Recently, it has been discovered that the PEG layer on nanoparticle surface can create steric hindrance, preventing efficient cellular uptake of PEGylated nanoparticles. Thus, it would be ideal to have a nanoparticle system that sheds the PEG layer upon reaching the tumor microenvironment. Hypoxia, which is a hallmark of cancerous tumors, can be used as a trigger to shed the PEG layer from the nanoparticle surface. In this study, a hypoxia-sensitive PEG-azobenzene-PEI-DOPE (PAPD) construct, with an azobenzene group as a hypoxia-sensitive moiety, was prepared. The feasibility of co-delivering Doxorubicin (Dox) and anti-P-gp siRNA (siPgp) using the PAPD nanoparticles was evaluated in monolayers of the Adriamycin-resistant human ovarian cancer cell line, A2780 ADR, and in 3D spheroids of the multidrug-resistant human breast cancer cell line, MCF7 ADR. Under hypoxic conditions, the PAPD nanoparticles showed up to a 60% increase in cellular uptake by monolayers and a significantly greater tumor penetration in a spheroid model. siPgp, when delivered using PAPD nanoparticles, showed up to a 60% P-gp downregulation under hypoxic conditions. The combination of siPgp and Dox delivered using PAPD nanoparticles led to an 80% cytotoxicity in cell monolayers and 20% cytotoxicity in spheroids under hypoxic conditions. In this research, a novel hypoxia-sensitive nanoparticle system was developed that demonstrated improved delivery of an encapsulated cargo and augmented cytotoxicity on multidrug-resistant cancer cells under hypoxic conditions.
Keywords: Hypoxia; Nanoparticles; PEG; Polymeric micelles; siRNA.
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