Galactose-containing Amphiphilic Triblock Copolymer Synthesis Via ATRP And Self-assembly Behavior

During the past few years, polylactides (PLAs) have become one of the most preferredpolymers for developing new generation devices for biomedical applications. Up to now, theyhave been used as biomedical materials, finding applications as scaffolds for tissueregeneration, bioresorbable sutures, matrices for prolonged drug delivery systems, and so on.Although PLA has so many good properties, such as biodegradability, biocompatibility, highmechanical strength, and so forth, its application in some fields is still limited because of itshydrophobicity and lack of functional or reactive pendant groups along the molecular chain.In order to successful biological and biomedical applications of PLA, one serious challenge isassociated with modification of PLA and introduce reactive pendant groups in PLA.Well-defined amphiphilic poly(6-O-methacryloyl-D-galactopyranose)-b-poly(L-lactide)-b-poly(6-O-methacryloyl-D-galactopyranose)(PMAGP-PLA-PMAGP) triblock copolymerswith varied compositions and molecular weights were obtained. The synthesis strategyconsisted of a four-step procedure. First,L-lactic acid and1,4-butylene glycol as raw materials,Sn(ot)2as catalyst, double-hydroxyl-terminated polylactic acid (HO-PLA-OH) wassynthesized by condensation polymerization, followed by the HO-PLA-OH was quantitativelyconverted into macroinitiator (Br-PLA-Br) via esterification reaction with α-bromoisobutyrylbromide, then the atom transfer radical polymerization (ATRP) of6-O-methacryloyl-1,2,3,4-di-O-isopropylidene-D-galactopyranose (MAIpGP) using Br-PLA-Br as the macroinitiator,created initital products PMAIpGP-PLA-PMAIpGP, finally, PMAGP-PLA-PMAGP wereobtained by deprotection of the protecting groups on the PMAIpGP-PLA-PMAIpGP. Thetriblock copolymer, macroinitiator and polylactide were characterized by1H NMR and gelpermeation chromatography (GPC).The critical micelle concentration (CMC) of the triblock copolymers were determinedusing pyrene as a fluorescent probe, in order to confirm the amphiphilic property andself-assembling behavior of PMAGP-b-PLA-b-PMAGP. The CMC value increased obviouslywith the increase of molecular weight, indicating that the triblock copolymers contain longerhydrophilic PMAGP segment tend to have higher CMC values.Zetasizer Nano ZS (Malvern Instruments) with a dynamic light scattering (DLS) system and transmission electron microscope (TEM) were used to measure the average diameter andobserve the morphology of polymer micelles, respectively. It is clear that the micelles are welldispersed as individual nanoparticles with a regular spherical shape, and the averagediameters of resultant micelles increase with the raise of the molecular weights. PTX could beencapsulated by the micelles during the process of self-assembled, and the in vitro release ofPTX from micelles have a remarkable difference at varied pH media, indicating that therelease processes were pH-dependent.The hemolysis assay and cell cytotoxicity assay indicated that the galactose-containingpolymeric micelles possess excellent biocompatibility and nontoxic, which is favorable to beused as intravenous drugs.Asialoglycoprotein (ASGP) receptors were expressed plentifully on the surface ofhepatoma cells, whereas targeting could be accomplished via introducing galactose residueswhich can bind specifically to the ASGP receptors on hepatoma cells, into drug deliveryvehicles for the treatment of liver cancers. The cellular uptake assay demonstrated that thegalactose-containing micelles could be selectively recognized and subsequently accumulate inHepG2cells. All of these results demonstrated that galactose-containing polymeric NPs arepotential carriers for hepatoma-targeted drug delivery and liver cancer therapy in clinicalmedicine.