Spatial heterogeneity of nanomedicine investigated by multiscale imaging of the drug, the nanoparticle and the tumour environment
Open accessAbstract
Genetic and phenotypic tumour heterogeneity is an important cause of therapy resistance. Moreover, non-uniform spatial drug distribution in cancer treatment may cause pseudo-resistance, meaning that a treatment is ineffective because the drug does not reach its target at sufficient concentrations. Together with tumour heterogeneity, non-uniform drug distribution causes "therapy heterogeneity": a spatially heterogeneous treatment effect. Spatial heterogeneity in drug distribution occurs on all scales ranging from interpatient differences to intratumour differences on tissue or cellular scale. Nanomedicine aims to improve the balance between efficacy and safety of drugs by targeting drug-loaded nanoparticles specifically to tumours. Spatial heterogeneity in nanoparticle and payload distribution could be an important factor that limits their efficacy in patients. Therefore, imaging spatial nanoparticle distribution and imaging the tumour environment giving rise to this distribution could help understand (lack of) clinical success of nanomedicine. Imaging the nanoparticle, drug and tumour environment can lead to improvements of new nanotherapies, increase understanding of underlying mechanisms of heterogeneous distribution, facilitate patient selection for nanotherapies and help assess the effect of treatments that aim to reduce heterogeneity in nanoparticle distribution. In this review, we discuss three groups of imaging modalities applied in nanomedicine research: non-invasive clinical imaging methods (nuclear imaging, MRI, CT, ultrasound), optical imaging and mass spectrometry imaging. Because each imaging modality provides information at a different scale and has its own strengths and weaknesses, choosing wisely and combining modalities will lead to a wealth of information that will help bring nanomedicine forward.
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Integrating multimodal imaging will benefit quantitative evaluation of the EPR effect in tumors in humans and suitable animal models, advancing EPR-mediated drug delivery strategies.
“Integrating multimodal imaging will benefit the quantitative evaluation of the EPR effect in tumors both in human and suitable animal models ensuing advancement of EPR-mediated drug delivery strategies [19].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [19]
The Discussion/Conclusion sections on multimodal imaging and clinical translation say that combining imaging modalities can improve characterization of drug and nanoparticle distribution and help develop future nanotherapies in preclinical and clinical research. The paper does not specifically say that this integration will quantitatively evaluate the EPR effect in both human tumours and suitable animal models, so that more specific part is not supported. (LLM, conf=0.82)
Experimental — accuracy not yet measuredSelecting astutely and integrating multiple imaging techniques will deliver sufficient information on therapeutic NPs distribution in tumors.
“Thus, selecting astutely and integrating multiple techniques will deliver sufficient information on therapeutic NPs distribution in tumors [19].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [19]
The Discussion/Conclusion section says that combining imaging techniques will strengthen understanding of nanotherapy heterogeneity and that choosing modalities wisely will lay a foundation for future nanotherapies. It does not establish that doing so will deliver sufficient information about therapeutic nanoparticle distribution in tumours; that guarantee is stronger than the paper's conclusion. Page numbers were not available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDynamic contrast-enhanced CT has been utilized to evaluate intratumoral perfusion, permeability, and aggregation of CT contrast agent-carrying NPs in tumors in mice.
“However, dynamic contrast-enhanced (DCE)CT has been utilized to evaluate the intratumoral perfusion, permeability, and aggregation of CT contrast agent-carrying NPs in tumors in mice [19,132,133].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [19]
The Introduction’s “Imaging the tumour environment” section says DCE-CT has been used in mice to measure intratumoural perfusion, permeability, and accumulation of CT contrast agent-containing nanoparticles. The claim substitutes “aggregation” for “accumulation”; the passage does not establish that DCE-CT evaluated nanoparticle aggregation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDelivered nanodrug was associated with tumor sites higher in macrophages, as well as high stromal regions.
“The delivered nanodrug was associated with tumor sites higher in macrophages, as well as high stromal regions [19,144].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [19]
In “Imaging the tumour environment” (page unavailable), the paper reports that nanoparticles tend to accumulate in tumour-associated macrophages and that increasing their number enhanced liposomal doxorubicin accumulation in a radiation-treated tumour model. It does not report an association between delivered nanodrug and high-stroma tumour regions; its mention of stromal cells concerns a need to study nanoparticle interactions. (LLM, conf=0.85)
Experimental — accuracy not yet measuredBy integration of molecular imaging and bioanalytical techniques, MSI and IMC determined biodistribution of drug and drug metabolites delivered via PLGA-PEG NPs and overlaid this with imaging of AZD2811 in context of TME markers in different PDX animal models.
“By integration of molecular imaging and bioanalytical techniques, MSI and IMC determined the biodistribution of drug and drug metabolites delivered via PLGA-PEG NPs and overlaid this with imaging of AZD2811 in the context of TME markers in different PDX animal models.”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [19]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Multiscale imaging modalities could analyze heterogeneity of nanodrugs' spatial distribution in tumors.
“Multiscale imaging modalities could analyze the heterogeneity of the nanodrugs’ spatial distribution in the tumors [19].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [19]
BLI is used to assess nanodrug efficiency based on endogenic luminescence of tumors to confirm NPs diagnostics or theranostic prospects and to integrate with other imaging modalities.
“BLI is used to assess nanodrug efficiency based on the endogenic luminescence of tumors to confirm NPs diagnostics or theranostic prospects and to integrate with other imaging modalities [19,134,135,136].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [19]
Combination of imaging data from multimodal hybrid methods provides a prospect to integrate information related to NP distribution and TME on multiple scales.
“The combination of imaging data collected from multimodal hybrid methods provides a prospect to integrate information related to NP distribution and TME on multiple scales [19].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [19]
Hybridization of MSI and imaging mass cytometry with immunohistochemistry and fluorescence in situ hybridization allowed monitoring of drug levels within tumor regions.
“The hybridization of MSI and imaging mass cytometry (IMC) with immunohistochemistry and fluorescence in situ (hybridization) allowed the monitoring of drug levels within tumor regions [19].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [19]
Extensive use of intravital microscopy could enhance the opportunity to characterize the TME on tissue and cellular scale to produce nanodrugs with foreseeable and desirable physicochemical and immunological behaviors.
“For this purpose, extensive use of intravital microscopy (IVM) could enhance the opportunity to characterize the TME on tissue and cellular scale to produce nanodrugs with foreseeable and desirable physicochemical and immunological behaviors [19].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [19]
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- Authors
- de Maar, J. S., Sofias, A. M., Porta Siegel, T., Vreeken, R. J., Moonen, C., Bos, C., & Deckers, R.
- Affiliations
- Norwegian University of Science and Technology (NO)
- Janssen (Belgium) (BE)
- Utrecht University (NL)
- Corresponding author
- Deckers, Roel
- Venue
- Theranostics
- Publisher
- Ivyspring International Publisher
- Published
- 2020
- Volume
- 10
- Issue
- 4
- Pages
- 1884-1909
- ISSN
- 1838-7640 (ISSN-L)
- PMC
- PMC6993242
- OpenAlex
- W3004179479
- Cited by
- 71
- References
- 353
- Citations by year
- 2026: 21 · 2025: 13 · 2024: 8 · 2023: 4 · 2022: 12 · 2021: 8 · 2020: 5
- FWCI
- 0.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Theranostics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Universitair Medisch Centrum Utrecht
- Helse Midt-Norge (90284100, 90062100)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- nanomedicine, spatial heterogeneity, tumor heterogeneity, drug distribution, nanoparticle distribution, treatment resistance, pseudoresistance, multiscale imaging, scintigraphy, magnetic resonance imaging, CT, ultrasound, optical imaging, mass spectrometry imaging, tumor microenvironment, nanotherapy, patient selection
- MeSH terms
- Animals, Pharmaceutical Preparations, Environment, Humans, Magnetic Resonance Imaging, Neoplasms, Mass Spectrometry, Tomography, X-Ray Computed, Ultrasonography, Drug Delivery Systems, Patient Selection, Drug Resistance, Neoplasm, Nanomedicine, Mice, Rats, Nanoparticles, Optical Imaging, Multimodal Imaging
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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