Research For The Preparation And Antitumor Effect Of A Novel Phosphatidyl-mitoxantrone Nanomedicine

Multidrug resistance to chemotherapeutics due to P-gp(P-glycoprotein)-mediated efflux has been identified as a major cause of the failure of cancer treatments.Recently,many research indicated that nanomedicine entering cells mainly by the endocytosis can reverse the drug-resistance.Herein,we demonstrate a novel self-assembled amphipathic nanoparticle in aqueous water that is hydrophilic anticancer drug Mitoxantrone(MA)bonded to phosphatidylcholine(PC)catalyzed by phospholipase D(PLD).In turn,it can be hydrolyzed by PLD which are aboundant in several human tumours to release MA,due to its two catalytic functions:hydrolysis and transesterification.To research the physical properties,eneyme-triggered release ability and antitumor efficiency,we did experiments and obtained results as follows:The PMA nanoparticles with an average particle size of(98.59±2.31)nm and a standard zeta potential of(43.2±4.75)mV indicating that can enhance the tumor target by EPR and increased blood circulating time was investigated with Malvern Instrument and TEM.Because of the eneyme-triggered ability,we simulated the physiological environment and controled the expression of PLD,and the release profiles indicated that the nanoparticles displayed sustained release of the drug over a period of 24 h without burst release,which suggested a time-and PLD-dependent drug release profile in cells.Confocal and flow cytometry were used to demonstrate the ability of PMA to modulate uptake and distribution in cells.It found that the PMA nanoparticles exhibit the ability of accumulating in MCF-7/ADR by evading the bump of P-gp while free MA cannot,which lead to the fact that PMA was more toxic than free MA in MCF-7/ADR as verified by the cytotoxicity experiment.To verify the mechanism of reverse the drug-resistance,we chose four endocytosis inhibitions,and the results proved that PMA nanoparticles entered the cells mainly through the caveolae-mediated endocytosis pathway with participation from the Golgi apparatus,which might be the results of efficient drug accumulation and release in cells.Similarly,analysis of in vivo effects indicated that PMA had stronger antitumor activity and lower systemic toxicity than free MA.In summary,the findings here indicated that PMA nanoparticles with good biocompatible,excellent physical properties,few side-effects,effective inhibitory and non-destructive delivery pathways might provide a great promising approach for the treatment of MDR cells.