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Preclinical Imaging and Its Importance in Drug Discovery and Development

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Preclinical Imaging and Its Importance in Drug Discovery and Development Imaging Systems Preclinical Imaging and its Importance in Drug Discovery and Development By Alexandra De Lille Advances in non-invasive, in vivo imaging techniques have raised the use at Caliper Life Sciences of animal models in preclinical R&D to a new level, enabling the underlying biological processes of disease to be revealed and the effects of therapeutic intervention to be monitored. During the preclinical stage of Molecular imaging utilises highly settings, both bioluminescence and research in drug discovery and specific probes and gene reporters fluorescencein vivo imaging are the development, in vitro and in vivo tests to monitor gene expression, most established modalities in the are conducted to ensure safe testing tumour growth and metastasis, preclinical environment. They are in humans prior to the initiation of bacterial and viral infections, relatively inexpensive, yet highly clinical trials. Preclinical research cell homing, and biomarker and sensitive technologies with a flexible employs animal models to facilitate compound biodistribution. The toolbox of reporters and disease- the investigation of human disease hand-in-hand development of specific, targeting probes. and to aid in the development of molecular imaging instrumentation, treatment. The biological relevance transgenic animal models, cells Non-invasive imaging enables the of an animal model is critical to the and probes facilitate this dynamic same animal to be followed over predictive value of clinical outcome. interrogation of molecular pathways time. This principle of longitudinal The recent development of non- in vivo. Therefore, the application studies increases the statistical invasive, in vivo imaging techniques of molecular imaging is key in power of the model significantly, has vastly advanced the sophistication revealing the underlying biological since each animal serves as its of animal models. Non-invasive processes of disease and monitoring own control. Subsequently, this animal imaging delivers fast, therapeutic intervention. practice reduces the number of longitudinal, accurate, real-time and animals needed while providing quantitative assessments of treatment In the clinic, positron emission accurate, whole body, life animal efficacy. The implementation of tomography (PET) and single- and physiologically relevant preclinical imaging enables photon emission computed information. Nonetheless, a single translational medicine, de-risks tomography (SPECT) scanners are imaging modality may not address compound candidates, significantly the primary technologies utilised all biological questions asked shortens ‘time to the clinic’, and to visualise molecular processes in of the model. Multiplexing with lowers costs while maximising humans by means of radioisotopes. various reporters or probes, or the biological understanding. While optical imaging is an emerging combination of molecular and imaging modality in clinical anatomical imaging modalities Molecular Imaging Beyond traditional anatomical imaging modalities, the field of molecular imaging (MI) has developed exponentially over the past decade. Keywords Molecular imaging is a highly sensitive, Preclinical imaging quantitative technique, capable Molecular imaging (MI) of visualising Positron emission biological processes tomography (PET) Figure 1: Brain tumour model expressing non-invasively, a bioluminescent report to track tumour Computed tomography (CT) in living animals. burden and therapeutic effect Images: Caliper Life Sciences 60 Innovations in Pharmaceutical Technology Issue 39 IPT 39 2011.indd 60 25/11/2011 11:14 iptonline.com within a single animal study is Coronal (z=6.5) Sagittal (x=6.3) Figure 2: Co-registered image increasingly prevalent, with each of 5.0 showing accumulation these parameters offering an added of 2-DG750 at MDA-MB231 dimension to the validation of a metastasis sites specific drug or treatment regime. 4.0 Multimodality Imaging 3.0 With MI, we can detect signal with x 106 an extremely high sensitivity but we inherently lack anatomical context. 2.0 MI is commonly complemented Transaxial (= -11.1) by anatomical imaging. Computed 1.0 2-DG750 targeting tomography (CT) or magnetic resonance imaging (MRI) modalities Subject height: 19.8mm Perspective offer excellent spatial resolution Bioluminescence and signal-to-noise characteristics; they also help provide anatomical and organ identification. Many localisation and staging of disease, pre-clinical imaging modalities while MI provides specificity and have cardiac and respiratory gating differentiation of diseased from methods integrated in order to normal tissue. While MRI provides reduce motion artifacts and enhance non-ionising 3D imaging and is image resolution. Lastly, multi- the best technique for soft tissue modality co-registration and data personalised medicine, tailoring resolution, longer acquisition times integration can be challenging if diagnosis and treatment to the and the high Tesla requirement animals are repositioned in between individual patient’s genetic make-up. for high resolution of small modalities or imaging sessions. animals, organs and structures Various software and hardware Imaging can be implemented are relatively costly. Dedicated solutions are available. The mouse at various stages of the drug preclinical microCT instrumentation imaging shuttle from Caliper has development process, and it is may be more readily accessible. built-in fiducial markers compatible important to design an imaging Since CT scanners utilise ionising with the IVIS® Spectrum, Quantum master plan in the early stages. radiation, the cumulative effect FX µCT and many other microCT, In vivo imaging as a whole is a of radiation exposure must be MRI, PET and SPECT scanners from biology-driven practice, in which the carefully considered, especially in diverse vendors. Moreover, the Living disease dictates the animal model longitudinal studies where the total Image® software allows for seamless and the imaging modality. Today, dose may be lethal – the mouse co-registration between the IVIS® it is possible to carry the same LD50/30 (kills 50 per cent within Spectrum and Quantum FX µCT biomarker from in vitro testing all 30 days) is 5-7.6 Gy (1)). DICOM data. Additionally, any the way through to clinical trials, DICOM, TIFF, RAW and VOX and potentially use this same High speed (17 seconds), low dose volumetric data files can be biomarker as a campaign diagnostic (14mGy per scan), high resolution imported to co-register data from or prognostic test. Translation from (10µm) microCT scanners are other 3D modalities. Ultimately, bench to bedside and subsequent now commercially available (for the practice of biology-driven back-translation to the bench is a example, the Quantum µCT and multimodality imaging requires powerful cycle of information- IVIS® SpectrumCT from Caliper access to core imaging facilities. gathering in drug development. Life Sciences). These features Ensuring a smart choice of animal enable longitudinal imaging Translational Imaging models, reporters and imaging for anatomical reference and The primary goal of translational modalities at the earliest preclinical quantification in sensitive disease imaging is to improve the odds time point can reduce time in each models such as tumour models of clinical success and reduce phase of development. Careful and bone remodelling. Short development time and costs. quantitative modelling and acquisition times also permit the Currently, only eight per cent of new de-risking of each NME throughout use of (clinical) contrast agents, molecular entities (NMEs) make it development optimises pipeline facilitating affordable contrast agent to the market at an estimated R&D management and facilitates imaging with uCT for vascularisation, cost of $1.8 billion per NME (2). As a decision-making towards perfusion and cardiac hypertrophy secondary goal, imaging can facilitate abrogating or accelerating trials. Innovations in Pharmaceutical Technology Issue 39 61 IPT 39 2011.indd 61 25/11/2011 11:14 iptonline.com of the isotype. However, it is equally (unbound) antibody signals in the important to assess the stability of blood pool. Alternative targeting the molecule in serum, its primary agents – such as wavelength intended in vivo environment. Serum responsive smart probes that shift proteins affect the physicochemical wavelength upon binding – facilitate properties of the molecule, lowering the differentiation of bound versus their potency. The ability to rapidly unbound probe. screen antibodies directly after circulation in blood is an important The IVIS® Spectrum CT is uniquely step in the therapeutic antibody equipped with a transillumination development decision-making fluorescence imaging module process. Caliper’s LabChip GXII and advanced 3D reconstruction offers a high throughput analytical software algorithms facilitating in technique with very good precision situ tomographic reconstruction and sensitivity. Fluorescently and absolute quantification in labelled mAbs can easily be picomolar concentrations of the analysed directly from blood, bound marker signal. Anatomical providing real-time information on context is quickly rendered by the behaviour of candidate mAbs co-registration with a built-in in blood. There is no need for gel microCT scanner. slabs – electropherograms will give Figure 3: A Hypothetical Example a reading in just seconds from a The hypothetical animal model 2D Cerenkov A good example would be the microfluidic chip. comprises immunocompromised
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