Synthesis And Properties Of Multi-responsive Amphiphilic Polyphosphazene Drug Carrier

Nano-drug delivery system in the field of drug transport and drug-controlled areas have great application prospects.Drug carriers need to overcome the body's various biological barriers,so the design of synthetic tumor microenvironment responsive drug carrier in the anti-tumor drug delivery research has been widely concerned.(1)In order to prolong the cycle time of the drug carrier in the human body,the most common method is to modify the polyethylene glycol(PEG)on the surface of the nanoparticles to give a hydrophilic shell,but the PEGylated modification will cover the targeting group,(MMP-2)is highly expressed in the solid tumor site,so that the polypeptide can be hydrolyzed between Gly*Leu,so that under the action of MMP-2,the expression of MMP-2 can be reduced In addition,cathepsin B is capable of degrading the polypeptide at a specific site(Gly*Lys),and the ability of the tumor cells to grow into the cell and the endosomes The pH value is low,so the antitumor drug adriamycin can be linked with the acid-sensitive cis-aconitic anhydride,and then linked with the polymer,under the conditions of cathepsin B and lower pH,the drug carrier In the tumor cells within the release,to achieve long cycle and reduce the anti-tumor drugs on normal cells side effects.(2)Design and synthesis of amphiphilic polyphosphazenes with different hydrophobicity ratios.Poly(ethylene glycol)monomethyl ether(MPEG)was conjugated with heptapeptide GlyProLeuGly*LeuAlaGly(MMP-2 sensitive,liquid phase method)as the hydrophilic side.The pentapeptide GlyPheLeuGly*Lys(cathepsin B sensitive,liquid phase synthesis)as hydrophobic end,its structure was characterized;its micellar behavior in water,proved to form a micellar structure;determination of different hydrophobicity ratio of amphiphilic polyphosphine Nitrile low critical solution temperature(LCST),the LCST were higher than 37?,it could be used for intravenous injection;The critical micelle concentration(CMC)of M-HP/NP/PP-1?M-HP/NP/PP-2 and M-HP/NP/PP-3 were 0.0784 g/L,0.0405 g/L,0.0210 g/L,respectively by Pyrene fluorescence probe method.The CMC in PBS solution was 0.0521 g/L,0.0329 g/L and 0.0166 g/L,respectively.The decrease of the content of hydrophobic segments and the decreasing tendency of CMC decreased with the increase of the content of hydrophilic segments.The hydrodynamic diameters were 133.6±7.6 nm,126.0±6.3 nm and 116.1±6.7 nm,respectively,with the increase of the proportion of hydrophilic segments,the proportion of hydrophobic segments decreases,and the hydrodynamic diameter decreases.(3)Synthesis of drug-loaded amphiphilic polyphosphazenes and their structures were characterized.The drug loading of drug-loaded amphiphilic polyphosphazene was 15.35%,which is determined by standard curve method.The particle sizes of M-HP/NP/PP-CAD and M-HP/NP/PP-SAD were 80.49±3.45 nm and 88.47 ± 3.21 nm respectively through DLS.At the same time,the CMCs of M-HP/NP/PP-CAD and M-HP/NP/PP-SAD were 0.0130 g/L and 0.0132 g/L.The particle size and CMC of the drug-loaded amphiphilic polyphosphazene were both smaller than the amphiphilic polyphosphazene,indicating that the particle size and CMC decrease with the increase of the hydrophobic part.And in vitro release experiments was performed.The cumulative release of M-HP/NP/PP-CAD were 31.02%?35.71%?44.39%at pH 7.4,6.8 and 5.0,however,cumulative release of M-HP/NP/PP-SAD were 14.13%?14.66%? 15.38%at pH 7.4,6.8 and 5.0.Comparison of M-HP/NP/PP-CAD and M-HP/NP/PP-SAD indicates that M-HP/NP/PP-CAD was more sensitive to pH.The cumulative release of the drug was the highest at pH 5.0.This feature reduces the side effects of antineoplastic agents on normal tissue cells.Through these studies,we hope to provide a theoretical basis for the study of antineoplastic drug carriers and tumor therapy.