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Article

Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment

1
Institute of Pharmacy, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
2
Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovský Sq. 2, 162 06 Prague 6, Czech Republic
3
University Clinic for Internal Medicine IV, Hematology/Oncology, Medical Faculty of Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(17), 6029; https://doi.org/10.3390/ijms21176029
Received: 18 July 2020 / Revised: 14 August 2020 / Accepted: 18 August 2020 / Published: 21 August 2020
Stimulus-sensitive polymer drug conjugates based on high molecular weight N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers carrying doxorubicin via a pH-dependent cleavable bond (pHPMA-Dox) were previously shown to be able to overcome multi-drug resistance. Nevertheless, a tumor type dependent differential response was observed. Although an improved and more selective tumor accumulation of pHPMA-Dox is generally achieved due to the enhanced permeability and retention (EPR) effect, little is known about the fate of these conjugates upon entering the tumor tissue, which could explain the different responses. In this study, we compared in vitro and in vivo accumulation and Dox-activation of pHPMA-Dox in three cancer cell line models (1411HP, A2780cis, HT29) and derived xenograft tumors using a near-infrared fluorescence-labeled pHPMA-Dox conjugate. Firstly, cytotoxicity assays using different pH conditions proved a stepwise, pH-dependent increase in cytotoxic activity and revealed comparable sensitivity among the cell lines. Using multispectral fluorescence microscopy, we were able to track the distribution of drug and polymeric carrier simultaneously on cellular and histological levels. Microscopic analyses of cell monolayers confirmed the assumed mechanism of cell internalization of the whole conjugate followed by intracellular cleavage and nuclear accumulation of Dox in all three cell lines. In contrast, intratumoral distribution and drug release in xenograft tumors were completely different and were associated with different tissue substructures and microenvironments analyzed by Azan- and Hypoxisense®-staining. In 1411HP tumors, large vessels and less hypoxic/acidic microenvironments were associated with a pattern resulting from consistent tissue distribution and cellular uptake as whole conjugate followed by intracellular drug release. In A2780cis tumors, an inconsistent pattern of distribution partly resulting from premature drug release was associated with a more hypoxic/acidic microenvironment, compacted tumor tissue with compressed vessels and specific pre-damaged tissue structures. A completely different distribution pattern was observed in HT29 tumors, resulting from high accumulation of polymer in abundant fibrotic structures, with small embedded vessels featuring this tumor type together with pronounced premature drug release due to the strongly hypoxic/acidic microenvironment. In conclusion, the pattern of intratumoral distribution and drug release strongly depends on the tumor substructure and microenvironment and may result in different degrees of therapeutic efficacy. This reflects the pronounced heterogeneity observed in the clinical application of nanomedicines and can be exploited for the future design of such conjugates. View Full-Text
Keywords: HPMA copolymer; polymer drug conjugates; pH-sensitive drug release; tumor microenvironment; chemotherapy resistance HPMA copolymer; polymer drug conjugates; pH-sensitive drug release; tumor microenvironment; chemotherapy resistance
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MDPI and ACS Style

Noack, A.-K.; Lucas, H.; Chytil, P.; Etrych, T.; Mäder, K.; Mueller, T. Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment. Int. J. Mol. Sci. 2020, 21, 6029. https://doi.org/10.3390/ijms21176029

AMA Style

Noack A-K, Lucas H, Chytil P, Etrych T, Mäder K, Mueller T. Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment. International Journal of Molecular Sciences. 2020; 21(17):6029. https://doi.org/10.3390/ijms21176029

Chicago/Turabian Style

Noack, Anne-Kathrin, Henrike Lucas, Petr Chytil, Tomáš Etrych, Karsten Mäder, and Thomas Mueller. 2020. "Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment" International Journal of Molecular Sciences 21, no. 17: 6029. https://doi.org/10.3390/ijms21176029

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