Superior penetration and cytotoxicity of HPMA copolymer conjugates of pirarubicin in tumor cell spheroid

0507279 - ÚMCH 2020 RIV US eng J - Journal Article
Nakamura, H. - Koziolová, Eva - Chytil, Petr - Etrych, Tomáš - Haratake, M. - Maeda, H.
Superior penetration and cytotoxicity of HPMA copolymer conjugates of pirarubicin in tumor cell spheroid.
Molecular Pharmaceutics. Roč. 16, č. 8 (2019), s. 3452-3459. ISSN 1543-8384. E-ISSN 1543-8392
R&D Projects: GA ČR(CZ) GA17-13283S; GA MŠMT(CZ) LQ1604; GA MZd(CZ) NV16-28600A
Grant - others:AV ČR(CZ) JSPS-16-05
Program: Bilaterální spolupráce
Institutional support: RVO:61389013
Keywords : pirarubicin (THP) * tumor spheroid cell * HPMA polymer
OECD category: Polymer science
Impact factor: 4.321, year: 2019
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.9b00248

N-(2-Hydroxypropyl)methacrylamide copolymer conjugates of pirarubicin (THP), P-THP, accumulates selectively in solid tumor tissue by the enhanced permeability and retention (EPR) effect. Despite of high accumulation in solid tumors, some macromolecular antitumor agents show poor therapeutic outcome because of poor tissue diffusion into the tumor as well as obstructed tumor blood flow. Here, we confirmed that cellular uptake of P-THP was 25 times less than that of free THP at 1–4 h incubation time in vitro. The passage of P-THP through the confluent tight-monolayer cells junction was 12 times higher than free THP, and P-THP penetrated deeper into the tumor cell spheroid (1.3–1.7-fold) than free THP in 4 h. In addition, P-THP showed cytotoxicity comparable to that of free THP to tumor-cells in spheroid form, despite of 7 times lower cytotoxicity of P-THP to the monolayer cells to that of free THP in vitro. These results indicate that P-THP administration can exhibit deeper diffusion into the tumor cell spheroid than free THP. As a consequence, P-THP exhibits more efficient antitumor activity than free THP in vivo, which is also supported by better pharmacokinetics and tumor accumulation of P-THP than free THP.
Permanent Link: http://hdl.handle.net/11104/0298882