Dual-sensitive and biodegradable core-crosslinked HPMA copolymer–doxorubicin conjugate-based nanoparticles for cancer therapy

In this study, to increase the blood stability and circulation time of polymeric nanoparticles as well as to investigate the effects of the structure on therapeutic indexes, 2 types of N-(2-hydroxypropyl)methacrylamide (HPMA) block copolymer–doxorubicin (copolymer–DOX) conjugates, including an amphiphilic linear one and a core cross-linked one, were designed. Comparative studies on their self-assembled nanoparticles, as advanced drug delivery systems, were investigated. Both conjugates could self-assemble into polymeric nanoparticles (block copolymer-NPs and cross-linked copolymer-NPs) with sizes of ∼20 nm. Those cross-linked nanoparticles demonstrated pH-sensitive drug release features as a much higher accumulative drug release (∼80.2%) in the presence of glutathione (GSH) and pH 5.0 was observed than that in PBS (pH 7.4) without GSH (about 27.0%, 24 h). The degraded segments with low MW (MW ∼28 kDa) can be observed in the presence of a reduction agent. In addition, in vivo pharmacokinetic behaviour studies showed that the cross-linked copolymer-NPs resulted in good blood stability and long-lasting circulation time compared with the linear block copolymer-NPs and the free drug. The cell viability test and migration and invasion assay showed that both nanoparticles can inhibit cancer cell proliferation. Finally, the cross-linked copolymer-NPs exhibited the best in vivo anticancer efficacy due to the highest tumor inhibition rate of 77.75% on the A549 lung tumor model. These results suggested that cross-linked copolymer-NPs could be a potential delivery system in cancer therapy.