<img height="1" width="1" src="https://www.facebook.com/tr?id=1582471781774081&amp;ev=PageView &amp;noscript=1">
  • Menu
  • crown-logo-symbol-1-400x551

Find it Quickly

Get Started

Select the option that best describes what you are looking for

  • Services
  • Models
  • Scientific Information

Search Here For Services

Click Here to Start Over

Search Here For Models

Click Here to Start Over

Search Here For Scientific Information

Click Here to Start Over

In Vitro

Boost oncology drug discovery with XenoBase®, featuring the largest cell line selection and exclusive 3D organoid models. Benefit from OrganoidXplore™ and OmniScreen™ for rapid, in-depth analysis.

Learn More

In Vivo

Enhance drug development with our validated in vivo models, in vitro/ex vivo assays, and in silico modeling. Tailored solutions to optimize your candidates.

Learn More

Tissue

Experience ISO-certified biobanking quality. Access top biospecimens from a global clinical network, annotated by experts for precise research.

Learn More

Biomarkers and Bioanalysis

Leverage our global labs and 150+ scientists for fast, tailored project execution. Benefit from our expertise, cutting-edge tech, and validated workflows for reliable data outcomes.

Learn More

Data Science and Bioinformatics

Harness your data and discover biomarkers with our top bioinformatics expertise. Maximize data value and gain critical insights to accelerate drug discovery and elevate projects.

Learn More

KRAS

Accelerate innovative cancer treatments with our advanced models and precise drug screening for KRAS mutations, efficiently turning insights into clinical breakthroughs.

Learn More

EGFR

Advance translational pharmacology with our diverse pre-clinical models, robust assays, and data science-driven biomarker analysis, multi-omics, and spatial biology.

Learn More

Drug Resistance

Our suite integrates preclinical solutions, bioanalytical read-outs, and multi-omics to uncover drug resistance markers and expedite discovery with our unique four-step strategy.

Learn More

Patient Tissue

Enhance treatments with our human tumor and mouse models, including xenografts and organoids, for accurate cancer biology representation.

Learn More

Bioinformatics

Apply the most appropriate in silico framework to your pharmacology data or historical datasets to elevate your study design and analysis, and to improve your chances of clinical success.

Learn More

Biomarker Analysis

Integrate advanced statistics into your drug development projects to gain significant biological insight into your therapeutic candidate, with our expert team of bioinformaticians.

Learn More

CRISPR/Cas9

Accelerate your discoveries with our reliable CRISPR solutions. Our global CRISPR licenses cover an integrated drug discovery platform for in vitro and in vivo efficacy studies.

Learn More

Genomics

Rely on our experienced genomics services to deliver high quality, interpretable results using highly sensitive PCR-based, real-time PCR, and NGS technologies and advanced data analytics.

Learn More

In Vitro High Content Imaging

Gain more insights into tumor growth and disease progression by leveraging our 2D and 3D fluorescence optical imaging.

Learn More

Mass Spectrometry-based Proteomics

Next-generation ion mobility mass spectrometry (MS)-based proteomics services available globally to help meet your study needs.

Learn More

Ex Vivo Patient Tissue

Gain better insight into the phenotypic response of your therapeutic candidate in organoids and ex vivo patient tissue.

Learn More

Spatial Multi-Omics Analysis

Certified CRO services with NanoString GeoMx Digital Spatial Profiling.

Learn More

Biomarker Discovery

De-risk your drug development with early identification of candidate biomarkers and utilize our biomarker discovery services to optimize clinical trial design.

Learn More

DMPK Services

Rapidly evaluate your molecule’s pharmaceutical and safety properties with our in vivo drug metabolism and pharmacokinetic (DMPK) services to select the most robust drug formulations.

Learn More

Efficacy Testing

Explore how the novel HuGEMM™ and HuCELL™ platforms can assess the efficacy of your molecule and accelerate your immuno-oncology drug discovery programs.

Learn More

Laboratory Services

Employ cutting-edge multi-omics methods to obtain accurate and comprehensive data for optimal data-based decisions.

Learn More

Pharmacology & Bioanalytical Services

Leverage our suite of structural biology services including, recombinant protein expression and protein crystallography, and target validation services including RNAi.

Learn More

Screens

Find the most appropriate screen to accelerate your drug development: discover in vivo screens with MuScreen™ and in vitro cell line screening with OmniScreen™.

Learn More

Toxicology

Carry out safety pharmacology studies as standalone assessments or embedded within our overall toxicological profiling to assess cardiovascular, metabolic and renal/urinary systems.

Learn More

Our Company

Global CRO in California, USA offering preclinical and translational oncology platforms with high-quality in vivo, in vitro, and ex vivo models.

Learn More

Our Purpose

Learn more about the impact we make through our scientific talent, high-quality standards, and innovation.

Learn More

Our Responsibility

We build a sustainable future by supporting employee growth, fostering leadership, and exceeding customer needs. Our values focus on innovation, social responsibility, and community well-being.

Learn More

Meet Our Leadership Team

We build a sustainable future by fostering leadership, employee growth, and exceeding customer needs with innovation and social responsibility.

Learn More

Scientific Advisory Board

Our Scientific Advisory Board of experts shapes our strategy and ensures top scientific standards in research and development.

Learn More

News & Events

Stay updated with Crown Bioscience's latest news, achievements, and announcements. Check our schedule for upcoming events and plan your visit.

Learn More

Career Opportunities

Join us for a fast-paced career addressing life science needs with innovative technologies. Thrive in a respectful, growth-focused environment.

Learn More

Scientific Publications

Access our latest scientific research and peer-reviewed articles. Discover cutting-edge findings and insights driving innovation and excellence in bioscience.

Learn More

Resources

Discover valuable insights and curated materials to support your R&D efforts. Explore the latest trends, innovations, and expertly curated content in bioscience.

Learn More

Blogs

Explore our blogs for the latest insights, research breakthroughs, and industry trends. Stay educated with expert perspectives and in-depth articles driving innovation in bioscience.

Learn More

  • Platforms
  • Target Solutions
  • Technologies
  • Service Types

Preclinical Imaging of Non-Solid Tumors

Imaging leukemia white blood cells from systemic cancer

Imaging leukemia white blood cells from systemic cancerLearn how preclinical imaging helps overcome the particular challenges associated with modeling leukemia and other non-solid tumors.

Preclinical Animal Models in Cancer Research and Drug Development

Preclinical animal models are used in cancer research for two principal reasons. One is to enable us to examine biological models which are physiologically representative of the human condition, and to use these to improve our understanding of the clinical situation.

Models are also used as part of a therapeutic development portfolio. They allow us to establish whether a novel agent reaches its site of action at an achievable concentration for significant antitumor efficacy, without showing unreasonable toxicity.

Conventional Model Types

Subcutaneous cell line models help us assess the therapeutic potential of novel agents. However, with tumors growing as a defined mass on the flank of an animal, they often don’t physiologically represent disease.

PDX models, where tissues are derived from patient samples rather than cell lines, are an improvement and do better recapitulate the clinical morphology of cancer. It is, however, rare to find metastatic involvement when using subcutaneous models [1].

Orthotopic xenograft models, where implanted cells are grown in their respective clinically relevant host tissues, allow for the development of a more representative tumor microenvironment. They also potentially offer a more faithful pattern of disease spread and metastasis.

Systemic Tumor Models

When we look at systemic (or “liquid”) cancers, such as leukemia, growing these as solid tumors has little clinical relevance. Classically, leukemias have been implanted directly into the circulatory blood via tail vein or direct cardiac injection. However, this type of implantation is inherently inconsistent with varied growth and take rates.

More recently, techniques have been developed to allow direct implantation of cells into the bone marrow compartment via direct intratibial or intrafemoral injection. This places leukemic cells in their natural environment and leads to much more consistent engraftment and growth.

Improvements in Recipient Animal Strains

Nude or athymic mice lack functional T cells, but residual immunity in these strains limits their ability to engraft human leukemic cells. Human leukemic engraftment couldn’t really be meaningfully studied in preclinical models until the development of more immunocompromised mouse strains. This includes models such as the non-obese diabetic, severely-compromised immunodeficient (NOD/SCID) mouse which lacks T and B cells [2].

Improved NOD/SCID mouse strains such as the NSG™ and the NOG® mouse have now been developed which lack both natural killer (NK) cell and macrophage activity [3]. The further depletion of immunity in these animals allows more efficient engraftment of human leukemic cells than in conventional NOD/SCID mice [4].

Measuring Disease Burden of Non-Solid Cancers

Even allowing for improvements in implantation, measurement of disease burden in systemic models remains problematic, relying on terminal endpoints such as hind limb paralysis.

FACS analysis can be used with blood sampling or bone marrow puncture. Often however, disease does not show at measurable levels in peripheral blood until late stage. This means that if a researcher waits until disease is at a measurable level before treatment, there is only a very small therapeutic window.

When using bone marrow puncture, disease levels may vary throughout the bone marrow compartment. Therefore, results from bone marrow sampling can be inconsistent and can easily over- or underestimate the level of disease in an animal.

In both of these cases, it should also be noted that it is possible to alter the course of the disease while removing leukemic cells from the animal. This makes it hard to interpret the therapeutic effect of test items in the model.

As disease burden is difficult to measure, animal selection and randomization is challenging. To accommodate for this, larger groups of animals are needed to control for variability throughout the study.

Optical Imaging Technology

Bioluminescent Imaging

One way to address the challenges associated with systemic disease is to utilize optical imaging technology (which we’ve previously reviewed for overall preclinical applications). By implanting luciferase-labeled cells (luc+) orthotopically, we can model disease in a reliable and reproducible manner.

Bioluminescence is a biochemical reaction, where light is emitted when an enzyme is exposed to its substrate. Firefly luciferase, plus its substrate, luciferin, are most often used in optical imaging, though many other luciferases are also available. Usually, the subject is injected with luciferin immediately before imaging begins. When the luciferin reaches luciferase-expressing cells, light is emitted. This is detected and the signal correlated to disease burden.

Using state-of-the-art imaging techniques, we’re able to follow systemic disease throughout study duration, and provide insight into test item effects at an early stage of treatment.

Optical imaging also allows us to track both disease development and spread in individual animals throughout the whole course of a study. The presence and location of disease in animals can be confirmed immediately post implantation, before treatment starts, and at multiple time points over the course of disease development. This means that each animal essentially becomes its own control.

This allows for real time assessment of disease burden, rational randomization of study groups, and smaller group sizes. Imaging data can even be used to determine appropriate time points for FACS sampling if required.

Fluorescent Imaging

In addition to bioluminescent imaging methods, a number of fluorophores have been developed which emit in the near infra-red portion of the spectrum (emission wavelengths >680nm). At these wavelengths in vivo tissue is basically transparent, making these fluorophores ideal for optical imaging at depth.

Fluorophores can be used to label a wide range of agents, such as antibodies and small molecule drugs. This gives us the ability to visualize a range of biological events taking place within a live animal in real time.

Optical Imaging of Leukemia Models

Optical imaging has been used in the development of several elegant leukemia models, allowing the study of multiple aspects of disease. This includes leukemic stem cells and competitive implantation, the spread of systemic disease from a single site of implantation, and therapeutic models to study the effect of novel agents [5,6].

Combining this data with other complementary imaging technologies (e.g. X-Ray, CT, or MRI) allows coregistration of anatomical and biological data enabling a deeper understanding of the mechanisms at play in systemic disease.

Conclusion

Optical imaging allows us to answer a range of biological questions about systemic disease in a rapid, sensitive, reliable, and cost-effective manner:

  • Multiple biological questions can be answered in the same experiment by using a variety of bioluminescent and fluorescent markers.

  • Systemic disease can be followed in real time, in live animals, with the ability to assess disease burden throughout the course of the study.

  • The number of mice needed per study is reduced, with longitudinal follow up of each animal at several time points.

  • The in vivo biodistribution of therapeutics such as antibodies, ADCs, nanoparticles, and small molecules can be visualized.

  • Anatomical reference points can be provided alongside biological data through combination with other imaging modalities.

  • Through combination with more conventional techniques such as FACS analysis, a fully comprehensive data set can be provided.

References

[1] Khanna, Hunter. Modelling metastasis in vivo. Carcinogenesis 2005;26:513–23

[2] Shultz et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. Journal of Immunology 2005;174:6477–89.

[3] Ito et al. NOD/SCID/ gamma (c) null mouse: an excellent recipient mouse model for engraftment of human cells Blood 2002;100:3175–82.

[4] Agliano et al. Human acute leukemia cells injected in NOD/LtSz/IL-2R gamma null mice generate a faster and more efficient disease compared to other NOD/SCID related strains. International Journal of Cancer 2008;123:2222–7.

[5] Pesnel et al. Optical imaging of diseminated leukemia models in mice with near infrared probe conjugated to a monoclonal antibody. PLoS One 2012: 7(1) 10.1371/journal.pone.0030690.

[6] Bomken et al. Lentiviral marking of patient derived acute lymphoblastic leukemic cells allows in vivo tracking of disease progression. Leukemia 2013;27(3):718-21.


Related Posts