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

Abstract

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.

Magnetic Nanocarriers Enhance Drug Delivery Selectively to Human Leukemic Cells

“…The observed enhanced cytotoxicities of Dox@PMNPs compared to free Dox against leukemic cells, with the least sensitivity towards the normal PBMC cells suggest huge potentials for the Dox nanocarriers as efficient and selective drug delivery vehicles. We anticipate that the observed enhanced cytotoxic effects of Dox@PMNPs is mostly dependent upon the selective and differential uptake of Dox@PMNPs, and subsequent release of Dox intracellularly due to the biochemical changes inside the cells (mainly pH, hydrolysis, and endosomal/lysosomal hydrolytic enzymes) [41,42]. The payload then translocates to the nucleus in a sustained way exerting its cytotoxic action [38].…”

Fluorescent graphene quantum dots as traceable, pH-sensitive drug delivery systems

“…Dox-GQDs and Dox-RGD-GQDs showed a slightly lower lethal effect compared with free Dox. This can be attributed to the diffusion abilities of free, but not of conjugated Dox, 41,42 which accelerates the internalization of Dox and its availability inside the cells. Figure 6A and B also show a consistently higher lethal effect for Dox-RGD-GQDs than for Dox-GQDs (RGD-free), which could be attributed to the enhanced cellular uptake that the RGD peptides provide to the Dox-RGD-GQDs, thus indirectly confirming the efficacy of RGD to locally accumulate the DDS within cancer cells, thereby facilitating uptake and increasing the availability of Dox to the cells.…”

Functionalization of Block Copolymer Vesicle Surfaces

“…Spherical and worm-like polymersomes decorated with folate as a targeting ligand were investigated as nanocarrier system for a combined targeted delivery of an anticancer drug and a magnetic resonance imaging contrast agent [68,69]. To this end, heterobifunctional asymmetric triblock copolymers folate-PEG 5000 -b-poly(glutamate hydrazone doxorubicin)-b-PEG 2000 -acrylate, and FA-PEG 114 -b-PLA-b-PEG 46 -acrylate were synthesized and allowed to self-assemble into vesicles.…”