High efficacy vasopermeability drug candidates identified by screening in an ex ovo chorioallantoic membrane model

Abstract

The use of rodent models to evaluate efficacy during testing is accompanied by significant economic and regulatory hurdles which compound the costs of screening for promising drug candidates. Vasopermeation Enhancement Agents (VEAs) are a new class of biologics that are designed to increase the uptake of cancer therapeutics at the tumor site by modifying vascular permeability in the tumor to increase the therapeutic index of co-administered drugs. To evaluate the efficacy of a panel of VEA clinical candidates, we compared the rodent Miles assay to an equivalent assay in the ex ovo chicken embryo model. Both model systems identified the same candidate (PVL 10) as the most active promoter of vasopermeation in non-tumor tissues. An ex ovo chicken embryo system was utilized to test each candidate VEA in two human tumor models at a range of concentrations. Vasopermeation activity due to VEA was dependent on tumor type, with HEp3 tumors displaying higher levels of vasopermeation than MDA-MB-435. One candidate (PVL 10) proved optimal for HEp3 tumors and another (PVL 2) for MDA-MB-435. The use of the ex ovo chicken embryo model provides a rapid and less costly alternative to the use of rodent models for preclinical screening of drug candidates.

Proteomic Analysis of Chicken Chorioallantoic Membrane (CAM) during Embryonic Development Provides Functional Insight

“…The CAM is a thin translucent extraembryonic membrane that is connected to the embryo through a continuous circulatory system ( Figure 1 ) [ 25 , 26 ]. The CAM vasculature is accessible and can be easily imaged, making it a useful model for evaluation of angiogenesis and for investigating tumorigenesis [ 27 , 28 ]. In addition, the CAM system enables the injection of pharmacological agents into the vasculature and direct assessment of regional responses.…”

“…In addition, the CAM system enables the injection of pharmacological agents into the vasculature and direct assessment of regional responses. Furthermore, its ex ovo format has been utilized to study vascular permeability and vascular leakage [ 27 ]. Moreover, fertilized chicken eggs are readily available, and the embryo grows rapidly, making the CAM model ideal for the growth of human and murine xenografts and large-scale studies that do not trigger animal welfare concerns [ 28 ].…”

“…The impact of compounds (for example, biologics, anticancer agents, gases, and organometallic compounds) on CAM development can be assessed [ 11 ]. In addition, the CAM model has been used to evaluate various drug delivery systems (DDS) [ 13 , 27 ]. Furthermore, CAM has been utilized as a model tissue to evaluate two-photon excitation photodynamic therapy of age-related macular degeneration [ 26 ] and for surgical retina [ 22 ] and neurosurgery research [ 24 ].…”

Exploitation of the chick embryo chorioallantoic membrane (CAM) as a platform for anti-metastatic drug testing

“…However, the complex interactions within the organism are hardly mimicked in 3D co-culture techniques 2 and complementary preclinical tools are needed. Up until now, many successful drug tests were performed on primary nodules of the CAM and confirm utilization of this model as a reliable preclinical model for testing novel therapeutics 17,26,33 . The effect of nanoparticle-based anticancer drugs on ovarian cancer cells in the CAM model has also been reported 18 .…”

Chick Chorioallantoic Membrane as a Patient-Derived Xenograft Model for Uveal Melanoma: Imaging Modalities for Growth and Vascular Evaluation

“…The chick chorioallantoic membrane (CAM) assay has emerged as a suitable and reproducible in vivo model in preclinical cancer research. The CAM is a highly vascularized extraembryonic membrane that is formed by the partial fusing of the chick's chorion and its allantois during embryonal development and is connected to the embryo through a continuous circulatory system [22,30,31]. The embryo is not fully immunocompetent until day 18, which results in it being ideal for tissue grafting during the early development stages [19,32].…”