Small micelle nano-drug as well as preparation method and application thereof

[0040] The synthesis of PEG-P(CL-DTC) block copolymer is based on MeO-PEG-OH ( M n = 2.0 kg / mol) is obtained by ring-opening polymerization of DTC and CL initiated by a macromolecular initiator and diphenyl phosphate (DPP) as a catalyst. Specifically, in an inert gas glove box, MeO-PEG-OH (800 mg, 0.4 mmol), DPP (1.0 g, 4 mmol), DTC (400 mg, 2.1 mmol), CL (400 mg, 3.5 mmol) and anhydrous DCM (3.2 mL), stirred and dissolved, sealed, removed from the glove box, and placed in a 40 ºC oil bath with magnetic stirring for 48 h. After the reaction was completed, glacial acetic acid was added to terminate the reaction, precipitated twice in 30 times the volume of glacial ether, filtered by suction, and dried in vacuum for 24 h to obtain PEG 2k -P(CL 1k -DTC 1k ), the preparation route is as follows:

[0041]

[0042] Its proton magnetic spectrum shows each characteristic peak of polymer: PEG: δ 3.38 (C H 3 O-) and 3.64 (-C H 2 C H 2 O-); DTC: δ 3.00 (-C(C H 2 SS

[0054] Example 1 Preparation and characterization of PTX micelles

[0055] Combine PTX and PEG 2k -P(CL 1k -DTC 1k ) were dissolved in PEG 350 according to different mass ratios (5 / 100, 10 / 100, 20 / 100, 30 / 100), and the polymer concentration was 50 mg / mL. After conventional ultrasonication for 5 min, 100 mL of the mixed solution was poured into the bottom of 900 mL of PB solution (pH 7.4, 10 mM) at 37 °C, and stood without stirring during the process. After injection, use a pipette gun to stick to the liquid surface and pipette 5 times to obtain a theoretical PTX drug loading of 4.8 wt. %~23.1 wt. % micellar MPTX, which is a non-targeting small micellar nanomedicine. The particle size and particle size distribution (PDI) were determined by DLS, and the micelle morphology was determined by TEM. MPTX was dissolved in acetonitrile containing 20 mM DTT (the polymer concentration was 0.1 mg / mL), and then the PTX concentration was tested by HPLC, and the drug loading a

[0066] Example 2 Preparation and property research of various PTX micelles

[0067] The targeting micelles loaded with PTX are composed of amphiphilic block polymer PEG 2k -P(CL 1k -DTC 1k ) and the polymer Ta-PEG-P (CL-DTC) coupled with targeting molecules (Ta is the polypeptide cRGD, ATN1 or ATN2) are self-assembled in the aqueous phase. 2.5%, 5%, 7.5%, 10% or 20% of ATN1-PEG-P (CL-DTC), ATN2-PEG-P (CL -DTC) or cRGD-PEG-P (CL-DTC) as the initial polymer solution, then mixed with the PTX solution, all the other steps are the same as in Example 1, to obtain micelles ATN1-MPTX, ATN2-MPTX of different polypeptide surface densities and cRGD-MPTX, targeting small micellar nanomedicines.

[0068] After mixing PEG-(CL-DTC) and targeting polymers coupled with cRGD, PHSCNK or PhScNK in different proportions, targeting micelles were prepared, and the same method as in Example 1 was used to keep the PTX drug loading at 4.8 wt. %, three series of micellar cRGD-MPTX, ATN1-MPTX and ATN2-