Shaping Tumor Targeting: How Nanoparticle Morphology Influences Penetration and Accumulation in 3D Breast Cancer Models
Abstract
Efficient nanomedicine delivery to solid tumors requires both tissue penetration and cellular accumulation, yet how nanocarrier architecture governs these processes remains poorly understood. Here, molecular polymer brushes spanning hydrodynamic radii (Rh) of 10–45 nm and aspect ratios of 1.2–8.1, with identical polysarcosine surface chemistry, are used to investigate transport in two extracellular matrix (ECM)-embedded breast cancer tumoroids: BT549 and MDA-MB-468 cells, separately. Passive transport reveals tumor entry as a major 2 barrier, while diffusion inside the tumoroid depends much less on particle morphology. While all particles enter the tumor spheroids, the smallest, near-spherical PeptoBrush (PB50, Rh = 10 nm) is the most efficient architecture for tumor penetration, which underlines that in an orientation of worm-like PeptoBrushes does not occur at the matrix tumor interphase under the experimental conditions. Functionalization of PB50 with an average of two cetuximab molecules strongly enhances EGFR-mediated tumor-cell association and accumulation while preserving deep tissue penetration. Time-resolved imaging reveals initial peripheral enrichment followed by progressive penetration toward the tumoroid core, consistent with a transient binding-site barrier. These findings distinguish two complementary determinants of intratumoral distribution in the extracellular matrix tumoroid model: nanocarrier morphology governs passive penetration, whereas antibody-mediated recognition drives cellular binding and tumoroid accumulation.
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BibTeX
@misc{zhao2026shaping,
title = {{Shaping Tumor Targeting: How Nanoparticle Morphology Influences Penetration and Accumulation in 3D Breast Cancer Models}},
author = {Bonan Zhao and Michiel van Dijk and Anne van Gelder and Christine Seidl and Lin Jian and Kaloian Koynov and Rüdiger Berger and Lu Su and Erik H.J. Danen and Matthias Barz},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009201/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009201/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Shaping Tumor Targeting: How Nanoparticle Morphology Influences Penetration and Accumulation in 3D Breast Cancer Models
AU - Bonan Zhao
AU - Michiel van Dijk
AU - Anne van Gelder
AU - Christine Seidl
AU - Lin Jian
AU - Kaloian Koynov
AU - Rüdiger Berger
AU - Lu Su
AU - Erik H.J. Danen
AU - Matthias Barz
PY - 2026
DA - 2026/09/21
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009201/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009201/v1
AB - Efficient nanomedicine delivery to solid tumors requires both tissue penetration and cellular accumulation, yet how nanocarrier architecture governs these processes remains poorly understood. Here, molecular polymer brushes spanning hydrodynamic radii (Rh) of 10–45 nm and aspect ratios of 1.2–8.1, with identical polysarcosine surface chemistry, are used to investigate transport in two extracellular matrix (ECM)-embedded breast cancer tumoroids: BT549 and MDA-MB-468 cells, separately. Passive transport reveals tumor entry as a major 2 barrier, while diffusion inside the tumoroid depends much less on particle morphology. While all particles enter the tumor spheroids, the smallest, near-spherical PeptoBrush (PB50, Rh = 10 nm) is the most efficient architecture for tumor penetration, which underlines that in an orientation of worm-like PeptoBrushes does not occur at the matrix tumor interphase under the experimental conditions. Functionalization of PB50 with an average of two cetuximab molecules strongly enhances EGFR-mediated tumor-cell association and accumulation while preserving deep tissue penetration. Time-resolved imaging reveals initial peripheral enrichment followed by progressive penetration toward the tumoroid core, consistent with a transient binding-site barrier. These findings distinguish two complementary determinants of intratumoral distribution in the extracellular matrix tumoroid model: nanocarrier morphology governs passive penetration, whereas antibody-mediated recognition drives cellular binding and tumoroid accumulation.
ER -