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