One tough question induced by the hypoxia in cancer tissue is resistance to anticancer drugs basing on the reactive oxygen species (ROS) mechanism. Furthermore, the hypoxic regions locate in the center of tumor where tumor cells are easily residual and survival due to the poor drug-delivery efficiency even with nanocarriers. In this paper, these problems were well addressed through the rational combination of the enhanced penetration, self-inducing high level of intracellular ROS, and synchronously pH-sensitive drug release, realized by a simple structural and accessible copolymer, poly(poly(ethylene glycol) methyl ether methacrylate-co-(2-methylpropenoic acid-glycerol-cinnamaldehyde)) (PgEMC). For one thing, PgEMC could self-assemble into stable nanoparticles with PEG shell and optimizing diameters of 60 nm to simultaneously facilitate long blood circulation and deep tumor penetration. Second, cinnamylaldehyde moieties could detach from PgEMC NPs in intracellular acidic environment and trigger high level of ROS to allay the doxorubicin (DOX) resistance induced by hypoxia in solid malignancies. Furthermore, the DOX payload in PgEMC NPs could be synchronously released with the intracellular disassembly of PgEMC NPs due to the detaching of cinnamylaldehyde moieties. In 4T1 cells treated with PgEMC/DOX NPs, remarkable elevation of ROS level and enhanced DOX sensitivity in hypoxia environment were observed in in vitro studies. The results of tumor spheroid penetration indicated that 60 nm sized DOX-loaded PgEMC NPs (PgEMC60/DOX) could distribute into deep site of tumor at a high intensity. In vivo studies using a 4T1 breast tumor model, PgEMC60/DOX NPs, showed significant inhibition over 95.4% of the tumor growth. These results reveal that integrating optimizing size, self-inducing ROS, and pH-sensitive drug release into one small-sized nanoparticle can efficiently overcome the poor tumor penetration and hypoxia-induced chemotherapy resistance.
Keywords: chemotherapy resistance; hypoxia; penetration; polymer nanoparticles; reactive oxygen species.