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Acid-responsive HPMA copolymer-bradykinin conjugate enhances tumor-targeted delivery of nanomedicine
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SYSNO ASEP 0545461 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Acid-responsive HPMA copolymer-bradykinin conjugate enhances tumor-targeted delivery of nanomedicine Author(s) Appiah, E. (JP)
Nakamura, H. (JP)
Pola, Robert (UMCH-V) RID, ORCID
Grosmanová, Eliška (UMCH-V) RID
Lidický, Ondřej (UMCH-V) RID
Kuniyasu, A. (JP)
Etrych, Tomáš (UMCH-V) RID, ORCID
Haratake, M. (JP)Source Title Journal of Controlled Release. - : Elsevier - ISSN 0168-3659
Roč. 337, 10 September (2021), s. 546-556Number of pages 11 s. Language eng - English Country NL - Netherlands Keywords bradykinin ; HPMA polymer ; EPR effect Subject RIV CD - Macromolecular Chemistry OECD category Polymer science R&D Projects GA19-01417S GA ČR - Czech Science Foundation (CSF) Method of publishing Limited access Institutional support UMCH-V - RVO:61389013 UT WOS 000707387900001 EID SCOPUS 85113646633 DOI 10.1016/j.jconrel.2021.08.009 Annotation Obstructed blood flow and erratic blood supply in the tumor region attenuate the distribution and accumulation of nanomedicines in the tumor. Therefore, improvement of these conditions is crucial for efficient drug delivery. In this study, we designed and synthesized a novel N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymer conjugate of BK, which possessed adequate systemic stability and tumor-selective action required to improve the accumulation of nanomedicines in the tumor. Levulinoyl-BK (Lev-BK) was conjugated to an HPMA-based polymer via an acid-cleavable hydrazone bond (P-BK). An acid-responsive release of Lev-BK from P-BK was observed, and P-BK alone after intradermal application showed below 10% of the BK activity, thus proving a reduction in the vascular permeability activity of BK when attached to the polymer carrier. P-BK pre-treatment improved blood flow in the tumor tissue by 1.4–1.7-fold, which was maintained for more than 4 h. In addition, P-BK pre-treatment increased the tumor accumulation of pegylated liposomal doxorubicin (PLD) by approximately 3-fold. Furthermore, P-BK pre-treatment led to superior antitumor activity of PLD and significantly improved the survival of tumor-bearing mice. The release of BK from P-BK in the acidic milieu of the tumor was a prerequisite for P-BK to exert its effect, as the vascular permeability enhancing activity of P-BK was negligible. Collectively, P-BK pre-treatment improved intratumoral blood flow and augmented tumor accumulation of nanomedicine, thereby resulting in a significant suppression of tumor growth. Therefore, these findings demonstrate that P-BK is a potential concomitant drug for improving the tumor delivery of nanomedicines. Workplace Institute of Macromolecular Chemistry Contact Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358 Year of Publishing 2022 Electronic address https://www.sciencedirect.com/science/article/pii/S0168365921004156?via%3Dihub
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