1. Chemosensitization of tumors via simultaneous delivery of STAT3 inhibitor and doxorubicin through HPMA copolymer-based nanotherapeutics with pH-sensitive activation.
- Author
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Kovář M, Šubr V, Běhalová K, Studenovský M, Starenko D, Kovářová J, Procházková P, Etrych T, and Kostka L
- Subjects
- Mice, Humans, Animals, Polymethacrylic Acids, Hydrogen-Ion Concentration, STAT3 Transcription Factor metabolism, Doxorubicin pharmacology, Doxorubicin therapeutic use, Neoplasms drug therapy, Methacrylates
- Abstract
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 IC
50 ~0.6-7.9 μM and 0.7-10.9 μM, 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., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial or non-financial interests. The authors report no disclosures., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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