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Polyamide-imide drug-loaded nanoparticle and application thereof

A drug-loaded nano-imide technology, applied in the field of anti-tumor drugs, can solve the problems of unguaranteed therapeutic effect, cumbersome multi-step synthesis and availability of purification, and achieve the effect of improving efficiency

Active Publication Date: 2020-01-03
WUXI PEOPLES HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] It is worth noting that higher drug loading does not guarantee better therapeutic effect, because the physical and chemical properties of nanocarriers are also related to the cellular uptake of nanocarriers and subsequent targeted drug release.
Yuan et al. described a polymeric prodrug based on conjugated polyelectrolytes (CPEs) followed by DOX linkages, but tedious multi-step synthesis and purification made its availability challenging.

Method used

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  • Polyamide-imide drug-loaded nanoparticle and application thereof
  • Polyamide-imide drug-loaded nanoparticle and application thereof
  • Polyamide-imide drug-loaded nanoparticle and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Synthesis of DSSP-OH: Dissolve 2,2'-dipyridyl disulfide (5.6 g, 25.5 mmol) in 30 mL of methanol, add 0.5 mL of glacial acetic acid as a catalyst, add mercaptoethanol (1.34 g, 17.1 mmol) in 10 ml of methanol, and stirred at room temperature in the dark for 3 hours, after the reaction, the mixture was evaporated in vacuo to a yellow oil, using ethyl acetate: hexane = 3: 7 (v / v) The eluent, the crude product was purified by silica gel chromatography, yield: 54.8%, 1 HNMR (400MHz, chloroform-d) δ8.52(ddd, 1H), 7.61(m, 1H), 7.40(dt, 1H), 7.15(m, 1H), 5.77(t, 1H), 3.83(m, 2H ), 2.95(m, 2H);

[0045] Synthesis of CPT-DSSP: CPT (2.0 g, 5.74 mmol), 4-dimethylaminopyridine (DMAP, 2.10 g, 17.2 mmol) and triphosgene (0.567 g, 1.92 mmol) were suspended in 50 mL of anhydrous dichloromethane , and stirred at room temperature under argon for 30 minutes, then, a solution of DSSP-OH (1.18 g, 6.31 mmol) dissolved in anhydrous tetrahydrofuran (THF) was added dropwise to the above mixture...

Embodiment 2

[0053] In vitro drug release: reduction-responsive drug release kinetics from P1-P3 PDNPs by dialysis method. Typically, 1 mL of P1-P3 PDNPs stock solution was added to dialysis tubing (MWCO: 3500 Da) and dialyzed against PBS (10 mM) at 37 °C. For each PDNPs, different concentrations of GSH (2 µM, 5 mM and 10 mM) were used in dialysis. At various predetermined time points, aliquots of the solution were collected and replaced with the same volume of PBS. According to the fluorescence spectrophotometer (E x =370nm,E m = 435nm) to calculate the amount of released CPT. In addition to DOX fluorescence detection wavelength, E x =488nm,E m =591nm, the in vitro drug release of dual-loaded P1-P3 PDNPs was determined by the same method.

[0054] Cell culture: Mouse breast cancer cells (4T1 cells), cervical cancer cells (HeLa cells) and human fibrosarcoma cells (HT-1080 cells) were obtained from the cell bank of Shanghai Institute of Cell Biology, China. Cells were cultured in Dul...

Embodiment 3

[0059] The experimental result of embodiment 1 and embodiment 2:

[0060]Synthesis and characterization of PAI-CPT prodrug: This study used the previous research method to combine thiolactone maleimide monomer with 4,7,10-trioxy-1,13-tridecanediamine (diamine 220) Equimolar ratio condensation polymerization to synthesize aliphatic PAI (polyamide-imide), the synthetic route diagram is shown in figure 2 . Quantitative characterization of the aminolysis of thiolactone and amine-maleimide-Michael additions allows a very efficient synthesis of PAIs and facilitates the in situ one-pot modification of PAIs. Prior to PAI-CPT coupling, pyridyl disulfide-modified CPT (i.e. CPT-DSSP) prodrugs were synthesized by a two-step process with an overall yield of about 33%, 1 H and 13 C NMR results confirmed its chemical structure (see figure 1 ).

[0061] In the present invention, due to the presence of the pyridine disulfide moiety, the CPT-DSSP prodrug can not only release CPT in a redu...

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Abstract

The invention discloses a polyamide-imide drug-loaded nanoparticle and an application thereof. The structural formula of the polyamide-imide drug-loaded nanoparticle is shown as a formula (I), whereinR is R1 or R2, the R1 is camptothecin modified by sulfydryl and pyridine disulfide, the R2 is PEG 500, the molar ratio of the R1 to the R2 is (10-40):(60-90), X is an integer from 1 to 7, and y is aninteger from 1 to 3. The polyamide-imide drug-loaded nanoparticle is subjected to rapid cell internalization within 2 hours. In addition, due to the fact that disulfide bond connection exists betweena PAI stent and the drug, reduction reactive drug release can be achieved. In addition, the PAI-CPT PNDs can be used as a nano-carrier to load other anti-cancer drugs (such as DOX) for combined chemotherapy, and show a synergistic treatment effect.

Description

technical field [0001] The invention belongs to the technical field of antineoplastic drugs, in particular to a polyamide-imide drug-loaded nanoparticle and its application. Background technique [0002] Although small-molecule drug chemotherapy is one of the important paradigms for cancer therapy, it often exhibits poor bioavailability and uncontrollable pharmacokinetics, resulting in severe side effects and limited therapeutic efficacy. An effective strategy to address these issues is the use of nanoformulations, either by chemically coupling drugs to nanomaterials or by physically encapsulating drugs in nanocarriers. Compared with inorganic materials, polymer nanocarriers have good biocompatibility and tunable degradability, and are a promising drug delivery system for tumor chemotherapy [0003] It is worth noting that higher drug loading does not guarantee better therapeutic effects, because the physical and chemical properties of nanocarriers are also related to the c...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K31/704C08G73/14A61P35/00A61K31/4745
CPCA61K31/4745A61K31/704A61K47/6935A61P35/00C08G73/14A61K2300/00
Inventor 李苁杨树东
Owner WUXI PEOPLES HOSPITAL
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