Synthesis Of Stimulated Response Polyurethane Micelles And Research On Its Structure And Performance As Antitumor Drug Carrier

Stimuli-sensitive polyurethane micelles have been widely have been widely used as anticancer drug delivery systems.But there are still slow release rate,imcomplete release and the anti-dilution ability of micelles.In order to solve the problem of slow drug release rate,our group studied PU based nanocarriers with disulfide bonds located primarily at the interface between the hydrophobic core and the hydrophilic shell(PU-SS-I).However,about 30% PTX was not released in 48 hours for PU-SS-I system.We speculated that the occurrence of aggregation of hydrophobic cores upon shedding hydrophilic PEG coronas resulted the incomplete release.The encapsulated drugs in the hydrophobic aggregation will not be released until the degradation of the polyester.To verify the above hypothesis and to develop a new polyurethane based micelles with both p H and redox sensitive properties,a tertiary amine(N-methyl-diethanolamine,MDEA)was incorporated into the hydrophobic segments of PU-SS-I(the sample are denoted as PU-SS-N).Biodegradable polyurethane with only disulfide linkage located between the hydrophilic PEG segment and the hydrophobic PCL(PU-SS-I)and polyurethane with only p H sensitive tertiary amine(N-methyl-diethanolamine,MDEA)at the hydrophobic core(PU-N-C)were used as comparisons to investigate the relationship between drug release rate,drug release,cytotoxicity(IC50)and material structure.It was demonstrated that about 90% PTX was released from drug loaded PU-SS-N micelles while ~70% PTX from PU-SS-I micelles at an acidic and a reductive environment(p H=5.5,10 m M GSH).In addition,the PTX loaded dual-responsive micelles have better anti-tumor properties free PTX micelles.The rapid and complete redox and p H stimuli release properties of the PU-SS-N nanocarrier will be a promising anticancer drug delivery system to ensure sufficient drug concentration to kill the cancer cells and to prevent the emergency of MDR.In order to solve the issues of anti-dilution stability and early release of polymer micelles,the biodegradable inner cross-linked polyurethane micelles with dense PEG layers and clikable alkynyl on the surface were studied.First,MPEG-Diethanolamine,Propargyl-Diethanolamine and phenylmethane diisocyanate(HMDI)were used to synthesis the polyurethane oligomer(PUO)which can be self-assembled to micelles in aqueous solution.The PUO micelles are then crosslinked by a crosslinking agent with azide to form crosslinked polyurethane micelles(CLPUO).It was found that the crosslinked micelles had good stability and high drug loading.Moreover,under the conditions of p H and reduction,crosslinked micelles can be cross-linked and protonated to achieve controlled and rapid release of the drug.