Liposomal doxorubicin extravasation controlled by phenotype-specific transport properties of tumor microenvironment and vascular barrier
Open accessAbstract
Although nanotherapeutics can be advantageous over free chemotherapy, the benefits of drug vectors can vary from patient to patient based on differences in tumor microenvironments. Although systemic pharmacokinetics (PK) of drugs is considered as the major determinant of its efficacy in clinics, recent clinical and basic research indicates that tumor-based PK can provide better representation of therapeutic efficacy. Here, we have studied the role of the tumor extravascular tissue in the extravasation kinetics of doxorubicin (DOX), delivered by pegylated liposomes (PLD), to murine lung (3LL) and breast (4T1) tumors. We found that phenotypically different 3LL and 4T1 tumors shared the similar systemic PK, but DOX extravasation in the tumor extravascular tissue was substantially different. Liquid chromatography-mass spectrometry (LC-MS) measurements showed that DOX fluorescence imaged by fluorescence microscopy could be used as a marker to study tumor microenvironment PK, providing an excellent match to DOX kinetics in tumor tissues. Our results also suggest that therapeutic responses can be closely related to the interplay of concentration levels and exposure times in extravascular tissue of tumors. Finally, the computational model of capillary drug transport showed that internalization of drug vectors was critical and could lead to 2-3 orders of magnitude more efficient drug delivery into the extravascular tissue, compared to non-internalized localization of drug vectors, and explaining the differences in therapeutic efficacy between the 3LL and 4T1 tumors. These results show that drug transport and partitioning characteristics can be phenotype- and microenvironment-dependent and are highly important in drug delivery and therapeutic efficacy.
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Prior studies suggest that tumor permeability and nanoparticle size are critically important for nanoparticle drug distribution to tumors and resulting anticancer effects.
“This conclusion is consistent with the prior studies suggesting that the tumor permeability as the well as the size of the nanoparticles (including polymeric micelles of different type) are critically important for nanoparticle drug distribution to tumors and the resulting anticancer effects [36–38].”
From Co-delivery of Paclitaxel and Cisplatin in Poly(2-oxazoline) Polymeric Micelles: Implications for Drug Loading, Release, Pharmacokinetics and Outcome of Ovarian and Breast Cancer Treatments (2019) · cites this paper as [37]
The Concluding remarks (page not provided) say that transport properties of the tumor microenvironment and vascular barrier are critical to nanotherapeutic delivery and may help explain efficacy. The Drug transport model section says its model accounts for particle size, but the paper does not establish that nanoparticle size is critically important to tumor distribution or anticancer effects, nor does it examine polymeric micelles. (LLM, conf=0.85)
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- Authors
- Yokoi, K., Chan, D., Kojic, M., Milosevic, M., Engler, D., Matsunami, R., Tanei, T., Saito, Y., Ferrari, M., & Ziemys, A.
- Affiliations
- Houston Methodist (US)
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 217
- Pages
- 293-299
- ISSN
- 0168-3659 (ISSN-L)
- PMC
- PMC4623952
- OpenAlex
- W1790076696
- Cited by
- 36
- References
- 38
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 5 · 2017: 6 · 2016: 4
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Controlled Release (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Houston Methodist Research Institute
- Serbian Ministry of Education and Science (174028)
- National Institutes of Health (U54CA143837, U54CA151668)
- Ernest Cockrell Jr. Distinguished Endowed Chair
- US Department of Defense (W81XWH-09-1-0212)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- doxorubicin, PEGylated liposomes, tumor microenvironment, 4T1 breast tumor, drug partitioning, tumor phenotype, nanotherapeutics, drug delivery
- MeSH terms
- Animals, Antineoplastic Agents, Doxorubicin, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Phenotype, Polyethylene Glycols, Cell Line, Tumor, Tumor Microenvironment
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