Objectives

This narrative review examines currently applied in vitro, ex vivo, and in vivo models for oncological research, focusing on targeted radionuclide theranostics (TRT).
It discusses the advantages and limitations of each model, including 2D and 3D cell cultures (spheroids, organoids, tissue slices), and mouse cancer models (cell line-derived, patient-derived xenograft, humanized models).
It highlights the need for more advanced models in TRT research to better address specific phenomena like crossfire and abscopal effects, enhancing clinical relevance and effectiveness of preclinical evaluations.

Methodology

The review discusses various models without detailing specific engineering methodologies, but implicitly covers the following:
Cell Culture Techniques: 2D cell cultures, 3D cultures (spheroids, organoids, tissue slices), co-cultures, and microfluidic systems. Methods for generating these models (e.g., scaffold-based vs. scaffold-free for spheroids) are mentioned.
Animal Models: Cell line-derived models (subcutaneous and orthotopic), patient-derived xenograft (PDX) models, syngeneic models, genetically engineered mouse models (GEMMs), and humanized mouse models (HMMs). Methods for generating these models (e.g., xenografting, genetic engineering) are discussed.
Imaging Techniques: The review mentions the use of imaging techniques like PET, SPECT, MRI, and bioluminescence imaging to assess tumor growth, radiotracer distribution, and treatment response.

The review primarily summarizes existing literature and does not present new experimental data, but it cites studies with quantitative data supporting the claims about different models. Examples include:
Spheroid Sensitivity: Raitanen et al. showed LNCaP spheroids were 2.4-fold more sensitive to [177Lu]Lu-PSMA-I&T than 2D cultures.
Orthotopic vs. Subcutaneous Models: Zhang et al. showed higher tumor perfusion and [177Lu]Lu-DOTA-SP714 uptake, and lower hypoxia, in orthotopic PC3 tumors compared to subcutaneous tumors.
PDX Success Rate: A study evaluating [177Lu]Lu-EB-RGD in NSCLC PDX models reported successful generation in only 3 out of 8 samples.
Xerostomia in Patients: Almost 39% of patients treated with [177Lu]Lu-PSMA-617 experienced grade 1 or 2 xerostomia.

The review provides a comprehensive overview of preclinical models for TRT, but it could be strengthened by:
More Critical Analysis: While advantages and limitations are listed, a deeper critical analysis of the relative merits of different models for specific TRT research questions would be beneficial. For example, which model is best for studying the bystander effect, and why?
Focus on Quantitative Comparisons: The review could benefit from more quantitative comparisons between models. For example, providing typical ranges of tumor uptake (%ID/g) for different radiotracers in different models.
Addressing Model Validation: The review mentions the importance of validating GMCLs and PDX models, but it could expand on how this validation is best performed (e.g., specific genomic or proteomic analyses).
Discussion of Emerging Technologies: The review could include a brief discussion of emerging technologies that may further improve preclinical models, such as 3D bioprinting or advanced microphysiological systems.