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 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.
Department of Mechanical Engineering, University of Wisconsin—Milwaukee, Milwaukee, Wisconsin 53211, United States.
Xiaoqiang
X
Yang
Jamison J
JJ
Grailer
Ian J
IJ
Rowland
Alireza
A
Javadi
Samuel A
SA
Hurley
Vyara Z
VZ
Matson
Douglas A
DA
Steeber
Shaoqin
S
Gong
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D003287:Contrast Media / Q000737:chemistry; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D005290:Ferric Compounds / Q000737:chemistry; D058972:Folic Acid Transporters / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008279:Magnetic Resonance Imaging / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D012680:Sensitivity and Specificity
D000970:Antineoplastic Agents; D003287:Contrast Media; D004337:Drug Carriers; D005290:Ferric Compounds; D058972:Folic Acid Transporters; D011108:Polymers; C000499:ferric oxide; D004317:Doxorubicin