Folate-targeted iron oxide nanoparticles loaded with cisplatin for imaging and therapy in head and neck squamous cell carcinoma (HNSCC).

Abstract

e13110 Background: Cisplatin (DDP) is a widely used anticancer drug but its application has been limited by side effects and drug resistance. We have previously showed that selective delivery of DDP to tumors using novel nanoparticles could significantly enhance antitumor effects with reduced toxicity. As our group has reported that 45% of 105 HNSCC primary tumors were positive for folate receptor (FR) in Head Neck 31:475-81, 2009, we further developed DDP-loaded folate-targeted iron oxide nanoparticle (FA-IO-DDP) for HNSCC imaging and therapy. Methods: HNSCC cell lines were screened for FR expression by Western blot and surface expression was confirmed by FACS. Intracellular platinum (Pt) and Pt-DNA adducts were quantified by ICP-mass spectrometry. MTT assay was used for cytotoxicity test. T2 weighted MRI was used to detect signal changes induced by FA-IO-DDP. Biodistribution of the nanoparticles was studied using nude mice bearing high FR expressing KB3-1 xenograft. Results: Five cell lines expressing surface FR were identified among sixteen cell lines screened. Three cell lines, PCI15B, SQCCY1 and UMSCC11B with high, intermediate, and negative FR expression respectively, were selected for further investigation. FA-IO-DDP showed significantly enhanced cytotoxicity. Intracellular Pt and Pt-DNA adducts were increased in FR-positive PCI15B cells treated with FA-IO-DDP by 4 fold and 3.2 fold, respectively, compared to cells treated with non-targeted IO-DDP. Similar degree of enhanced uptake was observed in SQCCY1 but not in UMSCC11B. A significant change in T2 signal induced by increased internalization of IO in FA-IO-DDP treated PCI15B cells was detected by MRI. In KB3-1 xenograft model, FA-IO-DDP showed 5.4 fold higher accumulation in tumor compared to free DDP. Conclusions: Our study showed that novel FA-IO-DDP targeting FR remarkably enhanced antitumor effects of DDP in FR-positive HNSCC cells by increasing intracellular Pt concentration and Pt-DNA adducts. MRI may be used to monitor DDP delivery by IO nanoparticles in vivo. Ongoing studies are focused on antitumor effect and toxicities of the FA-IO-DDP using nude mice bearing PCI15B, SQCCY1 and UMSCC11B cells.