Development of an embedded multimodality imaging platform for onco-pharmacology using a smart anticancer prodrug as an example

Abstract

Increasingly, in vivo imaging holds a strategic position in bio-pharmaceutical innovation. We will present the implementation of an integrated multimodal imaging setup enabling the assessment of multiple, complementary parameters. The system allows the fusion of information provided by: Near infrared fluorescent biomarkers, bioluminescence (for tumor proliferation status), Photoacoustic and Ultrasound imaging. We will study representative applications to the development of a smart prodrug, delivering a highly cytotoxic chemotherapeutic agent to cancer tumors. The results realized the ability of this embedded, multimodality imaging platform to firstly detect bioluminescent and fluorescent signals, and secondly, record ultrasound and photoacoustic data from the same animal. This study demonstrated that the prodrug was effective in three different models of hypoxia in human cancers compared to the parental cytotoxic agent and the vehicle groups. Monitoring by photoacoustic imaging during the treatments revealed that the prodrug exhibits an intrinsic capability to prevent the progression of tumor hypoxia. it is essential for onco-pharmacology studies to precisely document the hypoxic status of tumors both before and during the time course of treatments. this approach opens new perspectives for exploitation of preclinical mouse models of cancer, especially when considering associations between hypoxia, neoangiogenesis and antitumor activity.

Validation of a combined ultrasound and bioluminescence imaging system with magnetic resonance imaging in orthotopic pancreatic murine tumors

“…Conversely, BLI requires a sealed, light tight enclosure with a non-obstructed path for light propagation between the target and camera. Therefore, dual-mode experiments have thus far required repeated manual repositioning of equipment and/or animal to toggle between US and BLI scanning 12 , which reduces throughput, ease of use, and inter-operator consistency. Recently, a new robotic “bottom-up” US imaging approach was introduced that addresses many of the aforementioned challenges 13 .…”

Encoding of the colorectal cancer metabolic program through MICU2

“…Ultrasound/photoacoustic imaging, bioluminescence imaging, and hypoxia immunostaining The protocols have already been described in detail. 57 Briefly, bioluminescence imaging was performed once a week until the end of the study using an IVIS-Lumina II (Perkin Elmer, France). Each mouse was injected intraperitoneally with 100mg/kg luciferin potassium salt (Promega, France).…”

Combination of Targeted Therapies for Colorectal Cancer Treatment

“…With the aim to overcome ADC limitations, we and others developed β-glucuronidase-responsive albumin-binding prodrugs designed for the selective release of anticancer agents in the tumor microenvironment. − As illustrated with the molecular system 1 (Figure ), these prodrugs bind selectively to serum albumin ,− via the Michael addition to produce the corresponding bioconjugate 2 in the bloodstream. The albumin–conjugate 2 accumulates then in malignant tissues ,− , where extracellular β-glucuronidase − triggers the release of monomethyl auristatin E ( MMAE ) through the self-immolative mechanism depicted in Figure .…”