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Biotinylated Polymer-Ruthenium Conjugates: In Vitro and In Vivo Studies in a Triple-Negative Breast Cancer Model.
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- Author(s): Côrte-Real, Leonor; Brás, Ana Rita; Pilon, Adhan; Mendes, Nuno; Ribeiro, Ana Sofia; Martins, Tiago D.; Farinha, José Paulo S.; Oliveira, M. Conceição; Gärtner, Fátima; Garcia, M. Helena; Preto, Ana; Valente, Andreia
- Source:
Pharmaceutics; Jul2022, Vol. 14 Issue 7, pN.PAG-N.PAG, 22p- Subject Terms:
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- Additional Information
- Subject Terms:
- Abstract: The need for new therapeutic approaches for triple-negative breast cancer is a clinically relevant problem that needs to be solved. Using a multi-targeting approach to enhance cancer cell uptake, we synthesized a new family of ruthenium(II) organometallic complexes envisaging simultaneous active and passive targeting, using biotin and polylactide (PLA), respectively. All compounds with the general formula, [Ru(η5-CpR)(P)(2,2′-bipy-4,4′-PLA-biotin)][CF
3 SO3 ], where R is -H or -CH3 and P is P(C6 H5 )3 , P(C6 H4 F)3 or P(C6 H4 OCH3 )3 , were tested against triple-negative breast cancer cells MDA-MB-231 showing IC50 values between 2.3–14.6 µM, much better than cisplatin, a classical chemotherapeutic drug, in the same experimental conditions. We selected compound 1 (where R is H and P is P(C6 H5 )3 ), for further studies as it was the one showing the best biological effect. In a competitive assay with biotin, we showed that cell uptake via SMVT receptors seems to be the main transport route into the cells for this compound, validating the strategy of including biotin in the design of the compound. The effects of the compound on the hallmarks of cancer show that the compound leads to apoptosis, interferes with proliferation by affecting the formation of cell colonies in a dose-dependent manner and disrupts the cell cytoskeleton. Preliminary in vivo assays in N: NIH(S)II-nu/nu mice show that the concentrations of compound 1 used in this experiment (maximum 4 mg/kg) are safe to use in vivo, although some signs of liver toxicity are already found. In addition, the new compound shows a tendency to control tumor growth, although not significantly. In sum, we showed that compound 1 shows promising anti-cancer effects, bringing a new avenue for triple-negative breast cancer therapy. [ABSTRACT FROM AUTHOR] - Abstract: Copyright of Pharmaceutics is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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