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Antibody-mediated targeting of iron oxide nanoparticles to the folate receptor alpha increases tumor cell association in vitro and in vivo.

Ndong C, Toraya-Brown S, Kekalo K, Baker I, Gerngross TU, Fiering SN, Griswold KE - Int J Nanomedicine (2015)

Bottom Line: Here, we describe molecular targeting of iron oxide nanoparticles (IONPs) to the folate receptor alpha (FOLRα) using an engineered antibody fragment (Ffab).Interestingly, Ffab-IONPs built with custom 120 nm nanoparticles exhibited lower in vitro targeting efficiency when compared to those built with commercially sourced 180 nm nanoparticles.In vivo, however, the two Ffab-IONP platforms achieved equivalent tumor homing, although the smaller 120 nm IONPs were more prone to liver sequestration.

View Article: PubMed Central - PubMed

Affiliation: Thayer School of Engineering, Dartmouth, Hanover, NH, USA.

ABSTRACT
Active molecular targeting has become an important aspect of nanoparticle development for oncology indications. Here, we describe molecular targeting of iron oxide nanoparticles (IONPs) to the folate receptor alpha (FOLRα) using an engineered antibody fragment (Ffab). Compared to control nanoparticles targeting the non-relevant botulinum toxin, the Ffab-IONP constructs selectively accumulated on FOLRα-overexpressing cancer cells in vitro, where they exhibited the capacity to internalize into intracellular vesicles. Similarly, Ffab-IONPs homed to FOLRα-positive tumors upon intraperitoneal administration in an orthotopic murine xenograft model of ovarian cancer, whereas negative control particles showed no detectable tumor accumulation. Interestingly, Ffab-IONPs built with custom 120 nm nanoparticles exhibited lower in vitro targeting efficiency when compared to those built with commercially sourced 180 nm nanoparticles. In vivo, however, the two Ffab-IONP platforms achieved equivalent tumor homing, although the smaller 120 nm IONPs were more prone to liver sequestration. Overall, the results show that Ffab-mediated targeting of IONPs yields specific, high-level accumulation within cancer cells, and this fact suggests that Ffab-IONPs could have future utility in ovarian cancer diagnostics and therapy.

No MeSH data available.


Related in: MedlinePlus

Histology of excised tumors from ovarian cancer model.Notes: Representative images where the tumor and peritoneal membrane are indicated. HE of tumor sections from animals treated with (A) PBS, (B) Bfab-BNF, or (C) Ffab-BNF. (D, E, F) Prussian blue staining of the same slides, respectively, to identify IONPs.Abbreviations: HE, hematoxylin eosin; PBS, phosphate-buffered saline; fab, an engineered monoclonal antibody fragment; Ffab, Farletuzufab, engineered from monoclonal antibody Farletuzumab; Bfab, Botulifab anti-botulinum toxin fab fragment; IONPs, iron oxide nanoparticles; BNF, bionized nanoferrite.
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f7-ijn-10-2595: Histology of excised tumors from ovarian cancer model.Notes: Representative images where the tumor and peritoneal membrane are indicated. HE of tumor sections from animals treated with (A) PBS, (B) Bfab-BNF, or (C) Ffab-BNF. (D, E, F) Prussian blue staining of the same slides, respectively, to identify IONPs.Abbreviations: HE, hematoxylin eosin; PBS, phosphate-buffered saline; fab, an engineered monoclonal antibody fragment; Ffab, Farletuzufab, engineered from monoclonal antibody Farletuzumab; Bfab, Botulifab anti-botulinum toxin fab fragment; IONPs, iron oxide nanoparticles; BNF, bionized nanoferrite.

Mentions: Based on the in vitro performance of targeted Ffab-IONPs, we anticipated that these nanoparticle constructs might also exhibit enhanced tumor localization in vivo. To test this hypothesis, a single dose (750 μg of iron) of each IONP was administered intraperitoneally (IP) to NSG mice bearing peritoneal tumors derived from human KB cells. Approximately 18 hours post-injection, tumors, surrounding fat, and other major organs in the abdominal cavity were harvested, and IONP content was quantified by ICP-MS (Figure 6 shows total tissue iron; Figure S5 shows tissue iron concentration). As seen in the in vitro cellular binding studies, the Bfab-CMD and Bfab-BNF negative controls failed to show significant iron accumulation within in vivo tumor masses (Figure 6A). In contrast, Ffab-BNF and Ffab-CMD yielded statistically significant increases in tumor-associated iron (Figure 6A), averaging ~5% or ~7%, respectively, of the initially injected dose. Histology of tissue sections showed the KB tumors to be largely localized on the peritoneal wall (Figure 7A–C), and Prussian blue staining for iron was qualitatively consistent with the ICP-MS analysis, revealing significant iron accumulation on the surface of and within tumors from animals treated with Ffab-BNF (compare Figure 7F to D and E).


Antibody-mediated targeting of iron oxide nanoparticles to the folate receptor alpha increases tumor cell association in vitro and in vivo.

Ndong C, Toraya-Brown S, Kekalo K, Baker I, Gerngross TU, Fiering SN, Griswold KE - Int J Nanomedicine (2015)

Histology of excised tumors from ovarian cancer model.Notes: Representative images where the tumor and peritoneal membrane are indicated. HE of tumor sections from animals treated with (A) PBS, (B) Bfab-BNF, or (C) Ffab-BNF. (D, E, F) Prussian blue staining of the same slides, respectively, to identify IONPs.Abbreviations: HE, hematoxylin eosin; PBS, phosphate-buffered saline; fab, an engineered monoclonal antibody fragment; Ffab, Farletuzufab, engineered from monoclonal antibody Farletuzumab; Bfab, Botulifab anti-botulinum toxin fab fragment; IONPs, iron oxide nanoparticles; BNF, bionized nanoferrite.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4388088&req=5

f7-ijn-10-2595: Histology of excised tumors from ovarian cancer model.Notes: Representative images where the tumor and peritoneal membrane are indicated. HE of tumor sections from animals treated with (A) PBS, (B) Bfab-BNF, or (C) Ffab-BNF. (D, E, F) Prussian blue staining of the same slides, respectively, to identify IONPs.Abbreviations: HE, hematoxylin eosin; PBS, phosphate-buffered saline; fab, an engineered monoclonal antibody fragment; Ffab, Farletuzufab, engineered from monoclonal antibody Farletuzumab; Bfab, Botulifab anti-botulinum toxin fab fragment; IONPs, iron oxide nanoparticles; BNF, bionized nanoferrite.
Mentions: Based on the in vitro performance of targeted Ffab-IONPs, we anticipated that these nanoparticle constructs might also exhibit enhanced tumor localization in vivo. To test this hypothesis, a single dose (750 μg of iron) of each IONP was administered intraperitoneally (IP) to NSG mice bearing peritoneal tumors derived from human KB cells. Approximately 18 hours post-injection, tumors, surrounding fat, and other major organs in the abdominal cavity were harvested, and IONP content was quantified by ICP-MS (Figure 6 shows total tissue iron; Figure S5 shows tissue iron concentration). As seen in the in vitro cellular binding studies, the Bfab-CMD and Bfab-BNF negative controls failed to show significant iron accumulation within in vivo tumor masses (Figure 6A). In contrast, Ffab-BNF and Ffab-CMD yielded statistically significant increases in tumor-associated iron (Figure 6A), averaging ~5% or ~7%, respectively, of the initially injected dose. Histology of tissue sections showed the KB tumors to be largely localized on the peritoneal wall (Figure 7A–C), and Prussian blue staining for iron was qualitatively consistent with the ICP-MS analysis, revealing significant iron accumulation on the surface of and within tumors from animals treated with Ffab-BNF (compare Figure 7F to D and E).

Bottom Line: Here, we describe molecular targeting of iron oxide nanoparticles (IONPs) to the folate receptor alpha (FOLRα) using an engineered antibody fragment (Ffab).Interestingly, Ffab-IONPs built with custom 120 nm nanoparticles exhibited lower in vitro targeting efficiency when compared to those built with commercially sourced 180 nm nanoparticles.In vivo, however, the two Ffab-IONP platforms achieved equivalent tumor homing, although the smaller 120 nm IONPs were more prone to liver sequestration.

View Article: PubMed Central - PubMed

Affiliation: Thayer School of Engineering, Dartmouth, Hanover, NH, USA.

ABSTRACT
Active molecular targeting has become an important aspect of nanoparticle development for oncology indications. Here, we describe molecular targeting of iron oxide nanoparticles (IONPs) to the folate receptor alpha (FOLRα) using an engineered antibody fragment (Ffab). Compared to control nanoparticles targeting the non-relevant botulinum toxin, the Ffab-IONP constructs selectively accumulated on FOLRα-overexpressing cancer cells in vitro, where they exhibited the capacity to internalize into intracellular vesicles. Similarly, Ffab-IONPs homed to FOLRα-positive tumors upon intraperitoneal administration in an orthotopic murine xenograft model of ovarian cancer, whereas negative control particles showed no detectable tumor accumulation. Interestingly, Ffab-IONPs built with custom 120 nm nanoparticles exhibited lower in vitro targeting efficiency when compared to those built with commercially sourced 180 nm nanoparticles. In vivo, however, the two Ffab-IONP platforms achieved equivalent tumor homing, although the smaller 120 nm IONPs were more prone to liver sequestration. Overall, the results show that Ffab-mediated targeting of IONPs yields specific, high-level accumulation within cancer cells, and this fact suggests that Ffab-IONPs could have future utility in ovarian cancer diagnostics and therapy.

No MeSH data available.


Related in: MedlinePlus