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: In a xenograft tumor animal model study, human HNSCC M4E cells were injected on both sides of each mouse. When tumors reached 5–7 mm in diameter, the mice were randomized into four groups with 6 mice in each group. Each group was given a single equivalent dose of 0.4 mg/kg Pc 4 in the form of free Pc 4, IO-Pc 4, and Fmp-IO-Pc 4 by intravenous (I.V.) injection, accordingly. Mice in the control group were given phosphate-buffered saline (PBS). Laser treatment of the tumors was conducted 48 h after administration of the drugs on the right side tumors only. Left side tumors remained untreated. Tumor size was measured every 2 days. Figure 4A shows that both targeted (Fmp-IO-Pc 4) and nontargeted (IO-Pc 4) NPs significantly reduced tumor growth compared to the PBS control group (p < 0.003 and 0.022, respectively), while free Pc 4 only marginally reduced the tumor size as compared with the PBS control (p < 0.07). IO-Pc 4 and Fmp-IO-Pc 4 treated groups had significantly smaller tumor volume than the free Pc 4 group (p = 0.05 and 0.04, respectively). To rule out any effect of the IO nanoparticles on tumor growth under laser treatment, since IO may be heated up under laser frequency, we performed the same in vivo experiment as described using the same IO concentration as Fmp-IO-Pc 4 (1.35 mg/kg Fe). No significant difference in tumor growth was observed between laser treated and nontreated tumors in the IO group (Supporting Information, Figure S3). There was no significant difference in treatment efficacy between Fmp-IO-Pc 4 and IO-Pc 4 (p = 0.9).