Targeting breast cancer cells with g4 pamam dendrimers and valproic acid derivative complexes

Alberto M. Muñoz, Manuel J. Fragoso-Vázquez, Berenice P. Martel, Alma Chávez-Blanco, Alfonso Dueñas-González, José R.garcía-Sánchez, Martiniano Bello, Aurelio Romero-Castro, José Correa-Basurto

    Research output: Contribution to journalArticlepeer-review

    7 Scopus citations

    Abstract

    Background: Our research group has developed some Valproic Acid (VPA) derivatives employed as anti-proliferative compounds targeting the HDAC8 enzyme. However, some of these compounds are poorly soluble in water. Objective: Employed the four generations of Polyamidoamine (G4 PAMAM) dendrimers as drug carriers of these compounds to increase their water solubility for further in vitro evaluation. Methods: VPA derivatives were subjected to Docking and Molecular Dynamics (MD) simulations to evaluate their affinity on G4 PAMAM. Then, HPLC-UV/VIS,1H NMR, MALDI-TOF and atomic force microscopy were employed to establish the formation of the drug-G4 PAMAM complexes. Results: The docking results showed that the amide groups of VPA derivatives make polar interactions with G4 PAMAM, whereas MD simulations corroborated the stability of the complexes. HPLC UV/VIS experiments showed an increase in the drug water solubility which was found to be directly proportional to the amount of G4 PAMAM.1H NMR showed a disappearance of the proton amine group signals, correlating with docking results. MALDI-TOF and atomic force microscopy suggested the drug-G4 PAMAM dendrimer complexes formation. In vitro studies showed that G4 PAMAM has toxicity in the micromolar concentration in MDA-MB-231, MCF7, and 3T3-L1 cell lines. VPA CF-G4 PAMAM dendrimer complex showed anti-proliferative properties in the micromolar concentration in MCF-7 and 3T3-L1, and in the milimolar concentration in MDA-MB-231, whereas VPA MF-G4 PAMAM dendrimer complex didn’t show effects on the three cell lines employed. Conclusion: These results demonstrate that G4 PAMAM dendrimers are capableof transporting poorly water-soluble aryl-VPA derivate compounds to increase its cytotoxic activity against neoplastic cell lines.

    Original languageEnglish
    Pages (from-to)1857-1872
    Number of pages16
    JournalAnti-Cancer Agents in Medicinal Chemistry
    Volume20
    Issue number15
    DOIs
    StatePublished - 2020

    Keywords

    • Atomic force microscopy
    • Breast cancer
    • HDAC inhibitors
    • HPLC
    • Molecular docking
    • Molecular dynamics
    • PAMAM dendrimers

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