Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment
Open accessAbstract
Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100–300 nm in diameter). An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents. Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment. One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined. The microenvironment was modulated: ( i ) spatially, by growing tumors in subcutaneous or cranial locations and ( ii ) temporally, by inducing vascular regression in hormone-dependent tumors. Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 1.2 μm. This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal. Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm. Albumin permeability was independent of pore cutoff size. These results have three major implications for the delivery of therapeutic agents: ( i ) delivery may be less efficient in cranial tumors than in subcutaneous tumors, ( ii ) delivery may be reduced during tumor regression induced by hormonal ablation, and ( iii ) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.
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The TRPV4 stimulation system offers a highly tunable system for modeling cancers with variable levels of vascular leakiness.
“to o ff er a highly tunable system for modeling cancers with variable levels of vascular leakiness. 7”
From Rapid Assessment of Nanoparticle Extravasation in a Microfluidic Tumor Model (2019) · cites this paper as [7]
Cites
Angiogenesis in cancer, vascular, rheumatoid and other disease
Folkman, J. (1995) · Nature Medicine · doi:10.1038/nm0195-27 · Cited by 7,627 · see citing works
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Angiogenesis in cancer and other diseases
Carmeliet, P., & Jain, R. K. (2000) · Nature · doi:10.1038/35025220 · Cited by 9,070 · see citing works
Self-citationNanocarriers as an emerging platform for cancer therapy
Peer, D., Karp, J. M., Hong, S., Farokhzad, O. C., Margalit, R., & Langer, R. (2007) · Nature Nanotechnology · doi:10.1038/nnano.2007.387 · Cited by 8,710 · see citing works
Principles of nanoparticle design for overcoming biological barriers to drug delivery
Blanco, E., Shen, H., & Ferrari, M. (2015) · Nature Biotechnology · doi:10.1038/nbt.3330 · Cited by 7,002 · see citing works
Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy
Jain, R. K. (2005) · Science · doi:10.1126/science.1104819 · Cited by 5,527 · see citing works
Self-citationAnalysis of nanoparticle delivery to tumours
Wilhelm, S., Tavares, A. J., Dai, Q., Ohta, S., Audet, J., Dvorak, H. F., & Chan, W. C. W. (2016) · Nature Reviews Materials · doi:10.1038/natrevmats.2016.14 · Cited by 5,218 · see citing works
Factors affecting the clearance and biodistribution of polymeric nanoparticles
Alexis, F., Pridgen, E., Molnar, L. K., & Farokhzad, O. C. (2008) · Molecular Pharmaceutics · doi:10.1021/mp800051m · Cited by 3,699 · see citing works
Drug penetration in solid tumours
Minchinton, A. I., & Tannock, I. F. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1893 · Cited by 2,805 · see citing works
Albumin as a drug carrier: Design of prodrugs, drug conjugates and nanoparticles
Kratz, F. (2008) · Journal of Controlled Release · doi:10.1016/j.jconrel.2008.05.010 · Cited by 2,151 · see citing works
The Effect of Nanoparticle Size on <i>In Vivo</i> Pharmacokinetics and Cellular Interaction
Hoshyar, N., Gray, S., Han, H., & Bao, G. (2016) · Nanomedicine · doi:10.2217/nnm.16.5 · Cited by 1,990 · see citing works
Micellar Nanocarriers: Pharmaceutical Perspectives
Torchilin, V. P. (2006) · Pharmaceutical Research · doi:10.1007/s11095-006-9132-0 · Cited by 1,910 · see citing works
Self-citationThe entry of nanoparticles into solid tumours
Sindhwani, S., Syed, A. M., Ngai, J., Kingston, B. R., Maiorino, L., Rothschild, J., MacMillan, P., Zhang, Y., Rajesh, N. U., Hoang, T., et al. (2020) · Nature Materials · doi:10.1038/s41563-019-0566-2 · Cited by 1,732 · see citing works
Openings Between Defective Endothelial Cells Explain Tumor Vessel Leakiness
Hashizume, H., Baluk, P., Morikawa, S., McLean, J. W., Thurston, G., Roberge, S., Jain, R. K., & McDonald, D. M. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65006-7 · Cited by 1,689 · see citing works
Self-citationNormalization of the Vasculature for Treatment of Cancer and Other Diseases
Goel, S., Duda, D. G., Xu, L., Munn, L. L., Boucher, Y., Fukumura, D., & Jain, R. K. (2011) · Physiological Reviews · doi:10.1152/physrev.00038.2010 · Cited by 1,605 · see citing works
Self-citationAntiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia
Jain, R. K. (2014) · Cancer Cell · doi:10.1016/j.ccell.2014.10.006 · Cited by 1,589 · see citing works
Self-citationNew developments in liposomal drug delivery
Pattni, B. S., Chupin, V. V., & Torchilin, V. P. (2015) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00046 · Cited by 1,600 · see citing works
Self-citationRussell, S. J., Peng, K.-W., & Bell, J. C. (2012) · Nature Biotechnology · doi:10.1038/nbt.2287 · Cited by 1,428 · see citing works
Block copolymer micelles in nanomedicine applications
Cabral, H., Miyata, K., Osada, K., & Kataoka, K. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00199 · Cited by 1,309 · see citing works
Normalizing Tumor Microenvironment to Treat Cancer: Bench to Bedside to Biomarkers
Jain, R. K. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.46.3653 · Cited by 1,248 · see citing works
Self-citationTong, R. T., Boucher, Y., Kozin, S. V., Winkler, F., Hicklin, D. J., & Jain, R. K. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0074 · Cited by 1,189 · see citing works
Self-citationChallenges in Development of Nanoparticle-Based Therapeutics
Desai, N. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9339-4 · Cited by 1,173 · see citing works
Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer
Jacobetz, M. A., Chan, D. S., Neesse, A., Bapiro, T. E., Cook, N., Frese, K. K., Feig, C., Nakagawa, T., Caldwell, M. E., Zecchini, H. I., et al. (2013) · Gut · doi:10.1136/gutjnl-2012-302529 · Cited by 1,120 · see citing works
Chauhan, V. P., Stylianopoulos, T., Martin, J. D., Popović, Z., Chen, O., Kamoun, W. S., Bawendi, M. G., Fukumura, D., & Jain, R. K. (2012) · Nature Nanotechnology · doi:10.1038/nnano.2012.45 · Cited by 1,101 · see citing works
Self-citationAmphiphilic block copolymers for drug delivery
Adams, M. L., Lavasanifar, A., & Kwon, G. S. (2003) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.10397 · Cited by 1,078 · see citing works
The Role of Mechanical Forces in Tumor Growth and Therapy
Jain, R. K., Martin, J. D., & Stylianopoulos, T. (2014) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071813-105259 · Cited by 1,044 · see citing works
Self-citationNanoparticles for Cancer Therapy: Current Progress and Challenges
Gavas, S., Quazi, S., & Karpiński, T. M. (2021) · Nanoscale Research Letters · doi:10.1186/s11671-021-03628-6 · Cited by 1,069 · see citing works
Physical stimuli-responsive polymeric micelles for anti-cancer drug delivery
Rapoport, N. (2007) · Progress in Polymer Science · doi:10.1016/j.progpolymsci.2007.05.009 · Cited by 1,002 · see citing works
Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors
Stylianopoulos, T., Martin, J. D., Chauhan, V. P., Jain, S. R., Diop-Frimpong, B., Bardeesy, N., Smith, B. L., Ferrone, C. R., Hornicek, F. J., Boucher, Y., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1213353109 · Cited by 943 · see citing works
Self-citationDuan, X., & Li, Y. (2013) · Small · doi:10.1002/smll.201201390 · Cited by 926 · see citing works
Nichols, J. W., & Bae, Y. H. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.03.057 · Cited by 834 · see citing works
Advances in polymeric micelles for drug delivery and tumor targeting
Kedar, U., Phutane, P., Shidhaye, S., & Kadam, V. (2010) · Nanomedicine: Nanotechnology, Biology and Medicine · doi:10.1016/j.nano.2010.05.005 · Cited by 791 · see citing works
The role of micelle size in tumor accumulation, penetration, and treatment
Wang, J., Mao, W., Lock, L. L., Tang, J., Sui, M., Sun, W., Cui, H., Xu, D., & Shen, Y. (2015) · ACS Nano · doi:10.1021/acsnano.5b02017 · Cited by 635 · see citing works
Jain, R. K., Tong, R. T., & Munn, L. L. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4102 · Cited by 612 · see citing works
Self-citationRecent Advances in Tumor Targeting via EPR Effect for Cancer Treatment
Subhan, M. A., Yalamarty, S. S. K., Filipczak, N., Parveen, F., & Torchilin, V. P. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11060571 · Cited by 623 · see citing works
Self-citationDelivery of Molecular and Nanoscale Medicine to Tumors: Transport Barriers and Strategies
Chauhan, V. P., Stylianopoulos, T., Boucher, Y., & Jain, R. K. (2011) · Annual Review of Chemical and Biomolecular Engineering · doi:10.1146/annurev-chembioeng-061010-114300 · Cited by 597 · see citing works
Self-citationTumor microenvironment abnormalities: Causes, consequences, and strategies to normalize
Fukumura, D., & Jain, R. K. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21187 · Cited by 584 · see citing works
Self-citationThe biology of brain metastases—translation to new therapies
Eichler, A. F., Chung, E., Kodack, D. P., Loeffler, J. S., Fukumura, D., & Jain, R. K. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2011.58 · Cited by 567 · see citing works
Self-citationAndresen, T. L., Jensen, S. S., & Jørgensen, K. (2005) · Progress in Lipid Research · doi:10.1016/j.plipres.2004.12.001 · Cited by 580 · see citing works
Improving drug delivery to solid tumors: Priming the tumor microenvironment
Khawar, I. A., Kim, J. H., & Kuh, H.-J. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.12.018 · Cited by 533 · see citing works
Combining two strategies to improve perfusion and drug delivery in solid tumors
Stylianopoulos, T., & Jain, R. K. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1318415110 · Cited by 508 · see citing works
Mechanisms of drug release in nanotherapeutic delivery systems
Wong, P. T., & Choi, S. K. (2015) · Chemical Reviews · doi:10.1021/cr5004634 · Cited by 507 · see citing works
Polymeric nanomedicine for cancer therapy
Park, J. H., Lee, S., Kim, J.-H., Park, K., Kim, K., & Kwon, I. C. (2008) · Progress in Polymer Science · doi:10.1016/j.progpolymsci.2007.09.003 · Cited by 506 · see citing works
Multifunctional polymeric micelles for delivery of drugs and siRNA
Jhaveri, A. M., & Torchilin, V. P. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00077 · Cited by 466 · see citing works
Self-citationSemple, S. C., Klimuk, S. K., Harasym, T. O., Dos Santos, N., Ansell, S. M., Wong, K. F., Maurer, N., Stark, H., Cullis, P. R., Hope, M. J., et al. (2001) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/s0005-2736(00)00343-6 · Cited by 454 · see citing works
Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research
Pinto, B., Henriques, A. C., Silva, P. M. A., & Bousbaa, H. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12121186 · Cited by 440 · see citing works
Jain, R. K., Safabakhsh, N., Sckell, A., Chen, Y., Jiang, P., Benjamin, L., Yuan, F., & Keshet, E. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.18.10820 · Cited by 374 · see citing works
Self-citationBioprinting for cancer research
Knowlton, S., Onal, S., Yu, C. H., Zhao, J. J., & Tasoglu, S. (2015) · Trends in Biotechnology · doi:10.1016/j.tibtech.2015.06.007 · Cited by 361 · see citing works
Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease.
Goel, S., Wong, A. H.-K., & Jain, R. K. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006486 · Cited by 352 · see citing works
Self-citationMultifunctional nanoparticles for imaging, delivery and targeting in cancer therapy
Gindy, M. E., & Prud'homme, R. K. (2009) · Expert Opinion on Drug Delivery · doi:10.1517/17425240902932908 · Cited by 298 · see citing works
Ultrasound-responsive systems as components for smart materials
Athanassiadis, A. G., Ma, Z., Moreno-Gomez, N., Melde, K., Choi, E., Goyal, R., & Fischer, P. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00622 · Cited by 293 · see citing works
Dendrimer-Based Drug Delivery Systems for Brain Targeting
Zhu, Y., Liu, C., & Pang, Z. (2019) · Biomolecules · doi:10.3390/biom9120790 · Cited by 220 · see citing works
Phototheranostics: Active Targeting of Orthotopic Glioma Using Biomimetic Proteolipid Nanoparticles
Jia, Y., Wang, X., Hu, D., Wang, P., Liu, Q., Zhang, X., Jiang, J., Liu, X., Sheng, Z., Liu, B., et al. (2019) · ACS Nano · doi:10.1021/acsnano.8b06556 · Cited by 211 · see citing works
Cabral, H., Nishiyama, N., Okazaki, S., Koyama, H., & Kataoka, K. (2005) · Journal of Controlled Release · doi:10.1016/j.jconrel.2004.08.022 · Cited by 201 · see citing works
Role of vascular normalization in benefit from metronomic chemotherapy
Mpekris, F., Baish, J. W., Stylianopoulos, T., & Jain, R. K. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700340114 · Cited by 178 · see citing works
Self-citationIn vivo delivery of RNAi with lipid-based nanoparticles
Huang, L., & Liu, Y. (2011) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071910-124709 · Cited by 174 · see citing works
Poly(Ethylene Glycol)–Polylactide Micelles for Cancer Therapy
Wang, J., Li, S., Han, Y., Guan, J., Chung, S., Wang, C., & Li, D. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00202 · Cited by 155 · see citing works
The Fluid Mechanics of Cancer and Its Therapy
Koumoutsakos, P., Pivkin, I., & Milde, F. (2013) · Annual Review of Fluid Mechanics · doi:10.1146/annurev-fluid-120710-101102 · Cited by 129 · see citing works
Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis
Subhan, M. A., Parveen, F., Filipczak, N., Yalamarty, S. S. K., & Torchilin, V. P. (2023) · Journal of Personalized Medicine · doi:10.3390/jpm13030389 · Cited by 98 · see citing works
Self-citationNanoparticle-based hyperthermia, a local treatment modulating the tumor extracellular matrix
Kolosnjaj-Tabi, J., Marangon, I., Nicolas-Boluda, A., Silva, A. K. A., & Gazeau, F. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.07.010 · Cited by 86 · see citing works
Cavitation properties of block copolymer stabilized phase-shift nanoemulsions used as drug carriers
Rapoport, N., Christensen, D. A., Kennedy, A. M., & Nam, K.-H. (2010) · Ultrasound in Medicine & Biology · doi:10.1016/j.ultrasmedbio.2009.11.009 · Cited by 79 · see citing works
Jin, Y., Liang, X., An, Y., & Dai, Z. (2016) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.6b00603 · Cited by 72 · see citing works
Phan, Q. T., Le, M. H., Le, T. T. H., Tran, T. H. H., Xuan, P. N., & Ha, P. T. (2016) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2016.05.003 · Cited by 68 · see citing works
Vascular microenvironment in gliomas
Vajkoczy, P., & Menger, M. D. (2004) · Cancer Treatment and Research · doi:10.1007/978-1-4419-8871-3_15 · Cited by 62 · see citing works
Improving nanotherapy delivery and action through image-guided systems pharmacology
Ng, T. S. C., Garlin, M. A., Weissleder, R., & Miller, M. A. (2020) · Theranostics · doi:10.7150/thno.37215 · Cited by 60 · see citing works
Gao, H., Chu, C., Cheng, Y., Zhang, Y., Pang, X., Li, D., Wang, X., Ren, E., Xie, F., Bai, Y., et al. (2020) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.0c03873 · Cited by 59 · see citing works
Nanodelivery Systems for Nucleic Acid Therapeutics in Drug Resistant Tumors
Iyer, A. K., Duan, Z., & Amiji, M. M. (2014) · Molecular Pharmaceutics · doi:10.1021/mp500024p · Cited by 55 · see citing works
Han, B., Qu, C., Park, K., Konieczny, S. F., & Korc, M. (2016) · Cancer Letters · doi:10.1016/j.canlet.2015.12.003 · Cited by 53 · see citing works
Rapid Assessment of Nanoparticle Extravasation in a Microfluidic Tumor Model
Vu, M. N., Rajasekhar, P., Poole, D. P., Khor, S. Y., Truong, N. P., Nowell, C. J., Quinn, J. F., Whittaker, M., Veldhuis, N. A., & Davis, T. P. (2019) · ACS Applied Nano Materials · doi:10.1021/acsanm.8b02056 · Cited by 52 · see citing works
Gupta, P. K., Pappuru, S., Gupta, S., Patra, B., Chakraborty, D., & Verma, R. S. (2019) · Materials Science and Engineering: C · doi:10.1016/j.msec.2019.03.041 · Cited by 44 · see citing works
Assessments of antibody biodistribution
Glassman, P. M., Abuqayyas, L., & Balthasar, J. P. (2015) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.365 · Cited by 42 · see citing works
Park, J., Pei, Y., Hyun, H., Castanares, M. A., Collins, D. S., & Yeo, Y. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.10.037 · Cited by 29 · see citing works
Recent Advances in the Development of Magnetic Nanoparticles for Biomedical Applications
Monteserín, M., Larumbe, S., Martínez, A. V., Burgui, S., & Francisco Martín, L. (2021) · Journal of Nanoscience and Nanotechnology · doi:10.1166/jnn.2021.19062 · Cited by 27 · see citing works
Salarvand, A., Shanei, A., Hejazi, S. H., Abedi, I., & Kakhki, N. A. (2025) · Advanced Biomedical Research · doi:10.4103/abr.abr_221_24 · Cited by 5 · see citing works
“[51,52] As a result, Gem‑PEG‑GNPs with a hydrodynamic size of 37.9 nm have low permeability for normal capillaries and cause higher accumulation in tumor due to the EPR effect.”
Influential
- Authors
- Hobbs, S. K., Monsky, W. L., Yuan, F., Roberts, W. G., Griffith, L., Torchilin, V. P., & Jain, R. K.
- Affiliations
- Harvard University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-04-14
- Volume
- 95
- Issue
- 8
- Pages
- 4607-4612
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC22537
- OpenAlex
- W1985858988
- Cited by
- 2,438
- References
- 1
- Citations by year
- 2026: 34 · 2025: 42 · 2024: 68 · 2023: 89 · 2022: 100 · 2021: 91 · 2020: 125 · 2019: 108 · 2018: 121 · 2017: 126 · 2016: 150 · 2015: 139 · 2014: 143 · 2013: 185 · 2012: 140
- FWCI
- 14.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R35CA056591, R35-CA-56591)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- tumor vasculature, tumor microenvironment, albumin permeability, cancer types, intracranial tumors, subcutaneous tumor, tumor regression, hormone withdrawal, basic fibroblast growth factor, gene delivery
- MeSH terms
- Adenocarcinoma, Animals, Colonic Neoplasms, Humans, Liposomes, Male, Microcirculation, Microspheres, Neoplasms, Experimental, Neovascularization, Pathologic, Orchiectomy, Fibroblast Growth Factor 2, Mice
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