title: Association of the anti-tuberculosis drug rifampicin with a PAMAM dendrimer.
abstract: The association of the anti-tuberculosis drug rifampicin (RIF) with a 4th-generation poly(amidoamine) (G4-PAMAM) dendrimer was investigated by means of molecular dynamics simulations. The RIF load capacity was estimated to be around 20 RIF per G4-PAMAM at neutral pH. The complex formed by 20 RIF molecules and the dendrimer (RIF20-PAMAM) was subjected to 100 ns molecular dynamics (MD) simulations at two different pH conditions (neutral and acidic). The complex was found to be significantly more stable in the simulation at neutral pH compared to the simulation at low pH in which the RIF molecules were rapidly and almost simultaneously expelled to the solvent bulk. The high stability of the RIF-PAMAM complex under physiological pH and the rapid release of RIF molecules under acidic medium provide an interesting switch for drug targeting since the Mycobacterium resides within acidic domains of the macrophage. Altogether, these results suggest that, at least in terms of stability and pH-dependent release, PAMAM-like dendrimers may be considered suitable drug delivery systems for RIF and derivatives.
authors.affiliation: Departamento de Engenharia Elétrica, PUC-Rio, Rio de Janeiro, Brazil.
authors.forename: Reinaldo G
authors.initials: RG
authors.lastname: Bellini
authors.affiliation: Departamento de Química, Universidade Federal de Viçosa, Viçosa, Brazil.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Guimarães
authors.affiliation: Departamento de Engenharia Elétrica, PUC-Rio, Rio de Janeiro, Brazil.
authors.forename: Marco A C
authors.initials: MA
authors.lastname: Pacheco
authors.affiliation: Departamento de Engenharia Elétrica, PUC-Rio, Rio de Janeiro, Brazil.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Dias
authors.affiliation: Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Vanessa R
authors.initials: VR
authors.lastname: Furtado
authors.affiliation: Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Ricardo B
authors.initials: RB
authors.lastname: de Alencastro
authors.affiliation: Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: bruno@iq.ufrj.br.
authors.forename: Bruno A C
authors.initials: BA
authors.lastname: Horta
mesh_terms: D000995:Antitubercular Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D050091:Dendrimers / Q000737:chemistry / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism*; D012293:Rifampin / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility; D014867:Water
chemical_list: D000995:Antitubercular Agents; D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; C531249:Poly(amidoamine); D011073:Polyamines; D014867:Water; D012293:Rifampin
keywords: Computer simulation; Dendrimer; Drug delivery; Molecular dynamics; PAMAM; Rifampicin