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.
Discussion: In vitro studies showed that G4 PAMAM has toxicity in the micromolar concentration in MDAMB-
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 MDAMB-
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 watersoluble
aryl-VPA derivate compounds to increase its cytotoxic activity against neoplastic cell lines.