title: Development of noncytotoxic PLGA nanoparticles to improve the effect of a new inhibitor of p53-MDM2 interaction.
abstract: One possible approach to overcome solubility complications and enhance the biological activity of drugs is their incorporation into drug delivery systems. Within this scope, several nanosphere and nanocapsule formulations of a new inhibitor of p53-MDM2 interaction (xanthone 1) were developed and their physicochemical properties analyzed. Through the investigation of the effect of several empty nanoparticles on the growth of MCF-7 cells, it was possible to observe that four out of five formulations were cytotoxic and that some correlations between the toxic potential of these polymeric nanoparticles and their properties/composition could be extrapolated. One empty formulation of nanocapsules developed by emulsification/solvent evaporation and containing PLGA, PVA and Mygliol(®) 812 was found to be noncytotoxic to this cell line. The corresponding compound 1-loaded nanocapsules showed an incorporation efficiency of 77% and revealed to be more potent than the free drug against cell growth inhibition, which may be related to the enhancement in its intracellular delivery. In an integrative study, the intracellular uptake of nanocapsules was confirmed using fluorescent 6-coumarin and well as compound 1 release from nanocapsules. Overall, it was possible to enhance the effect of the hit inhibitor of p53-MDM2 interaction through the development of suitable noncytotoxic polymeric nanoparticles.
authors.affiliation: Centro de Química Medicinal - Universidade do Porto (CEQUIMED-UP), Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, Portugal.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Paiva
authors.forename: Rita A
authors.initials: RA
authors.lastname: Pinto
authors.forename: Maribel
authors.initials: M
authors.lastname: Teixeira
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Barbosa
authors.forename: Raquel T
authors.initials: RT
authors.lastname: Lima
authors.forename: M Helena
authors.initials: MH
authors.lastname: Vasconcelos
authors.forename: Emília
authors.initials: E
authors.lastname: Sousa
authors.forename: Madalena
authors.initials: M
authors.lastname: Pinto
mesh_terms: D001692:Biological Transport; D049109:Cell Proliferation / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D003374:Coumarins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry* / Q000633:toxicity; D061986:MCF-7 Cells; D008855:Microscopy, Electron, Scanning; D058990:Molecular Targeted Therapy; D053769:Nanocapsules; D036103:Nanotechnology; D011100:Polyglycolic Acid / Q000737:chemistry* / Q000633:toxicity; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011142:Polyvinyl Alcohol / Q000737:chemistry; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D014280:Triglycerides / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044004:Xanthones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D003374:Coumarins; D004337:Drug Carriers; D005456:Fluorescent Dyes; D053769:Nanocapsules; C495901:TP53 protein, human; D014280:Triglycerides; D016159:Tumor Suppressor Protein p53; D044004:Xanthones; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C022834:miglyol 812; D011142:Polyvinyl Alcohol; C009689:xanthone; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Antitumor; Poly(d,l-lactide-co-glycolide); Polymeric nanoparticles; Xanthones