Rational Design of Nanoparticles to Overcome Poor Tumor Penetration and Hypoxia induced Chemotherapy Resistance: Combination of Optimizing Size and Self inducing High Level of Reactive Oxygen Species.
One tough question induced by the hypoxia in cancer tissue is resistance to the anticancer drugs basing on reactive oxygen species (ROS) mechanism. Furthermore, the hypoxic regions locate in the center of tumor where tumor cells are easy to 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. Other more, 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, remarkably elevation of ROS level, and the enhanced DOX sensitivity in hypoxia environment were observed in vitro studies. Tumor spheroid penetration results certificated 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 integrated 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.
ACS applied materials interfaces