Megamers (MG): A new nano drug delivery system?

PRISCILA SCHILRREFF, ROLANDO C. R. LILLO, EDER L. ROMERO Y MARÍA J. MORILLA

Rosario, Santa Fé, Argentina

Taller; 1º Taller de Organos Artificiales, Biomateriales e Ingeniería de Tejidos. BIOOMAT 2009; 2009

Megamers (MG): A new nano drug delivery system? Priscila Schilrreff, Rolando C. R. Lillo, Eder L. Romero and María J. Morilla, NANOMEDICINE RESEARCH PROGRAMA (NRP). Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Bernal, Argentina.   Polypeptide or oligopeptide drugs have significant therapeutic potential in the clinics, but their poor oral bioavailability, mainly due to human body's natural defence and digestive mechanisms, requires these agents to be administered primarily by parenteral routes. Their short plasma half-lives and the poor results obtained upon repeated parenteral injections have led to the search for novel delivery devices that allow for friendly routes of administration, for instance the oral route. In order to allow the oral administration of polypeptides, the maintenance of their chemical structure along the gastrointestinal transit, mucoadhesion and increased possibilities of para-celular transport across the enterocytes must be achieved. To that aim, we propose the polypeptides to form complexes with structure-controlled MG -core-shell nanoparticles formed by dendrimers-. The synthesis of the MG, saturated core-shell (tecto) dendrimers, involved the combination of a limited amount of an amine-terminated dendrimeric core reagent (PAMAM dendrimer of generation (G) 5, with an excess of a carboxylic acid terminated dendrimeric shell reagent G 2,5, whit a subsequent covalent bond formation. The resultant product was purified by size exclusion chromatography (SEC) and lyophilized as a white rubbery solid. Formation of MG was determined by: a) SDS-PAGE (polyAcrylamide gel electrophoresis) b) HPLC (high performance liquid chromatography) c) SEC d) size and Z potential by NanoZ sizer and e) thermogravimetric analysis (TGA). MG showed to be structurally stable, monodisperse, with a molecular size distribution of 8 ± 1.5 nm and a MW of 95000 Da. Finally, FITC labelled MG showed to cross the epithelial barrier when incubated with Caco-2 cells, in the absence of cytotoxicity, measured as mitochondrial succinate dehydrogenase activity employing a tetrazolium salt (MTT) and as lactate dehydrogenase (LDH) leakage. MG demonstrated to be a promising device to deliver intact molecules of polypeptides towards the epithelial barrier in an oral administration.   Keywords: nanoparticles, megamer, dendrimer, polypeptides, oral delivery.