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MRI-detectable polymeric micelles incorporating platinum anticancer drugs enhance survival in an advanced hepatocellular carcinoma model.

Vinh NQ, Naka S, Cabral H, Murayama H, Kaida S, Kataoka K, Morikawa S, Tani T - Int J Nanomedicine (2015)

Bottom Line: The development of tumor-targeting systems may improve treatment outcomes.Moreover, the micelles did not induce severe adverse reactions and significantly improved survival outcomes in comparison to oxaliplatin or saline controls.Our results suggest that Gd-DTPA/DACHPt-loaded micelles are a promising approach for effective diagnosis and treatment of advanced HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Shiga University of Medical Science, Shiga, Japan.

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most intractable and lethal cancers; most cases are diagnosed at advanced stages with underlying liver dysfunction and are frequently resistant to conventional chemotherapy and radiotherapy. The development of tumor-targeting systems may improve treatment outcomes. Nanomedicine platforms are of particular interest for enhancing chemotherapeutic efficiency, and they include polymeric micelles, which enable targeting of multiple drugs to solid tumors, including imaging and therapeutic agents. This allows concurrent diagnosis, targeting strategy validation, and efficacy assessment. We used polymeric micelles containing the T1-weighted magnetic resonance imaging contrast agent gadolinium-diethylenetriaminpentaacetic acid (Gd-DTPA) and the parent complex of the anticancer drug oxaliplatin [(1,2-diaminocyclohexane)platinum(II) (DACHPt)] for simultaneous imaging and therapy in an orthotopic rat model of HCC. The Gd-DTPA/DACHPt-loaded micelles were injected into the hepatic artery, and magnetic resonance imaging performance and antitumor activity against HCC, as well as adverse drug reactions were assessed. After a single administration, the micelles achieved strong and specific tumor contrast enhancement, induced high levels of tumor apoptosis, and significantly suppressed tumor size and growth. Moreover, the micelles did not induce severe adverse reactions and significantly improved survival outcomes in comparison to oxaliplatin or saline controls. Our results suggest that Gd-DTPA/DACHPt-loaded micelles are a promising approach for effective diagnosis and treatment of advanced HCC.

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Related in: MedlinePlus

Apoptotic area percentages among the tumors at 3 days postinjection were 92.4%±3.4% with the micelles (n=10), 45.3%±20.8% with oxaliplatin (n=10), and 9.65%±5.9% with saline (n=10).Notes: Gd DTPA/DACHPt-loaded micelles induced significant tumor cell death much more efficiently than free oxaliplatin and saline (*P<0.001).Abbreviations: DACHPt, (1,2-diaminocyclohexane)platinum(II); Gd-DTPA, gadolinium-diethylenetriaminpentaacetic acid.
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f5-ijn-10-4137: Apoptotic area percentages among the tumors at 3 days postinjection were 92.4%±3.4% with the micelles (n=10), 45.3%±20.8% with oxaliplatin (n=10), and 9.65%±5.9% with saline (n=10).Notes: Gd DTPA/DACHPt-loaded micelles induced significant tumor cell death much more efficiently than free oxaliplatin and saline (*P<0.001).Abbreviations: DACHPt, (1,2-diaminocyclohexane)platinum(II); Gd-DTPA, gadolinium-diethylenetriaminpentaacetic acid.

Mentions: Three days after injecting the micelles, oxaliplatin, or saline, the microscopic observation of H&E-stained tumor sections revealed two different regions: one comprised typical malignant cells and the other comprised disrupted cells characterized by missing nuclei, indistinct cell walls, or nuclei without surrounding cell structures. Collation with the fluorescent TUNEL assay results showed that these disrupted regions corresponded to regions with high levels of positive fluorescein-12-dUTP incorporation (TUNEL-positive; Figure 4D and E). We observed a significant difference in apoptotic area in tumors treated with the micelles, oxaliplatin, or saline (Figure 5). The mean tumor apoptosis percentages at 3 days postinjection were 92.4%±3.4% with the micelles (n=10), 45.3%±20.8% with oxaliplatin (n=10), and 9.65%±5.9% with saline (n=10). These results clearly showed that Gd DTPA/DACHPt-loaded micelles induced tumor cell death much more efficiently than free oxaliplatin and saline (P<0.001).


MRI-detectable polymeric micelles incorporating platinum anticancer drugs enhance survival in an advanced hepatocellular carcinoma model.

Vinh NQ, Naka S, Cabral H, Murayama H, Kaida S, Kataoka K, Morikawa S, Tani T - Int J Nanomedicine (2015)

Apoptotic area percentages among the tumors at 3 days postinjection were 92.4%±3.4% with the micelles (n=10), 45.3%±20.8% with oxaliplatin (n=10), and 9.65%±5.9% with saline (n=10).Notes: Gd DTPA/DACHPt-loaded micelles induced significant tumor cell death much more efficiently than free oxaliplatin and saline (*P<0.001).Abbreviations: DACHPt, (1,2-diaminocyclohexane)platinum(II); Gd-DTPA, gadolinium-diethylenetriaminpentaacetic acid.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4487238&req=5

f5-ijn-10-4137: Apoptotic area percentages among the tumors at 3 days postinjection were 92.4%±3.4% with the micelles (n=10), 45.3%±20.8% with oxaliplatin (n=10), and 9.65%±5.9% with saline (n=10).Notes: Gd DTPA/DACHPt-loaded micelles induced significant tumor cell death much more efficiently than free oxaliplatin and saline (*P<0.001).Abbreviations: DACHPt, (1,2-diaminocyclohexane)platinum(II); Gd-DTPA, gadolinium-diethylenetriaminpentaacetic acid.
Mentions: Three days after injecting the micelles, oxaliplatin, or saline, the microscopic observation of H&E-stained tumor sections revealed two different regions: one comprised typical malignant cells and the other comprised disrupted cells characterized by missing nuclei, indistinct cell walls, or nuclei without surrounding cell structures. Collation with the fluorescent TUNEL assay results showed that these disrupted regions corresponded to regions with high levels of positive fluorescein-12-dUTP incorporation (TUNEL-positive; Figure 4D and E). We observed a significant difference in apoptotic area in tumors treated with the micelles, oxaliplatin, or saline (Figure 5). The mean tumor apoptosis percentages at 3 days postinjection were 92.4%±3.4% with the micelles (n=10), 45.3%±20.8% with oxaliplatin (n=10), and 9.65%±5.9% with saline (n=10). These results clearly showed that Gd DTPA/DACHPt-loaded micelles induced tumor cell death much more efficiently than free oxaliplatin and saline (P<0.001).

Bottom Line: The development of tumor-targeting systems may improve treatment outcomes.Moreover, the micelles did not induce severe adverse reactions and significantly improved survival outcomes in comparison to oxaliplatin or saline controls.Our results suggest that Gd-DTPA/DACHPt-loaded micelles are a promising approach for effective diagnosis and treatment of advanced HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Shiga University of Medical Science, Shiga, Japan.

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most intractable and lethal cancers; most cases are diagnosed at advanced stages with underlying liver dysfunction and are frequently resistant to conventional chemotherapy and radiotherapy. The development of tumor-targeting systems may improve treatment outcomes. Nanomedicine platforms are of particular interest for enhancing chemotherapeutic efficiency, and they include polymeric micelles, which enable targeting of multiple drugs to solid tumors, including imaging and therapeutic agents. This allows concurrent diagnosis, targeting strategy validation, and efficacy assessment. We used polymeric micelles containing the T1-weighted magnetic resonance imaging contrast agent gadolinium-diethylenetriaminpentaacetic acid (Gd-DTPA) and the parent complex of the anticancer drug oxaliplatin [(1,2-diaminocyclohexane)platinum(II) (DACHPt)] for simultaneous imaging and therapy in an orthotopic rat model of HCC. The Gd-DTPA/DACHPt-loaded micelles were injected into the hepatic artery, and magnetic resonance imaging performance and antitumor activity against HCC, as well as adverse drug reactions were assessed. After a single administration, the micelles achieved strong and specific tumor contrast enhancement, induced high levels of tumor apoptosis, and significantly suppressed tumor size and growth. Moreover, the micelles did not induce severe adverse reactions and significantly improved survival outcomes in comparison to oxaliplatin or saline controls. Our results suggest that Gd-DTPA/DACHPt-loaded micelles are a promising approach for effective diagnosis and treatment of advanced HCC.

No MeSH data available.


Related in: MedlinePlus