Optical tissue clearing and machine learning can precisely characterize extravasation and blood vessel architecture...

Area of Science:

• Neuroscience
• Pharmacology
• Biomedical Imaging

Background:

• Accurate quantification of drug accumulation in brain tissue is crucial for developing therapeutics for brain disorders.
• Transcardial perfusion is a standard method to assess drug extravasation into the brain by removing intravascular drug fractions.
• The efficiency of transcardial perfusion can be compromised by pathological changes in the tumor microenvironment, a factor often overlooked.

Purpose of the Study:

• To investigate the impact of tumor vasculature on transcardial perfusion efficiency.
• To develop advanced imaging and analysis techniques for precise quantification of drug extravasation in brain tumors.
• To characterize brain tumor angioarchitecture and its correlation with drug extravasation patterns.

Main Methods:

• Utilized 3D deep imaging of optically cleared tumor samples to overcome limitations of traditional perfusion methods.
• Developed two machine learning-based semi-automated image analysis workflows.
• Quantified compound extravasation patterns and tumor angioarchitecture in large 3D datasets.

Main Results:

• Demonstrated that transcardial perfusion is insufficient for removing injected compounds from tumor vasculature, leading to significant overestimation of extravasation compared to healthy vasculature.
• Successfully characterized compound extravasation patterns and tumor angioarchitecture using the developed 3D imaging and machine learning workflows.
• Established a methodology for precise and comprehensive analysis of extravasation in brain tumors.

Conclusions:

• Transcardial perfusion is unreliable for quantifying drug extravasation in brain tumors due to incomplete intravascular washout.
• 3D deep imaging combined with machine learning offers a precise method for analyzing drug extravasation and tumor vasculature.
• This approach enables detailed correlation between extravasation patterns and the heterogeneous features of brain tumor vasculature, advancing therapeutic development.