Folate-conjugated PH-responsive Nanocarrier Designed For Active Tumor Targeting And Controlled Release Of Doxorubicin

Folic acid is one of the necessary B vitamins for the human body.For instance,the folate,conjugated with an appropriate design,can be directed to the cancer cells in the body and internalized in the target cells via receptor-mediated endocytosis.Due to the low-molecular-weight vitamin,binding with high affinity to the folate receptor?FR?that are selectively overexpressed on the surface of cancer cells,a membrane-anchored protein has been widely used to modify nanocarriers to further improve the passive targeting systems and accumulate drugs in cancer cells by FR-mediated endocytosis.In this study,a series of amphiphilic block copolymers were prepared via ATRP and ROP techniques decorated with folate ligands.The performances of these micelles as drug delivery carriers such as drug loading capacity,in vitro drug release behavior,and in vitro anticancer activities were evaluated.The main research work is as follows:?1?AnoveltypeofamphiphilicpH-responsive folate-poly??-caprolactone?-block-poly?2-hydroxyethylmethacrylate?-co-poly?2-?dimethyla mino?-ethylmethacrylate??FA-PCL-b-P?HEMA-co-DMAEMA??block copolymers were designed and synthesized via a continuous activators regenerated by atom transfer radical polymerization?ATRP?and ring opening polymerization?ROP?techniques.The critical micelle concentrations?CMC?of?FA-PCL-b-P?HEMA-co-DMAEMA??in aqueous solution was extremely low(about 6.54 mg L^-1).The average hydrodynamic diameter of the self-assembled blank micelles nanoparticle was approximately 100 nm.Then in vitro release behavior of DOX-loaded micelles was exhibited pH-dependent properties.The DOX release rate was significantly accelerated when solution pH decreased from 7.4 to 5.0.In vitro antitumor efficiency was evaluated by incubating the DOX loaded micelles with HeLa cells.?2?Thermo-responsiveamphiphilictriblockcopolymersTTC-PCL-P?MEDSA-co-NIPAM?were synthesized by atom transfer radical polymerization of MEDSA and NIPAM co-monomers using a TTC-PCL macroinitiator.The resulting copolymers were characterized by ¹H NMR,FT-IR and GPC.Thermo-responsive micelles were obtained by self-assembly of copolymers in aqueous medium.The micelles are spherical in shape with sizes varying from 91.8 nm to 125.2 nm.A hydrophobic anticancer drug,doxorubicin,was encapsulated in micelles by using dialysis method.The properties of drug loaded micelles were determined by dynamic light scattering,transmission electron microscopy and lower critical solution temperature?LCST?measurements.?3?Herein,we demonstrate a design and synthesis of a new multifunctional nanocarriers with pH,temperature and redox-sensitive stimulus response amphiphilic block copolymer?-CD-PEI-P?DMAEMA-co-NIPAM?-SS-FAviareversibleaddition fragmentation chain transfer.The resulting copolymers were characterized by ¹H NMR,FT-IR,GPC,DLS,TEM and UV-vis.The polymer could be cleaved efficiently,and DOX was readily released under reductive condition similar to intracellular environment.The polymer was well characterized and studied in terms of its drug delivery properties in FR positive HeLa cells under various conditions.