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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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Tissue biodistribution of free Pc 4 and both targeted and nontargeted IO-Pc 4 NPs. Drug distribution studies show that Fmp-IO-Pc 4 has a more prolonged existence in xenografted tumors than free Pc 4 and nontargeted IO-Pc 4. Mice were given Pc 4, IO-Pc 4 or Fmp-IO-Pc 4. Mouse whole-body images and organ images were taken 4, 24, and 48 h after drug administration. (A–C) Images of different organs, including the xenograft tumors, and levels of Pc 4 delivered as free Pc 4, IO-Pc 4 and Fmp-IO-Pc 4 at different time points, respectively (images represent 1 out of 3 mice). (D) Levels of Pc 4 delivered as free Pc 4, IO-Pc 4, and Fmp-IO-Pc 4 in tumors at different time points by whole-body imaging. As shown, the targeted nanoparticle Fmp-IO-Pc 4 has a more prolonged retention in tumors than either free Pc4 or the nontargeted nanoparticle IO-Pc 4. (E) Pc4 staining in fixed tumor tissue from the free Pc 4, IO-Pc 4, and Fmp-IO-Pc 4 groups. 4′,6-Diamidino-2-phenylindole (DAPI)was used for nuclear labeling. Greater Pc 4 presence was observed in tumor tissues in Fmp-IO-Pc 4 treated mice than in those treated with IO-Pc 4 or free Pc 4 (images represent 1 out of 3 mice). (F) Tumor sections from 3 mice injected with free Pc 4, IO-Pc 4 and Fmp-IO-Pc 4, respectively. No blue staining was found in tumor cells from free Pc 4 treated mice. Higher numbers of tumor cells with blue staining were observed in tumors from Fmp-IO-Pc4 treated mice than from IO-Pc 4 treated mice.
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fig5: Tissue biodistribution of free Pc 4 and both targeted and nontargeted IO-Pc 4 NPs. Drug distribution studies show that Fmp-IO-Pc 4 has a more prolonged existence in xenografted tumors than free Pc 4 and nontargeted IO-Pc 4. Mice were given Pc 4, IO-Pc 4 or Fmp-IO-Pc 4. Mouse whole-body images and organ images were taken 4, 24, and 48 h after drug administration. (A–C) Images of different organs, including the xenograft tumors, and levels of Pc 4 delivered as free Pc 4, IO-Pc 4 and Fmp-IO-Pc 4 at different time points, respectively (images represent 1 out of 3 mice). (D) Levels of Pc 4 delivered as free Pc 4, IO-Pc 4, and Fmp-IO-Pc 4 in tumors at different time points by whole-body imaging. As shown, the targeted nanoparticle Fmp-IO-Pc 4 has a more prolonged retention in tumors than either free Pc4 or the nontargeted nanoparticle IO-Pc 4. (E) Pc4 staining in fixed tumor tissue from the free Pc 4, IO-Pc 4, and Fmp-IO-Pc 4 groups. 4′,6-Diamidino-2-phenylindole (DAPI)was used for nuclear labeling. Greater Pc 4 presence was observed in tumor tissues in Fmp-IO-Pc 4 treated mice than in those treated with IO-Pc 4 or free Pc 4 (images represent 1 out of 3 mice). (F) Tumor sections from 3 mice injected with free Pc 4, IO-Pc 4 and Fmp-IO-Pc 4, respectively. No blue staining was found in tumor cells from free Pc 4 treated mice. Higher numbers of tumor cells with blue staining were observed in tumors from Fmp-IO-Pc4 treated mice than from IO-Pc 4 treated mice.

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.


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)

Tissue biodistribution of free Pc 4 and both targeted and nontargeted IO-Pc 4 NPs. Drug distribution studies show that Fmp-IO-Pc 4 has a more prolonged existence in xenografted tumors than free Pc 4 and nontargeted IO-Pc 4. Mice were given Pc 4, IO-Pc 4 or Fmp-IO-Pc 4. Mouse whole-body images and organ images were taken 4, 24, and 48 h after drug administration. (A–C) Images of different organs, including the xenograft tumors, and levels of Pc 4 delivered as free Pc 4, IO-Pc 4 and Fmp-IO-Pc 4 at different time points, respectively (images represent 1 out of 3 mice). (D) Levels of Pc 4 delivered as free Pc 4, IO-Pc 4, and Fmp-IO-Pc 4 in tumors at different time points by whole-body imaging. As shown, the targeted nanoparticle Fmp-IO-Pc 4 has a more prolonged retention in tumors than either free Pc4 or the nontargeted nanoparticle IO-Pc 4. (E) Pc4 staining in fixed tumor tissue from the free Pc 4, IO-Pc 4, and Fmp-IO-Pc 4 groups. 4′,6-Diamidino-2-phenylindole (DAPI)was used for nuclear labeling. Greater Pc 4 presence was observed in tumor tissues in Fmp-IO-Pc 4 treated mice than in those treated with IO-Pc 4 or free Pc 4 (images represent 1 out of 3 mice). (F) Tumor sections from 3 mice injected with free Pc 4, IO-Pc 4 and Fmp-IO-Pc 4, respectively. No blue staining was found in tumor cells from free Pc 4 treated mice. Higher numbers of tumor cells with blue staining were observed in tumors from Fmp-IO-Pc4 treated mice than from IO-Pc 4 treated mice.
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fig5: Tissue biodistribution of free Pc 4 and both targeted and nontargeted IO-Pc 4 NPs. Drug distribution studies show that Fmp-IO-Pc 4 has a more prolonged existence in xenografted tumors than free Pc 4 and nontargeted IO-Pc 4. Mice were given Pc 4, IO-Pc 4 or Fmp-IO-Pc 4. Mouse whole-body images and organ images were taken 4, 24, and 48 h after drug administration. (A–C) Images of different organs, including the xenograft tumors, and levels of Pc 4 delivered as free Pc 4, IO-Pc 4 and Fmp-IO-Pc 4 at different time points, respectively (images represent 1 out of 3 mice). (D) Levels of Pc 4 delivered as free Pc 4, IO-Pc 4, and Fmp-IO-Pc 4 in tumors at different time points by whole-body imaging. As shown, the targeted nanoparticle Fmp-IO-Pc 4 has a more prolonged retention in tumors than either free Pc4 or the nontargeted nanoparticle IO-Pc 4. (E) Pc4 staining in fixed tumor tissue from the free Pc 4, IO-Pc 4, and Fmp-IO-Pc 4 groups. 4′,6-Diamidino-2-phenylindole (DAPI)was used for nuclear labeling. Greater Pc 4 presence was observed in tumor tissues in Fmp-IO-Pc 4 treated mice than in those treated with IO-Pc 4 or free Pc 4 (images represent 1 out of 3 mice). (F) Tumor sections from 3 mice injected with free Pc 4, IO-Pc 4 and Fmp-IO-Pc 4, respectively. No blue staining was found in tumor cells from free Pc 4 treated mice. Higher numbers of tumor cells with blue staining were observed in tumors from Fmp-IO-Pc4 treated mice than from IO-Pc 4 treated mice.
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.

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