Pharmacokinetic Study Of MPEG-PDLLA In Rats Based On UPLC-MS/MS Tandem In-source CID

MPoly(ethylene glycol)-block-poly(D,L,lactic acid)(mPEG-PDLLA)is a biocompatible and amphiphilic block copolymer composed of a hydrophilic PEG block and a hydrophobic PLA block,which can self-assemble into micelles in water.Combination mPEG-PDLLA and traditional small molecule drugs will improve the drug release effection and prolong the half-life.As a polydisperse polymer with high molecular weight,mPEG-PDLLA has countless molecular weights.In this study,mPEG-PDLLA was broken in front of the quadrupole,a series of PEG-specifc and PLA-specifc ions were generated in the ion source with in-source collision induced dissociation.Among them,fragments of PEG were m/z at 133.08592,177.11214 and so on,the adjacent fragments had a m/z difference of 44 Da which was equal to the mass of a PEG structural unit,fragments of PLA were m/z at 145.1,217.12,361.2,433.1,505.1,577.1 and so on,the adjacent fragments had a m/z difference of 72 Da which was equal to the mass of a PLA structural unit.According to the sensitivity and slectivity,m/z 505 was selected as the parent ion,and further broken into daughter ions at m/z 217.0.Finally,mass transition m/z 505.0 to m/z 217.0 was selected for the quantitation of PEG-PDLLA.After optimizing the liquid chromatography conditions and sample extraction method,we developed an ultra-high performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS)coupled with in-source collision induced dissociation(CID)technique for the analysis of mPEG-PDLLA in different rat substrates.This assay achieved a lower limit of quantitation(LLOQ)of 0.05 μg/mL.The linear range was from 0.05 to 5 μg/mL.Intra-day and inter-day accuracy and precision were within ±15%.MPEG-PDLLA had a quick clear elimination phase after intravenous administration in 1.25,2.50 and 5 mg/kg,and the plasma elimination half-life(t1/2)was almost 1.16 hours.The fast elimination may relate to the fast biodegradability of PLA.The results will be helpful for the rapid release of loaded drugs with mPEG-PDLLA.The results of tissue distribution showed that after drug administration,mPEG-PDLLA was rapidly and widely distributed in the rat,mainly distributed in the heart,liver,lung,kidney,bladder and spleen due to high perfusion rate.After 4 hours,the concentration of mPEG-PDLLA in different tissues rapidly decreased,especially in liver and lung to about 10% of the peak values which show that there is no obvious cumulative effect of mPEG-PDLLA.In summary,we developed an ultra-high performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS)coupled with in-source collision induced dissociation(CID)in different biological substrates.The method was successfully applied to the pharmacokinetic study and tissue distribution in rats,it would provide some theoretical support for the application of polymer excipients in the development of nanoparticles.