polymer was successfully synthesized and the composition was consistent with the feed ratio.

Example

[0059] Example 2 ~ Example 12

[0060] The equipment and operation are the same as in Example 1, except that the carboxybetaine tert-butyl methyl methacrylate (CB-tBU), methacrylamide ethylpyridine disulfide (DS) and diisopropylamino methacrylate are adjusted. The ratio of ethyl ester (DPA) and other monomers to the chain transfer agent trithiododecyl-2-isopropanoate (CTAm) to obtain triblock polymers with different degrees of polymerization, as shown in Table 1:

[0061] Table 1: pH and redox dual sensitive polymers

[0062]

[0063] N a It is the molar ratio of RGD to PCB-b-PDS-b-PDPA triblock polymer.

Example Embodiment

[0064] Example 13 (I-13):

[0065] According to the method and device of Example 1(a), CB-tBU was replaced with RGD-linked polyethylene glycol acrylate (RGD-PEG480-AC), and the number average molecular weight of the polyethylene glycol segment was 480 to obtain RGD-PEG480- b-PDS-b-PDPA. NMR characterization of its composition RGD-PEG480 10 -b-PDS 10 -b-PDPA 25 (I-13), the subscript is the degree of polymerization of the corresponding monomer.

PUM

Property	Measurement	Unit
Particle size	142.0 ~ 153.0	nm
Particle size	160.0 ~ 354.0	nm

Description & Claims & Application Information

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Classification and recommendation of technical efficacy words

low toxicity
good biocompatibility

ph and oxidation-reduction dual-sensitive layer cross-linking nanoparticle as well as preparation method and application thereof

AI-Extracted Technical Summary

Problems solved by technology

Method used

Abstract

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Examples

Example Embodiment

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Example Embodiment

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Description & Claims & Application Information

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