Nanoparticles enter tumours through endothelial cells, gaps or other mechanisms, but how they exit is unclear. The current paradigm states that collapsed tumour lymphatic vessels impair the exit of nanoparticles and lead to enhanced retention. Here we show that nanoparticles exit the tumour through the lymphatic vessels within or surrounding the tumour. The dominant lymphatic exit mechanism depends on the nanoparticle size. Nanoparticles that exit the tumour through the lymphatics are returned to the blood system, allowing them to recirculate and interact with the tumour in another pass. Our results enable us to define a mechanism of nanoparticle delivery to solid tumours alternative to the enhanced permeability and retention effect. We call this mechanism the active transport and retention principle. This delivery principle provides a new framework to engineer nanomedicines for cancer treatment and detection.
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The accompanying code for Figs. 1b–d and 2b–d and Supplementary Fig. 16 can be found at the GitHub repository: https://github.com/luan-matthew/Nanoparticle-and-Tumour-Lymphatic-3D-Image-Analysis. The accompanying code and data for Supplementary Figs. 27–29 can be found at the GitHub repository: https://github.com/luan-matthew/Nanoparticle-Exit-Compartment-Model.
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We thank M. Ganguly, V. Bradaschia, K. Duffin and G. Ossetchkine at the Centre for Phenogenomics for histology and fluorescence imaging. We thank A. Darbandi and D. Holmyard at SickKids hospital for their help in preparing tissue samples for TEM. We thank K. Lau and P. Paroutis at the SickKids Imaging Facility for use of the light-sheet microscope. We thank G. Zheng, J. Chen and J. Bu at the Toronto Nanomedicine Fabrication Centre for use of the ICP-MS instrument, and J. Jonkman at the Advanced Optical Microscopy Facility for the help with and use of the intravital microscope and fluorescence macroscope. We thank B. Kingston, M. Osborne and Y. Zhang for editorial comments. This work was supported by the Canadian Cancer Society (grant 705285-1), the Canadian Institute of Health Research (grants FDN159932 and MOP-1301431), NanoMedicines Innovation Network (2019-T3-01) and the Canadian Research Chairs Program (grant 950-223824). We thank the Natural Sciences and Engineering Research Council of Canada (S.M.M.), Ontario Graduate Scholarship (P.M. and S.M.M.), the Walter Summer Memorial Scholarship (P.M.) and the Faculty of Applied Science & Engineering Graduate Student Endowment Fund (B.S.) for student fellowships and scholarships.
W.C.W.C consults for the Cystic Fibrosis Foundation, Foresite Capital and Merck.
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a, Quantification of 15 nm gold nanoparticles in B16F10 tumours at 1 hr, 4 hr, 12 hr, 24 hr, 48 hr, 72 hr, and 120 hr post-intravenous administration. The amount of nanoparticles in the tumour rises from 0.9%ID to 10.4%ID between 1 hr and 48 hr, but decreases to 5.7%ID after 120hrs post-injection. This decrease shows approximately half of accumulated nanoparticles exit the tumour. The tumour kinetic profile shows three regions: 1. nanoparticle tumour entry is dominant between 1 hr and 48 hr (labelled as Entry), 2. nanoparticle tumour exit is dominant between 48 hr and 72hrs (labelled as Exit), and 3. amount of nanoparticles retained between 72 hr and 120 hr (labelled as Retention). Data points and error bars represent the mean ± s.e.m. Statistical significance between the 48 hr and 120 hr timepoints using a two-tailed unpaired t-test with Welch’s correction. *P < 0.05. Exact P values are as follows: P = 0.0433. NP = nanoparticle. n = 10 mice for 1 hr timepoint; n = 6 mice for 4 hr timepoint; n = 9 mice for the 12 hr timepoint; n = 10 mice for the 24 hr timepoint; n = 8 mice for the 48 hr timepoint; n = 11 mice for the 72 hr timepoint; n = 14 mice for the 120 hr timepoint. b, Three potential mechanisms responsible for nanoparticle exit: 1. Lymphatic vessels inside of the tumour (intratumoural lymphatic vessels), 2. Lymphatic vessels surrounding the tumour (peritumoural lymphatic vessels), 3. Tumour blood vessels. Extended Data Fig. 1b created with BioRender.com.
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Nguyen, L.N.M., Lin, Z.P., Sindhwani, S. et al. The exit of nanoparticles from solid tumours. Nat. Mater. 22, 1261–1272 (2023). https://doi.org/10.1038/s41563-023-01630-0
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