Synergistic effect of acetazolamide-(2-hydroxy)propyl β-cyclodextrin in timolol liposomes for decreasing and prolonging intraocular pressure levels

The purpose of this study was to design, for the first time, a co-loaded liposomal formulation (CLL) for treatment of glaucoma including timolol maleate (TM) in the lipid bilayer and acetazolamide (Acz)-(2-hydroxy)propyl β-cyclodextrin (HPβCD) complexes (AczHP) solubilized in the aqueous core of liposomes. Formulations with TM (TM-L) and AczHP (AczHP-L), separately, were also prepared and characterized. A preliminary study comprising the Acz/HPβCD complexes and their interaction with cholesterol (a component of the lipid bilayer) was realized. Then, a screening study on formulation factors affecting the quality of the product was carried out following the design of the experiment methodology. In addition, in vitro release and permeation studies and in vivo lowering intraocular pressure (IOP) studies were performed. The results of the inclusion com-plexation behavior, characterization, and binding ability of Acz with HPβCD showed that HPβCD could enhance the water solubility of Acz despite the weak binding ability of the complex. Ch disturbed the stability and solubility parameters of Acz due to the fact of its competence by CD; thus, Chems (steroid derivative) was selected for further liposome formulation studies. The optimization of the lipid bilayer composition (DDAB, 0.0173 mmol and no double loading) and the extrusion as methods to reduce vesicle size were crucial for improving the physico-chemical properties and encapsulation efficiency of both drugs. In vitro release and permeation studies demonstrated that the CLL formulation showed improvement in in vitro drug release and permeation compared to the liposomal formulations with a single drug (TM-L and AczHP-L) and the standard solutions (TM-S and AczHP-S). CLL showed high efficacy in reducing and prolonging IOP, suggesting that the synergistic effect of TM and Acz on aqueous humor retention and the presence of this cyclodextrin and liposomes as permeation enhancers are responsible for the success of this strategy of co-loading for glaucoma therapy.Junta de Andalucía 2017/CTS214Universidad de Sevilla PPI546/202

Sapientia, 1987, Vol. XLII, nº 165-166 (número completo)

Contenido: Presentación / Guillermo P. Blanco -- La estudiosidad y la vida espiritual / Alberto Caturelli -- El maestro en teología en el proyecto de Santo Tomás / Abelardo Lobato -- El concepto de filosofía cristiana / Jesús García López -- Tiempo e inmanencia / Daniel O. Gamarra -- La prudencia en la actividad práctica / Margarita Mauri Álvarez -- El problema de la certeza en las ciencias prácticas / Federico Mihura Seeber -- En la Búsqueda de una nueva definición del derecho / Darío Composta -- Raíces metafísica

Trispecific T-cell engagers for dual tumor-targeting of colorectal cancer

International audienceRetargeting of T lymphocytes toward cancer cells by bispecific antibodies has demonstrated its therapeutic potential, with one such antibody approved for the treatment of acute lymphoblastic leukemia (blinatumomab) and several other in clinical trials. However, improvement of their efficacy and selectivity for solid tumors is still required. Here, we describe a novel tandem T-cell recruiting trispecific antibody for the treatment of colorectal cancer (CRC). This construct, termed trispecific T-cell engager (TriTE), consists of a CD3-specific single-chain Fv (scFv) flanked by anti-epidermal growth factor receptor (EGFR) and antiepithelial cell adhesion molecule (EpCAM) single-domain V HH antibodies. The TriTE was well expressed in mammalian and yeast cells, bound the cognate antigens of the three parental antibodies, and enabled the specific cytolysis of EGFR-and/or EpCAM-expressing cancer cells, without inducing T cell activation and cytoxicity against double-negative (EGFR − EpCAM −) cancer cells. Bivalent bispecific targeting of doublepositive HCT116 cells by TriTE improved in vitro potency up to 100-fold compared to single-positive cells and significantly prolonged survival in vivo. In addition, it was less efficient at killing single-positive target cells than the corresponding bispecific controls, leading to potentially enhanced tumor specificity. Moreover, dual targeting of two tumor-associated antigens may contribute toward preventing the tumor escape by antigen loss caused by selective pressures from conventional single-targeting T-cell engagers, and may help to overcome antigenic heterogeneity

Sapientia, 1987, Vol. XLII, nº 165-166 (número completo)

Contenido: Presentación / Guillermo P. Blanco -- La estudiosidad y la vida espiritual / Alberto Caturelli -- El maestro en teología en el proyecto de Santo Tomás / Abelardo Lobato -- El concepto de filosofía cristiana / Jesús García López -- Tiempo e inmanencia / Daniel O. Gamarra -- La prudencia en la actividad práctica / Margarita Mauri Álvarez -- El problema de la certeza en las ciencias prácticas / Federico Mihura Seeber -- En la Búsqueda de una nueva definición del derecho / Darío Composta -- Raíces metafísica