Chemosensitization of tumors via simultaneous delivery of STAT3 inhibitor and doxorubicin through HPMA copolymer-based nanotherapeutics with pH-sensitive activation
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
38158146
DOI
10.1016/j.nano.2023.102730
PII: S1549-9634(23)00081-3
Knihovny.cz E-resources
- Keywords
- Doxorubicin, HPMA copolymer carrier, STAT3 inhibitor, pH-sensitive drug release,
- MeSH
- Doxorubicin * pharmacology therapeutic use MeSH
- Hydrogen-Ion Concentration MeSH
- Polymethacrylic Acids MeSH
- Humans MeSH
- Methacrylates * MeSH
- Mice MeSH
- Neoplasms * drug therapy MeSH
- STAT3 Transcription Factor metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate MeSH Browser
- Doxorubicin * MeSH
- hydroxypropyl methacrylate MeSH Browser
- Polymethacrylic Acids MeSH
- Methacrylates * MeSH
- STAT3 protein, human MeSH Browser
- STAT3 Transcription Factor MeSH
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 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.
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