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Targeted iron-oxide nanoparticle for photodynamic therapy and imaging of head and neck cancer.

Wang D, Fei B, Halig LV, Qin X, Hu Z, Xu H, Wang YA, Chen Z, Kim S, Shin DM, Chen ZG - ACS Nano (2014)

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.

View Article: PubMed Central - PubMed

ABSTRACT
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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Inhibition of xenograft tumor formation by Pc 4 PDT delivered by IO nanoparticles. (A–D) Tumor growth and representative images of tumors on both sides of the mice in the PBS control, free Pc 4, IO-Pc 4, and Fmp-IO-Pc4 groups, respectively. Pc 4 was given at a concentration of 0.4 mg/kg. Laser treatment was performed 48 h after the drug administration. Three out of six mice from each group are shown as representatives. Statistical analysis indicated a significant difference in the longitudinal tumor volume across the 5 groups within the right side (laser treated), (p < 0.0013). Both IO-Pc 4 and Fmp-IO-Pc 4 groups had a significantly lower tumor growth volume than the PBS control group (p < 0.022 for IO-Pc 4 and 0.0038 for Fmp-IO-Pc 4). The Pc 4 group had a marginally significantly lower tumor growth volume than the control group (p < 0.071). The Pc 4 group had a significantly higher tumor growth volume than both the IO-Pc 4 and Fmp-IO-Pc 4 groups (p < 0.049 for IO-Pc 4 group and 0.040 for Fmp-IO-Pc 4). No tumor growth difference was found between IO-Pc 4 and Fmp-IO-Pc 4 groups (p = 0.98). There was no significant difference in the longitudinal tumor volume across the 4 groups on the left side tumor (no laser treatment, p = 0.4987). None of the pairwise comparisons in tumor volume between any two groups with untreated left tumors was significantly different (results are omitted). (E) Tumor growth curve using a lower dose (0.06 mg/kg) and shorter period of time between drug administration and laser treatment than used in (A–D). Tumors in the Fmp-IO-Pc 4 (targeted) group grew significantly slower than those in the IO-Pc 4 group (nontargeted) (p < 0.025).
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fig4: Inhibition of xenograft tumor formation by Pc 4 PDT delivered by IO nanoparticles. (A–D) Tumor growth and representative images of tumors on both sides of the mice in the PBS control, free Pc 4, IO-Pc 4, and Fmp-IO-Pc4 groups, respectively. Pc 4 was given at a concentration of 0.4 mg/kg. Laser treatment was performed 48 h after the drug administration. Three out of six mice from each group are shown as representatives. Statistical analysis indicated a significant difference in the longitudinal tumor volume across the 5 groups within the right side (laser treated), (p < 0.0013). Both IO-Pc 4 and Fmp-IO-Pc 4 groups had a significantly lower tumor growth volume than the PBS control group (p < 0.022 for IO-Pc 4 and 0.0038 for Fmp-IO-Pc 4). The Pc 4 group had a marginally significantly lower tumor growth volume than the control group (p < 0.071). The Pc 4 group had a significantly higher tumor growth volume than both the IO-Pc 4 and Fmp-IO-Pc 4 groups (p < 0.049 for IO-Pc 4 group and 0.040 for Fmp-IO-Pc 4). No tumor growth difference was found between IO-Pc 4 and Fmp-IO-Pc 4 groups (p = 0.98). There was no significant difference in the longitudinal tumor volume across the 4 groups on the left side tumor (no laser treatment, p = 0.4987). None of the pairwise comparisons in tumor volume between any two groups with untreated left tumors was significantly different (results are omitted). (E) Tumor growth curve using a lower dose (0.06 mg/kg) and shorter period of time between drug administration and laser treatment than used in (A–D). Tumors in the Fmp-IO-Pc 4 (targeted) group grew significantly slower than those in the IO-Pc 4 group (nontargeted) (p < 0.025).

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).


Targeted iron-oxide nanoparticle for photodynamic therapy and imaging of head and neck cancer.

Wang D, Fei B, Halig LV, Qin X, Hu Z, Xu H, Wang YA, Chen Z, Kim S, Shin DM, Chen ZG - ACS Nano (2014)

Inhibition of xenograft tumor formation by Pc 4 PDT delivered by IO nanoparticles. (A–D) Tumor growth and representative images of tumors on both sides of the mice in the PBS control, free Pc 4, IO-Pc 4, and Fmp-IO-Pc4 groups, respectively. Pc 4 was given at a concentration of 0.4 mg/kg. Laser treatment was performed 48 h after the drug administration. Three out of six mice from each group are shown as representatives. Statistical analysis indicated a significant difference in the longitudinal tumor volume across the 5 groups within the right side (laser treated), (p < 0.0013). Both IO-Pc 4 and Fmp-IO-Pc 4 groups had a significantly lower tumor growth volume than the PBS control group (p < 0.022 for IO-Pc 4 and 0.0038 for Fmp-IO-Pc 4). The Pc 4 group had a marginally significantly lower tumor growth volume than the control group (p < 0.071). The Pc 4 group had a significantly higher tumor growth volume than both the IO-Pc 4 and Fmp-IO-Pc 4 groups (p < 0.049 for IO-Pc 4 group and 0.040 for Fmp-IO-Pc 4). No tumor growth difference was found between IO-Pc 4 and Fmp-IO-Pc 4 groups (p = 0.98). There was no significant difference in the longitudinal tumor volume across the 4 groups on the left side tumor (no laser treatment, p = 0.4987). None of the pairwise comparisons in tumor volume between any two groups with untreated left tumors was significantly different (results are omitted). (E) Tumor growth curve using a lower dose (0.06 mg/kg) and shorter period of time between drug administration and laser treatment than used in (A–D). Tumors in the Fmp-IO-Pc 4 (targeted) group grew significantly slower than those in the IO-Pc 4 group (nontargeted) (p < 0.025).
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fig4: Inhibition of xenograft tumor formation by Pc 4 PDT delivered by IO nanoparticles. (A–D) Tumor growth and representative images of tumors on both sides of the mice in the PBS control, free Pc 4, IO-Pc 4, and Fmp-IO-Pc4 groups, respectively. Pc 4 was given at a concentration of 0.4 mg/kg. Laser treatment was performed 48 h after the drug administration. Three out of six mice from each group are shown as representatives. Statistical analysis indicated a significant difference in the longitudinal tumor volume across the 5 groups within the right side (laser treated), (p < 0.0013). Both IO-Pc 4 and Fmp-IO-Pc 4 groups had a significantly lower tumor growth volume than the PBS control group (p < 0.022 for IO-Pc 4 and 0.0038 for Fmp-IO-Pc 4). The Pc 4 group had a marginally significantly lower tumor growth volume than the control group (p < 0.071). The Pc 4 group had a significantly higher tumor growth volume than both the IO-Pc 4 and Fmp-IO-Pc 4 groups (p < 0.049 for IO-Pc 4 group and 0.040 for Fmp-IO-Pc 4). No tumor growth difference was found between IO-Pc 4 and Fmp-IO-Pc 4 groups (p = 0.98). There was no significant difference in the longitudinal tumor volume across the 4 groups on the left side tumor (no laser treatment, p = 0.4987). None of the pairwise comparisons in tumor volume between any two groups with untreated left tumors was significantly different (results are omitted). (E) Tumor growth curve using a lower dose (0.06 mg/kg) and shorter period of time between drug administration and laser treatment than used in (A–D). Tumors in the Fmp-IO-Pc 4 (targeted) group grew significantly slower than those in the IO-Pc 4 group (nontargeted) (p < 0.025).
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).

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.

View Article: PubMed Central - PubMed

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus