Chemosensitization of tumors via simultaneous delivery of STAT3 inhibitor and doxorubicin through HPMA copolymer-based nanotherapeutics with pH-sensitive activation.

0580702 - MBÚ 2025 RIV NL eng J - Článek v odborném periodiku
Kovář, Marek - Šubr, Vladimír - Běhalová, Kateřina - Studenovský, Martin - Starenko, Daniil - Kovářová, Jiřina - Procházková, Petra - Etrych, Tomáš - Kostka, Libor
Chemosensitization of tumors via simultaneous delivery of STAT3 inhibitor and doxorubicin through HPMA copolymer-based nanotherapeutics with pH-sensitive activation.
Nanomedicine: Nanotechnology, Biology and Medicine. Roč. 56, February 2024 (2024), s. 102730. ISSN 1549-9634. E-ISSN 1549-9642
Grant CEP: GA MZd(CZ) NU21-03-00273; GA MŠMT LX22NPO5102
Institucionální podpora: RVO:61388971 ; RVO:61389013
Klíčová slova: STAT3 inhibitor * Doxorubicin * HPMA copolymer carrier * pH-sensitive drug * release
Obor OECD: Pharmacology and pharmacy; Medicinal chemistry (UMCH-V)
Impakt faktor: 5.4, rok: 2022
Způsob publikování: Open access
https://www.sciencedirect.com/science/article/pii/S1549963423000813

We synthesized three novel STAT3 inhibitors (S3iD1-S3iD3) possessing oxoheptanoic residue enabling linkage to HPMA copolymer carrier via a pH-sensitive hydrazone bond. HPMA copolymer conjugates bearing doxorubicin (Dox) and our STAT3 inhibitors were synthesized to evaluate the anticancer effect of Dox and STAT3 inhibitor co-delivery into tumors. S3iD1-3 and their copolymer-bound counterparts (P-S3iD1-P-S3iD3) showed considerable in vitro cytostatic activities in five mouse and human cancer cell lines with IC50 ~0.6-7.9 muM and 0.7-10.9 muM, respectively. S3iD2 and S3iD3 were confirmed to inhibit the STAT3 signaling pathway. The combination of HPMA copolymer-bound Dox (P-Dox) and P-S3iD3 at the dosage showing negligible toxicity demonstrated significant antitumor activity in B16F10 melanoma-bearing mice and completely cured 2 out of 15 mice. P-Dox alone had a significantly lower therapeutic activity with no completely cured mice. Thus, polymer conjugates bearing STAT3 inhibitors may be used for the chemosensitization of chemorefractory tumors.
Trvalý link: https://hdl.handle.net/11104/0349459