Evaluation of Antitumor Activity of Long-Circulating and pH-Sensitive Liposomes Containing Ursolic Acid in Animal Models of Breast Tumor and Gliosarcoma.

Background Ursolic acid (UA) is a triterpene found in different plant species, possessing antitumor activity, which may be a result of its antiangiogenic effect. However, UA has low water solubility, which limits its use because the bioavailability is impaired. To overcome this inconvenience, we developed long-circulating and pH-sensitive liposomes containing ursolic acid (SpHL-UA). We investigated the antiangiogenic effect of free UA and SpHL-UA in murine brain cancer and human breast tumor models by means of determination of the relative tumor volume, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and histopathological analysis. Methods The animals were treated with dimethyl sulfoxide in 0.9% (w/v) NaCl, free UA, long-circulating and pH-sensitive liposomes without drug (SpHL), or SpHL-UA. The animals were submitted to each treatment by intraperitoneal injection for 5 days. The dose of free UA or SpHL-UA was equal to 23 mg/kg. Results Tumor growth inhibition was not observed in human breast tumor-bearing animals. For murine gliosarcoma-bearing animals, a slight tumor growth inhibition was observed in the groups treated with free UA or SpHL-UA (9% and 15%, respectively). No significant change in any of the parameters evaluated by DCE-MRI for both experimental models could be observed. Nevertheless, the evaluation of the mean values of magnetic resonance parameters of human breast tumor-bearing animals showed evidence of a possible antiangiogenic effect induced by SpHL-UA. Histopathological analysis did not present significant change for any treatment. Conclusion SpHL-UA did not show antiangiogenic activity in a gliosarcoma model and seemed to induce an antiangiogenic effect in the human breast tumor model.

Metastatic renal carcinoma: evaluation of antiangiogenic therapy with dynamic contrast-enhanced CT.

PURPOSE: To determine whether tumor perfusion parameters assessed by using dynamic contrast material-enhanced computed tomography (CT) could help predict and detect response in patients receiving antiangiogenic therapy for metastatic renal cell carcinoma. MATERIALS AND METHODS: Institutional ethics committee approval and informed consent were obtained. In two phase-III trials involving 51 patients with metastatic renal cell carcinoma (38 men, 13 women; age range, 30-80 years) receiving antiangiogenic drugs (sorafenib [n = 10], sunitinib [n = 22]), a placebo (n = 12), or interferon alfa (n = 7), serial dynamic contrast-enhanced CT was performed, during 90 seconds before and after injection of 80 mL of iobitridol. Perfusion parameters of a target metastatic tumor (tumor blood flow [TBF], tumor blood volume [TBV], mean transit time, and vascular permeability-surface area product) were calculated. Values before and after treatment were compared by using a Wilcoxon signed rank test, and relative changes in groups were compared by using the Wilcoxon rank sum test. Results were compared with Response Evaluation Criteria in Solid Tumors response and with progression-free and overall survival by using Kaplan-Meier curves. RESULTS: Among patients receiving antiangiogenic drugs, baseline perfusion parameters were higher in responders than in stable patients (TBF = 245.3 vs 119.5 mL/min/100 mL, P = .04; TBV = 15.5 vs 8.2 mL/100 mL, P = .02) but were not significantly predictive of survival. After the first cycle of treatment, there was a significant decrease in TBF (162.5 vs 76.7 mL/min/100 mL, P = .0002) and TBV (9.1 vs 3.9 mL/100 mL, P < .0001) in patients receiving antiangiogenic treatment. CONCLUSION: Renal carcinoma perfusion parameters determined with dynamic contrast-enhanced CT can help predict biologic response to antiangiogenic drugs before beginning therapy and help detect an effect after a single cycle of treatment.

Mapping the zonal organization of tumor perfusion and permeability in a rat glioma model by using dynamic contrast-enhanced synchrotron radiation CT.

PURPOSE: To depict and analyze in vivo the tumor zone organization of C6 gliomas depicted on quantitative parametric maps obtained with dynamic contrast material-enhanced synchrotron radiation computed tomography (CT) in a tightly controlled data-processing protocol. MATERIALS AND METHODS: Animal use was compliant with official French guidelines and was assessed by the local Internal Evaluation Committee for Animal Welfare and Rights. Fifteen Wistar rats with orthotopically implanted gliomas were studied at monochromatic synchrotron radiation CT after receiving a bolus injection of contrast material. The iodine concentration maps were analyzed by using a compartmental model selected from among a package of models. Choice of model and assessment of the relevance of the model were guided by quality criteria. Tissue blood flow (F(T)), tissue blood volume fraction (V(T)), permeability-surface area product (PS), artery-to-tissue delay (D(A-T)), and vascular mean transit time (MTT) maps were obtained. Parametric map findings were compared with histologic findings. Local regions of interest were selected in the contralateral hemisphere and in several tumor structures to characterize the tumor microvasculature. Differences in parameter values between regions were assessed with the Wilcoxon method. RESULTS: Whole-tumor parameters were expressed as means +/- standard errors of the mean: Mean F(T), V(T), PS, and D(A-T) values and MTT were 61.4 mL/min/100 mL +/- 15.3, 2.4% +/- 0.4, 0.37 mL/min/100 mL +/- 0.11, 0.24 second +/- 0.06; and 3.9 seconds +/- 0.83, respectively. MTT and mean PS were significantly lower (P < .01) in the normal contralateral tissue: 1.10 seconds +/- 0.06 and < or = 10(-5) mL/min/100 mL, respectively. Tumor regions were characterized by significantly different (P < .05) F(T) and V(T) pairs: 108 mL/min/100 mL and 3.66%, respectively, at the periphery; 45.9 mL/min/100 mL and 1.91%, respectively, in the intermediate zone; 5.1 mL/min/100 mL and 0.42%, respectively, in the center; and 210 mL/min/100 mL and 6.82%, respectively, in the maximal value region. CONCLUSION: Fine mapping of the glioma microcirculation is feasible with dynamic contrast-enhanced synchrotron radiation CT performed with well-controlled analytic protocols. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/2501071929/DC1.