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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.

No MeSH data available.


Related in: MedlinePlus

Images showing the tumors, histopathology, and tumor apoptosis.Notes: (A) Macroscopic image of a tumor. (B, C) Microscopic characterization of an N1-S1 hepatic tumor. Malignant cells with hyperchromatic nuclei, a high nuclear/cytoplasmic ratio, and poor differentiation, along with hypervascularization and scattered necrotic regions. (D, E) Microscopic analysis of H&E-stained tumor sections reveals two different regions: one containing typical malignant cells and the other containing disrupted cells characterized by missing nuclei, indistinct cell walls, or nuclei without surrounding cell structures. Upon collation with the observations from the fluorescent TUNEL assay, these disrupted cell regions were found to correspond with the regions with high levels of positive fluorescein-12-dUTP incorporation (TUNEL-positive regions).Abbreviations: DAPI, 4′,6-diamidino-2-phenylindole; H&E, hematoxylin and eosin; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling.
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f4-ijn-10-4137: Images showing the tumors, histopathology, and tumor apoptosis.Notes: (A) Macroscopic image of a tumor. (B, C) Microscopic characterization of an N1-S1 hepatic tumor. Malignant cells with hyperchromatic nuclei, a high nuclear/cytoplasmic ratio, and poor differentiation, along with hypervascularization and scattered necrotic regions. (D, E) Microscopic analysis of H&E-stained tumor sections reveals two different regions: one containing typical malignant cells and the other containing disrupted cells characterized by missing nuclei, indistinct cell walls, or nuclei without surrounding cell structures. Upon collation with the observations from the fluorescent TUNEL assay, these disrupted cell regions were found to correspond with the regions with high levels of positive fluorescein-12-dUTP incorporation (TUNEL-positive regions).Abbreviations: DAPI, 4′,6-diamidino-2-phenylindole; H&E, hematoxylin and eosin; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling.

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)

Images showing the tumors, histopathology, and tumor apoptosis.Notes: (A) Macroscopic image of a tumor. (B, C) Microscopic characterization of an N1-S1 hepatic tumor. Malignant cells with hyperchromatic nuclei, a high nuclear/cytoplasmic ratio, and poor differentiation, along with hypervascularization and scattered necrotic regions. (D, E) Microscopic analysis of H&E-stained tumor sections reveals two different regions: one containing typical malignant cells and the other containing disrupted cells characterized by missing nuclei, indistinct cell walls, or nuclei without surrounding cell structures. Upon collation with the observations from the fluorescent TUNEL assay, these disrupted cell regions were found to correspond with the regions with high levels of positive fluorescein-12-dUTP incorporation (TUNEL-positive regions).Abbreviations: DAPI, 4′,6-diamidino-2-phenylindole; H&E, hematoxylin and eosin; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4487238&req=5

f4-ijn-10-4137: Images showing the tumors, histopathology, and tumor apoptosis.Notes: (A) Macroscopic image of a tumor. (B, C) Microscopic characterization of an N1-S1 hepatic tumor. Malignant cells with hyperchromatic nuclei, a high nuclear/cytoplasmic ratio, and poor differentiation, along with hypervascularization and scattered necrotic regions. (D, E) Microscopic analysis of H&E-stained tumor sections reveals two different regions: one containing typical malignant cells and the other containing disrupted cells characterized by missing nuclei, indistinct cell walls, or nuclei without surrounding cell structures. Upon collation with the observations from the fluorescent TUNEL assay, these disrupted cell regions were found to correspond with the regions with high levels of positive fluorescein-12-dUTP incorporation (TUNEL-positive regions).Abbreviations: DAPI, 4′,6-diamidino-2-phenylindole; H&E, hematoxylin and eosin; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling.
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