Manipulating anthracyclines for deeper tissue penetration and implications for glycolytic tissues

Abels, E.R.; Linden, E. ter; Rohling, J.H.T.; Voortman, L.M.; Janssen, L.; Hornsveld, M.; Overkleeft, H.S.; Zanden, S.Y. van der; Broekman, M.L.D.; Neefjes, J.J.C.

doi:doi:10.1073/pnas.2510263122

How drugs penetrate tissues is poorly understood yet important, since drugs that fail to reach their target will be ineffective. We followed the fate of anthracycline cancer drugs at high resolution by exploiting their intrinsic fluorescence. In a cell-based spheroid model, the soluble compound fluorescein penetrates the entire spheroid, unlike hydrophobic fluorescent lipids, which only enter the outermost cell layer. Anthracyclines have intermediate hydrophobicity. They enter the nucleus of a few outer cell layers at neutral pH, but penetrate the spheroids more deeply under acidic conditions, with a reduction in cell entry and cytotoxicity. The glycolytic conditions that prevail in the tumor microenvironment may thus limit cell entry and contribute to anthracycline drug resistance. We evaluated a library of anthracycline variants to determine the physicochemical properties related to tissue penetration depth. We find that this is determined by only three chemical properties: molar...Show moreHow drugs penetrate tissues is poorly understood yet important, since drugs that fail to reach their target will be ineffective. We followed the fate of anthracycline cancer drugs at high resolution by exploiting their intrinsic fluorescence. In a cell-based spheroid model, the soluble compound fluorescein penetrates the entire spheroid, unlike hydrophobic fluorescent lipids, which only enter the outermost cell layer. Anthracyclines have intermediate hydrophobicity. They enter the nucleus of a few outer cell layers at neutral pH, but penetrate the spheroids more deeply under acidic conditions, with a reduction in cell entry and cytotoxicity. The glycolytic conditions that prevail in the tumor microenvironment may thus limit cell entry and contribute to anthracycline drug resistance. We evaluated a library of anthracycline variants to determine the physicochemical properties related to tissue penetration depth. We find that this is determined by only three chemical properties: molar refractivity, topological polar surface area, and water solubility. Our findings suggest that modifications of anthracyclines may improve access and activity to deeply tissue-embedded targets such as pancreatic cancer. Significance Anthracyclines including doxorubicin are used by over 1 million cancer patients annually. Various tumors respond to these drugs, while others, such as pancreatic cancer, do not. We used the intrinsic fluorescence properties of these drugs to follow their tissue penetration over time and space. Doxorubicin and the other clinically used anthracyclines show limited tissue penetration at physiological pH. Under acidic glycolytic conditions, the single amine in these drugs is protonated and prevents efficient uptake, causing drug resistance. We used a library of anthracycline variants to identify chemical features that improve tissue penetration. We define modifications in anthracyclines allowing cell entry under glycolytic conditions. The concepts defined here support the design of anthracycline drugs that act at tumors currently inaccessible.Show less

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Manipulating anthracyclines for deeper tissue penetration and implications for glycolytic tissues