Multifunctional Stable and pH-Responsive Polymer Vesicles Formed by Heterofunctional Triblock Copolymer for Targeted Anticancer Drug Delivery and Ultrasensitive MR Imaging

A multifunctional stable and pH-responsive polymer veside nanocarner system was developed for combined tumor targeted delivery of an anticancer drug and superparamagnetic iron oxide (SPIO) nanoparticles (NPs) These multifunctional polymer vesides were formed by heterofunctional amphiphilic triblock copolymers, that is, R(folate (FA) or methoxy)-poly(ethylene glycol)(M-w 5000)-poly(glutamate hydrazone doxorubian)-poly(ethylen glycol) (M-w 2000)-acrylate (i e, R (FA or methoxy)-PEG(114) P(Glu Hyd DOX)-PEG(46)-acrylate) The amphiphilic triblock copolymers can self assemble into stable vesides in aqueous solution It was found that the long PEG segments were mostly segregated into the outer hydrophilic PEG layers of the vesides, thereby providing active tumor targeting via FA, while the short PEG segments were mostly segregated into the hydrophilic PEG layer of the vesides, therby making it possible to cross link the inner PEG layer via the acrylate groups for enhanced in vivo acrylate groups for enhanced in vivo stability The therapeutic drug DOX, was conjugated onto the polyglutamate segment, which formed the hydrophobic membrane of the vesidses using a pH-sensitive hydrazone bond to achieve pH-responsive drug release, while the hydrophilic SPIO NPs were encapsulated into the aqueous core of the stable vesides, allowing for ultrasensitive magnetic resonance imaging (MRI) detection The SPIO/DOX loaded vesides demonstrated a much higher r(2) relaxivity value than fendex, a commercially available SPIO-based T-2 contrast agent, which was attributed to the high SPIO NPs loading level and the SPIO dustering effect in the aqueous core of the vesides Results from flow cytometry and confocal laser scanning microscopy (CLSM) analysis showed that FA conjugated vesides exhibited higher, cellular uptake than FA free vesides which also led to higher cytotoxicity Thus, these tumor targeting multifunctional SPIO/DOX-loaded vesides will provide excellent in vivo stability, pH-controlled drug realease, as well as enhanced MRI contrast, thereby making targeted cancer therapy and diagnosis possible