Reduction-responsive targeted polyethylene glycol-polycarbonate maytansinoid prodrug micelles, its preparation method and application

A technology of polyethylene glycol and polycarbonate, which is applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., which can solve the problems of patients' pain, side effects, and inability to apply clinically

Active Publication Date: 2019-09-10
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are obvious deficiencies in these treatment methods: during the treatment process, it will cause irreversible damage to the normal tissues of the body, produce serious toxic and side effects, and bring great pain to patients.
However, due to the lack of specific selection for tumors and the slow release of anticancer drugs, the above-mentioned polymer prodrugs have unsatisfactory therapeutic effects in clinical trials, making them unable to be used clinically.

Method used

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  • Reduction-responsive targeted polyethylene glycol-polycarbonate maytansinoid prodrug micelles, its preparation method and application
  • Reduction-responsive targeted polyethylene glycol-polycarbonate maytansinoid prodrug micelles, its preparation method and application
  • Reduction-responsive targeted polyethylene glycol-polycarbonate maytansinoid prodrug micelles, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Embodiment one polymer (PEG-P(TMC- co- PDSC)) synthesis

[0087] Under a nitrogen atmosphere, 86.7 mg (0.32 mmol) of dithiopyridine carbonate monomer (PDSC) and 81.6 mg (0.8 mmol) of trimethylene carbonate (TMC) were dissolved in 2 mL of dichloromethane and added to a sealed reactor Li, then add 0.1 g (0.02 mmol) CH 3 O-PEG-OH (5 K) and 0.5 mL catalyst bis(bistrimethylsilyl)amine zinc in dichloromethane solution (0.1 mol / L), seal the reactor, transfer out of the glove box, 40 ℃ oil After reacting in the bath for 24 hours, glacial acetic acid terminated the reaction, precipitated in glacial ether, and finally filtered and vacuum-dried to obtain the polymer PEG-P (TMC- co- PDSC). The yield was 81.5%. The NMR picture is attached figure 1 , 1 H NMR (400 MHz, CDCl 3 ): TMC moieties: δ (ppm) 2.05, 4.23, PEG moieties: δ (ppm) 3.37, 3.65, PDSC moieties: δ (ppm) 1.12, 3.01, 4.11, 7.09, 7.65, 8.46. According to NMR calculation, the molecular weight is 11.8 kg / mol, and ...

Embodiment 2

[0091] Embodiment two amphiphilic polyethylene glycol-polycarbonate maytansinoid prodrug polymer (PEG-P(TMC- g -SSDM1)) synthesis

[0092] Under the protection of nitrogen, the polymer PEG-P (TMC- co- PDSC) (100 mg, 0.088 mmol dithiopyridine functional group), while adding a catalytic amount (100 μL) of glacial acetic acid, and then adding 25 mL of thiol-functionalized maytansine (DM1) (97.8 mg, 0.135 mmol) in DMF, the reactor was placed in an oil bath at 35°C, stirred for 48 hours, then dialyzed in DMF and water (Spectra / Pore, MWCO 7000), and freeze-dried with a yield of 75%. NMR results showed that its structure was amphiphilic polyethylene glycol-polycarbonate maytansine prodrug polymer, and the drug loading capacity of maytansine was 40 wt .%. The NMR picture is attached figure 2 , 1 H NMR (600 MHz, DMSO- d 6 ): PEG: δ 3.37, 3.64; TMC: δ 4.24, 2.04; DM1: δ5.22-7.24, 0.71-1.52, and 3.25-3.55. The NMR calculation gave a molecular weight of 18.1 kg / mol.

Embodiment 3

[0093] Example three polymers (Mal-PEG-P(TMC- co- PDSC)) synthesis

[0094] Under a nitrogen atmosphere, 86.7 mg (0.32 mmol) of dithiopyridine carbonate monomer (PDSC) and 81.6 mg (0.8 mmol) of trimethylene carbonate (TMC) were dissolved in 2 mL of dichloromethane and added to a sealed reactor Then add 0.1 g (0.02 mmol) MAL-PEG-OH (5 K) and 0.5 mL catalyst bis(bistrimethylsilyl)amine zinc in dichloromethane solution (0.1 mol / L), seal the reactor , transferred out of the glove box, reacted in an oil bath at 40°C for 24 hours, terminated the reaction with glacial acetic acid, precipitated in glacial ether, and finally obtained the polymer MAL-PEG-P (TMC- co- PDSC). The yield was 82.3%. The NMR picture is attached image 3 , 1 H NMR (400 MHz, CDCl 3 ): PEG moieties: δ 3.63; TMC moieties: δ4.23, 2.05; PDSC moieties: δ 8.46, 7.65, 7.09, 4.10, 3.01, 1.12, Maleimidegroup: δ 6.71. According to NMR calculation, the molecular weight is 12 kg / mol, and the degrees of polymerizati...

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Abstract

The invention discloses a reduction-responsive targeted polyethylene glycol-polycarbonate maytansine prodrug micelle, a preparation method and application thereof. The amphiphilic polyethylene glycol-polycarbonate maytansinoid prodrug polymer composed of amphiphilic polyethylene glycol-polycarbonate maytansinoid prodrug polymer and the terminal-bonded targeting molecule were automatically activated in buffer. Targeted polyethylene glycol-polycarbonate maytansine prodrug micelles with reduction response were assembled; the particle size of the micelles was 30-150 nanometers, and the drug-loading capacity of maytansine was 2-60 wt .%. The reduction-responsive targeted polycarbonate maytansinoid prodrug micelles provided by the present invention have targeting properties, amphiphilicity and biodegradability, and nano-medicines can be prepared therefrom, which can significantly improve the water-solubility of drugs and enhance drug Stability in circulation process, improvement of drug pharmacokinetic behavior and improvement of drug bioavailability; it can be applied in the preparation of malignant tumors such as targeted therapy drugs for melanoma.

Description

technical field [0001] The present invention relates to a polymer prodrug and its application, in particular to a reduction-responsive targeted polyethylene glycol-polycarbonate maytansinoid prodrug, its preparation method and its use in the preparation of targeted tumor therapy drugs The application belongs to the field of medical materials. Background technique [0002] Malignant tumors have become the main killer threatening human health, and its morbidity and mortality are increasing year by year. Current tumor treatment methods mainly include surgical resection, radiation therapy and chemotherapy. There are obvious deficiencies in these treatment methods: the treatment process will cause irreversible damage to the normal tissue of the body, produce serious toxic and side effects, and bring great pain to the patient. Maytansine is a potent tubulin inhibitor, which has a strong ability to kill many malignant tumors such as breast cancer, melanoma, multiple myeloma and l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/59A61K31/537A61K9/107C08J3/03C08G64/42C08G64/30C08G64/18A61P35/00C08L69/00
CPCA61K31/537C08G64/18C08G64/30C08G64/42C08J3/03C08J2369/00A61K47/6907A61K47/60A61K47/593A61P35/00
Inventor 钟志远程茹钟平
Owner SUZHOU UNIV
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