Modulation of Drug Resistance in Ovarian Adenocarcinoma Using Chemotherapy Entrapped in Hyaluronan-Grafted Nanoparticle Clusters

Resistance to anticancer drugs is considered a major cause of chemotherapy failure. One of the major mediators of resistance is the multidrug extrusion pump protein, P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter with broad substrate specificity. In order to bypass this drug resistance mechanism, we have devised phospholipid-based nanoparticle clusters coated with the glycosaminoglycan hyaluronan, the major ligand of CD44, which is upregulated and undergoes different splice variations in many types of cancer cells. These particles, termed glycosaminoglycan particle nanoclusters or gagomers (GAGs), were self-assembled into ∼500 nm diameter clusters, with zeta-potential values of ∼-70 mV. Flow cytometry analysis provided evidence that, unlike free doxorubicin (DOX), a model chemotherapy, DOX entrapped in the GAGs (DOX-GAGs) accumulated in P-gp-overexpressing human ovarian adenocarcinoma cell line and dramatically decreased cell viability, while drug-free GAGs and the commercially available drug DOXIL (PEGylated liposomal DOX) did not produce therapeutic benefit. Furthermore, by using RNA interference strategy, we showed that DOX-GAGs were able to overcome the P-gp-mediated resistant mechanism of these cells. Most importantly, DOX-GAGs showed a superior therapeutic effect over free DOX in a resistant human ovarian adenocarcinoma mouse xenograft model. Taken together, these results demonstrated that GAGs might serve as an efficient platform for delivery of therapeutic payloads by bypassing P-gp-mediated multidrug resistance.