Transferrin-Conjugated pH-Responsive γ-Cyclodextrin Nanoparticles for Antitumoral Topotecan Delivery

In this study, we developed gamma-cyclodextrin-based multifunctional nanoparticles (NPs) for tumor-targeted therapy. The NPs were self-assembled using a gamma-cyclodextrin (gamma CD) coupled with phenylacetic acid (PA), 2,3-dimethylmaleic anhydride (DMA), poly(ethylene glycol) (PEG), and transferrin (Tf), termed gamma CDP-(DMA/PEG-Tf) NPs. These gamma CDP-(DMA/PEG-Tf) NPs are effective in entrapping topotecan (TPT, as a model antitumor drug) resulting from the ionic interaction between pH-responsive DMA and TPT or the host-guest interaction between gamma CDP and TPT. More importantly, the gamma CDP-(DMA/PEG-Tf) NPs can induce ionic repulsion at an endosomal pH (similar to 6.0) resulting from the chemical detachment of DMA from gamma CDP, which is followed by extensive TPT release. We demonstrated that gamma CDP-(DMA/PEG-Tf) NPs led to a significant increase in cellular uptake and MDA-MB-231 tumor cell death. In vivo animal studies using an MDA-MB-231 tumor xenografted mice model supported the finding that gamma CDP-(DMA/PEG-Tf) NPs are effective carriers of TPT to Tf receptor-positive MDA-MB-231 tumor cells, promoting drug uptake into the tumors through the Tf ligand-mediated endocytic pathway and increasing their toxicity due to DMA-mediated cytosolic TPT delivery.