# Article Review: Exploring the landscape of current in vitro and in vivo models and their relevance for targeted radionuclide theranostics

# 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. ![](https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00259-025-07123-3/MediaObjects/259_2025_7123_Fig4_HTML.png)

# Results
- 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. ![](https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00259-025-07123-3/MediaObjects/259_2025_7123_Fig2_HTML.png)
- **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.

# Discussions
- 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). ![](https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00259-025-07123-3/MediaObjects/259_2025_7123_Fig3_HTML.png)
- **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.

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Reference: [Exploring the landscape of current in vitro and in vivo models and their relevance for targeted radionuclide theranostics](https://link.springer.com/article/10.1007/s00259-025-07123-3)