Monitoring Response to Anticancer Therapy by Targeting Microbubbles to Tumor Vasculature

Abstract

Purpose: New strategies to detect tumor angiogenesis and monitor response of tumor vasculature to therapy are needed. Contrast ultrasound imaging using microbubbles targeted to tumor endothelium offers a noninvasive method for monitoring and quantifying vascular effects of antitumor therapy.We investigated the use of targeted microbubbles to follow vascular response of therapy in a mouse model of pancreatic adenocarcinoma. Experimental Design: Microbubbles conjugated to monoclonal antibodies were used to image and quantify vascular effects of two different antitumor therapies in s.c. and orthotopic pancreatic tumors in mice. Tumor-bearing mice were treated with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies and/or gemcitabine, and the localization of microbubbles to endoglin (CD105), VEGF receptor 2 (VEGFR2), or VEGF-activated blood vessels (the VEGF-VEGFR complex) was monitored by contrast ultrasound. Results: Targeted microbubbles showed significant enhancement of tumor vasculature when compared with untargeted or control IgG^targeted microbubbles.Video intensity from targeted microbubbles correlated with the level of expression of the target (CD105, VEGFR2, or the VEGF-VEGFR complex) and with microvessel density in tumors under antiangiogenic or cytotoxic therapy. Conclusions: We conclude that targeted microbubbles represent a novel and attractive tool for noninvasive, vascular-targeted molecular imaging of tumor angiogenesis and for monitoring vascular effects specific to antitumor therapy in vivo.

Parametric contrast-enhanced ultrasound as an early predictor of radiation-based therapeutic response for lymph node metastases of nasopharyngeal carcinoma

“…Considering the apparent diffusion coefficient value of DWI and the perfusion parameter, K trans , of DCE-MRI as examples, the aforementioned parameters may allow the possibility to predict an early treatment response and prognosis for chemotherapy and radiotherapy (6,7). The aforementioned image modalities are mainly dependent on contrast agents that may cause an allergic reaction.…”

Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects

“…Recently, nondestructive semiquantitative ultrasound measurements on representative tumor slices were applied to monitor the expression of several antiangiogenic targets during therapy (20). However, long intervals between the subsequent scans (1 h) were necessary to ensure clearance of targeted microbubbles from the marker molecule contrasting with new destructive scan techniques that would allow multitarget scans within short time intervals and for the absolute volumetric quantification of target densities within the entire tumor (21).…”

Molecular Imaging of Tumor Angiogenesis

“…It was found that MJ7/18-conjugated microbubbles bound specifically to endothelial cells but not fibroblasts, while the control mAb-conjugated Av-MBs did not exhibit CD105-specific targeting. After demonstrating the proof-of-principle, a follow-up study was carried out to follow the vascular response of therapy in mouse models of subcutaneous and orthotopic pancreatic adenocarcinoma (Korpanty, Carbon et al 2007). For comprehensive investigation of angiogenesis in tumor-bearing mice treated with anti-VEGF mAbs and/or gemcitabine (a nucleoside analog with known activity against pancreatic adenocarcinoma), the localization of microbubbles targeting CD105, VEGFR-2, or VEGFactivated blood vessels 9the VEGF-VEGFR complex) was monitored by ultrasound (Di Marco, Di Cicilia et al 2010).…”