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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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MRI performance of Gd-DTPA/DACHPt-loaded micelles in an N1-S1 hepatic tumor (yellow arrow).Notes: (A) T1-GE MRI series after the injection of Gd-DTPA/DACHPt-loaded micelles. The MR images collected at 2 minutes and every 10 minutes after the injection showed that the tumor contrast enhancement remained stable for up to 3 hours. (B) The signal intensity of the tumor increased considerably to a level greater than that of the surrounding liver, whereas the signal intensity of the healthy liver remained near the initial values. (C, E) T1-GE MRI series after the injection of free Gd-DTPA or DACHPt micelles, any enhancement of the contrast was not observed in the tumor. (D, F) The tumor intensities remained lower than that of the healthy liver with both control treatments. A tube containing H2O was set at the upper right as a reference (white arrows).Abbreviations: DACHPt, (1,2-diaminocyclohexane)platinum(II); Gd-DTPA, gadolinium-diethylenetriaminpentaacetic acid; T1-GE MRI, T1-weighted gradient echo magnetic resonance imaging.
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f3-ijn-10-4137: MRI performance of Gd-DTPA/DACHPt-loaded micelles in an N1-S1 hepatic tumor (yellow arrow).Notes: (A) T1-GE MRI series after the injection of Gd-DTPA/DACHPt-loaded micelles. The MR images collected at 2 minutes and every 10 minutes after the injection showed that the tumor contrast enhancement remained stable for up to 3 hours. (B) The signal intensity of the tumor increased considerably to a level greater than that of the surrounding liver, whereas the signal intensity of the healthy liver remained near the initial values. (C, E) T1-GE MRI series after the injection of free Gd-DTPA or DACHPt micelles, any enhancement of the contrast was not observed in the tumor. (D, F) The tumor intensities remained lower than that of the healthy liver with both control treatments. A tube containing H2O was set at the upper right as a reference (white arrows).Abbreviations: DACHPt, (1,2-diaminocyclohexane)platinum(II); Gd-DTPA, gadolinium-diethylenetriaminpentaacetic acid; T1-GE MRI, T1-weighted gradient echo magnetic resonance imaging.

Mentions: The T1-weighted MR images (T1-GE and T1-SE) before the hepatic arterial injection of Gd-DTPA/DACHPt-loaded micelles showed lower signal intensity in the tumor than in the surrounding healthy liver. After injection of Gd-DTPA/DACHPt-loaded micelles (n=9), the signal intensity of the tumor increased considerably to a level greater than that of the surrounding liver on both T1-GE and T1-SE images, whereas the signal intensity of the healthy liver remained near the initial values (Figure 3A and B). Moreover, the MR images collected every 10 minutes showed that the tumor contrast enhancement remained stable for up to 3 hours, thus indicating retention of the micelles in the HCC tissues. Because hydrophilic Gd-DTPA is gradually released from the micelles, the signal began to slowly decrease at 3 hours postinjection, likely matching the discharge and clearance of Gd-DTPA from the tumor. It is worth noting that tumor enhancement was heterogeneous, and darker spots were observed within the tumors, perhaps related to necrotic regions without blood flow. No tumor contrast enhancement was observed with the injection of free Gd-DTPA (n=9) or DACHPt micelles (n=2), and the tumor intensities remained lower than that of the healthy liver with both control treatments (Figure 3C–F). Moreover, the macroscopic observations after MRI acquisition confirmed the tumor positions (Figure 4A), and histology revealed malignant cells with hyperchromatic nuclei, a high nuclear/cytoplasmic ratio, poor differentiation, hypervascularization, and scattered necrotic regions, supporting our hypothesis regarding the darker regions in the micelle-enhanced tumor contrast areas on MRI (Figure 4B and C).


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)

MRI performance of Gd-DTPA/DACHPt-loaded micelles in an N1-S1 hepatic tumor (yellow arrow).Notes: (A) T1-GE MRI series after the injection of Gd-DTPA/DACHPt-loaded micelles. The MR images collected at 2 minutes and every 10 minutes after the injection showed that the tumor contrast enhancement remained stable for up to 3 hours. (B) The signal intensity of the tumor increased considerably to a level greater than that of the surrounding liver, whereas the signal intensity of the healthy liver remained near the initial values. (C, E) T1-GE MRI series after the injection of free Gd-DTPA or DACHPt micelles, any enhancement of the contrast was not observed in the tumor. (D, F) The tumor intensities remained lower than that of the healthy liver with both control treatments. A tube containing H2O was set at the upper right as a reference (white arrows).Abbreviations: DACHPt, (1,2-diaminocyclohexane)platinum(II); Gd-DTPA, gadolinium-diethylenetriaminpentaacetic acid; T1-GE MRI, T1-weighted gradient echo magnetic resonance imaging.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4487238&req=5

f3-ijn-10-4137: MRI performance of Gd-DTPA/DACHPt-loaded micelles in an N1-S1 hepatic tumor (yellow arrow).Notes: (A) T1-GE MRI series after the injection of Gd-DTPA/DACHPt-loaded micelles. The MR images collected at 2 minutes and every 10 minutes after the injection showed that the tumor contrast enhancement remained stable for up to 3 hours. (B) The signal intensity of the tumor increased considerably to a level greater than that of the surrounding liver, whereas the signal intensity of the healthy liver remained near the initial values. (C, E) T1-GE MRI series after the injection of free Gd-DTPA or DACHPt micelles, any enhancement of the contrast was not observed in the tumor. (D, F) The tumor intensities remained lower than that of the healthy liver with both control treatments. A tube containing H2O was set at the upper right as a reference (white arrows).Abbreviations: DACHPt, (1,2-diaminocyclohexane)platinum(II); Gd-DTPA, gadolinium-diethylenetriaminpentaacetic acid; T1-GE MRI, T1-weighted gradient echo magnetic resonance imaging.
Mentions: The T1-weighted MR images (T1-GE and T1-SE) before the hepatic arterial injection of Gd-DTPA/DACHPt-loaded micelles showed lower signal intensity in the tumor than in the surrounding healthy liver. After injection of Gd-DTPA/DACHPt-loaded micelles (n=9), the signal intensity of the tumor increased considerably to a level greater than that of the surrounding liver on both T1-GE and T1-SE images, whereas the signal intensity of the healthy liver remained near the initial values (Figure 3A and B). Moreover, the MR images collected every 10 minutes showed that the tumor contrast enhancement remained stable for up to 3 hours, thus indicating retention of the micelles in the HCC tissues. Because hydrophilic Gd-DTPA is gradually released from the micelles, the signal began to slowly decrease at 3 hours postinjection, likely matching the discharge and clearance of Gd-DTPA from the tumor. It is worth noting that tumor enhancement was heterogeneous, and darker spots were observed within the tumors, perhaps related to necrotic regions without blood flow. No tumor contrast enhancement was observed with the injection of free Gd-DTPA (n=9) or DACHPt micelles (n=2), and the tumor intensities remained lower than that of the healthy liver with both control treatments (Figure 3C–F). Moreover, the macroscopic observations after MRI acquisition confirmed the tumor positions (Figure 4A), and histology revealed malignant cells with hyperchromatic nuclei, a high nuclear/cytoplasmic ratio, poor differentiation, hypervascularization, and scattered necrotic regions, supporting our hypothesis regarding the darker regions in the micelle-enhanced tumor contrast areas on MRI (Figure 4B and C).

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