Targeting Breast Cancer Cells with G4 PAMAM Dendrimers and Valproic Acid Derivative Complexes

Author(s):

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 and José Correa-Basurto*   Pages 1857 - 1872 ( 16 )

Abstract:

<P>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. </P><P> 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. </P><P> 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. </P><P> 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. </P><P> 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. </P><P> 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.</P>

Keywords:

PAMAM dendrimers, breast cancer, HDAC inhibitors, molecular docking, molecular dynamics, HPLC, atomic force microscopy.

Affiliation:

Laboratorio de Diseno y Desarrollo de Nuevos Farmacos e Innovacion Biotecnologica de la Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico. Plan de San Luis Y Diaz Miron S/N, Col. Casco de Santo Tomas, Mexico City, CP 11340, Departamento de Quimica Organica, Escuela Nacional de Ciencias, Biologicas, Instituto Politecnico Nacional, Prolongacion de Carpio y Plan de Ayala, Col. Casco de Santo Tomas, Mexico City, CP 11340, Laboratorio de Diseno y Desarrollo de Nuevos Farmacos e Innovacion Biotecnologica de la Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico. Plan de San Luis Y Diaz Miron S/N, Col. Casco de Santo Tomas, Mexico City, CP 11340, Division de Investigacion Basica, Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Tlalpan, Seccion XVI, Ciudad de Mexico, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico/Instituto Nacional de Cancerologia, Ciudad de Mexico, Laboratorio de oncologia Molecular y estres oxidativo de la Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico. Plan de San Luis Y Diaz Miron S/N, Col. Casco de Santo Tomas, Mexico City, CP 11340, Laboratorio de Diseno y Desarrollo de Nuevos Farmacos e Innovacion Biotecnologica de la Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico. Plan de San Luis Y Diaz Miron S/N, Col. Casco de Santo Tomas, Mexico City, CP 11340, Division de Ciencias de la Salud, Universidad de Quintana Roo. Av. Erik Paolo Martinez S/N. Esquina Av. 4 de Marzo, Col. Magisterial, Chetumal, Quintana Roo, C.P. 77039, Laboratorio de Diseno y Desarrollo de Nuevos Farmacos e Innovacion Biotecnologica de la Escuela Superior de Medicina, Instituto Politecnico Nacional, Mexico. Plan de San Luis Y Diaz Miron S/N, Col. Casco de Santo Tomas, Mexico City, CP 11340

Graphical Abstract:

Read Full-Text article