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Effect of cellular and microenvironmental multidrug resistance on tumor-targeted drug delivery in triple-negative breast cancer
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SYSNO ASEP 0567637 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Effect of cellular and microenvironmental multidrug resistance on tumor-targeted drug delivery in triple-negative breast cancer Author(s) Tezcan, O. (DE)
Elshafei, A. S. (DE)
Benderski, K. (DE)
Rama, E. (DE)
Wagner, M. (DE)
Moeckel, D. (DE)
Pola, Robert (UMCH-V) RID, ORCID
Pechar, Michal (UMCH-V) RID, ORCID
Etrych, Tomáš (UMCH-V) RID, ORCID
von Stillfried, S. (DE)
Kiessling, F. (DE)
Weiskirchen, R. (DE)
Meurer, S. (DE)
Lammers, T. (DE)Source Title Journal of Controlled Release. - : Elsevier - ISSN 0168-3659
Roč. 354, February (2023), s. 784-793Number of pages 10 s. Language eng - English Country NL - Netherlands Keywords nanomedicine ; drug targeting ; EPR effect Subject RIV CD - Macromolecular Chemistry OECD category Polymer science R&D Projects LTAUSA18083 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA22-12483S GA ČR - Czech Science Foundation (CSF) Method of publishing Limited access Institutional support UMCH-V - RVO:61389013 UT WOS 000961158400001 EID SCOPUS 85147190710 DOI 10.1016/j.jconrel.2022.12.056 Annotation Multidrug resistance (MDR) reduces the efficacy of chemotherapy. Besides inducing the expression of drug efflux pumps, chemotherapy treatment alters the composition of the tumor microenvironment (TME), thereby potentially limiting tumor-directed drug delivery. To study the impact of MDR signaling in cancer cells on TME remodeling and nanomedicine delivery, we generated multidrug-resistant 4T1 triple-negative breast cancer (TNBC) cells by exposing sensitive 4T1 cells to gradually increasing doxorubicin concentrations. In 2D and 3D cell cultures, resistant 4T1 cells are presented with a more mesenchymal phenotype and produced increased amounts of collagen. While sensitive and resistant 4T1 cells showed similar tumor growth kinetics in vivo, the TME of resistant tumors was enriched in collagen and fibronectin. Vascular perfusion was also significantly increased. Fluorophore-labeled polymeric (∼10 nm) and liposomal (∼100 nm) drug carriers were administered to mice with resistant and sensitive tumors. Their tumor accumulation and penetration were studied using multimodal and multiscale optical imaging. At the whole tumor level, polymers accumulate more efficiently in resistant than in sensitive tumors. For liposomes, the trend was similar, but the differences in tumor accumulation were insignificant. At the individual blood vessel level, both polymers and liposomes were less able to extravasate out of the vasculature and penetrate the interstitium in resistant tumors. In a final in vivo efficacy study, we observed a stronger inhibitory effect of cellular and microenvironmental MDR on liposomal doxorubicin performance than free doxorubicin. These results exemplify that besides classical cellular MDR, microenvironmental drug resistance features should be considered when aiming to target and treat multidrug-resistant tumors more efficiently. Workplace Institute of Macromolecular Chemistry Contact Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358 Year of Publishing 2024 Electronic address https://www.sciencedirect.com/science/article/pii/S0168365922008707?via%3Dihub
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