Targeted iron-oxide nanoparticle for photodynamic therapy and imaging of head and neck cancer.
Bottom Line: As expected, both IO-Pc 4 and Fmp-IO-Pc 4 reduced the size of HNSCC xenograft tumors more effectively than free Pc 4.Using a 10-fold lower dose of Pc 4 than that reported in the literature, the targeted Fmp-IO-Pc 4 NPs demonstrated significantly greater inhibition of tumor growth than nontargeted IO-Pc 4 NPs.These results suggest that the delivery of a PDT agent Pc 4 by IO NPs can enhance treatment efficacy and reduce PDT drug dose.
Photodynamic therapy (PDT) is a highly specific anticancer treatment modality for various cancers, particularly for recurrent cancers that no longer respond to conventional anticancer therapies. PDT has been under development for decades, but light-associated toxicity limits its clinical applications. To reduce the toxicity of PDT, we recently developed a targeted nanoparticle (NP) platform that combines a second-generation PDT drug, Pc 4, with a cancer targeting ligand, and iron oxide (IO) NPs. Carboxyl functionalized IO NPs were first conjugated with a fibronectin-mimetic peptide (Fmp), which binds integrin β1. Then the PDT drug Pc 4 was successfully encapsulated into the ligand-conjugated IO NPs to generate Fmp-IO-Pc 4. Our study indicated that both nontargeted IO-Pc 4 and targeted Fmp-IO-Pc 4 NPs accumulated in xenograft tumors with higher concentrations than nonformulated Pc 4. As expected, both IO-Pc 4 and Fmp-IO-Pc 4 reduced the size of HNSCC xenograft tumors more effectively than free Pc 4. Using a 10-fold lower dose of Pc 4 than that reported in the literature, the targeted Fmp-IO-Pc 4 NPs demonstrated significantly greater inhibition of tumor growth than nontargeted IO-Pc 4 NPs. These results suggest that the delivery of a PDT agent Pc 4 by IO NPs can enhance treatment efficacy and reduce PDT drug dose. The targeted IO-Pc 4 NPs have great potential to serve as both a magnetic resonance imaging (MRI) agent and PDT drug in the clinic.
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Mentions: To understand our observation of improved treatment efficacy when using NP-based Pc 4 compared with free Pc 4, the biodistribution of all three drugs was tracked using CRi Maestro imaging system (Caliper/PerkinElmer Life Sciences and Technology, Hopkinton, MA). Mice were given Pc 4, IO-Pc 4, and Fmp-IO-Pc 4 at an equivalent dose of 0.4 mg/kg Pc 4. Both whole-body and organ images of the mice were taken at 4, 24, and 48 h after drug administration. Figure 5A,B,C shows the fluorescence images and measured signals at different time points in different organs including xenografted tumors from the free Pc 4, IO-Pc 4, and Fmp-IO-Pc 4 groups. Figure 5D shows the Pc 4 signals in whole-body images from Pc 4, IO-Pc 4 and FmP-IO-Pc4-treated groups at different time points. As illustrated, the Pc 4 signals from the targeted NP Fmp-IO-Pc 4 group were slightly higher in tumors than those from the nontargeted NP IO-Pc 4 group at 4 and 48 h after drug injection. Both Fmp-IO-Pc 4 and IO-Pc 4 had significantly higher tumor retention than free Pc 4 (p < 0.05 in both cases) at 4, 24, and 48 h. Both IO Pc 4 NPs also showed a higher level of Pc 4 biodistribution in all major organs than free Pc 4 at 4 h, but the Pc 4 level in most of the organs except the skin was largely reduced after 48 h. Meanwhile, after 24 or 48 h, both IO-Pc 4 and Fmp-IO-Pc 4 maintained similar fluorescence signals as free Pc 4 in various organs, indicating that there is no prolonged NP drug retention in major organs compared to free Pc 4.