title: Design of smart GE11-PLGA/PEG-PLGA blend nanoparticulate platforms for parenteral administration of hydrophilic macromolecular drugs: synthesis, preparation and in vitro/ex vivo characterization.
abstract: Active drug targeting and controlled release of hydrophilic macromolecular drugs represent crucial points in designing efficient polymeric drug delivery nanoplatforms. In the present work EGFR-targeted polylactide-co-glycolide (PLGA) nanoparticles were made by a blend of two different PLGA-based polymers. The first, GE11-PLGA, in which PLGA was functionalized with GE11, a small peptide and EGFR allosteric ligand, able to give nanoparticles selective targeting features. The second polymer was a PEGylated PLGA (PEG-PLGA) aimed at improving nanoparticles hydrophilicity and stealth features. GE11 and GE11-PLGA were custom synthetized through a simple and inexpensive method. The nanoprecipitation technique was exploited for the preparation of polymeric nanoparticles composed by a 1:1weight ratio between GE11-PLGA and PEG-PLGA, obtaining smart nanoplatforms with proper size for parenteral administration (143.9±5.0nm). In vitro cellular uptake in EGFR-overexpressing cell line (A549) demonstrated an active internalization of GE11-functionalized nanoparticles. GE11-PLGA/PEG-PLGA blend nanoparticles were loaded with Myoglobin, a model hydrophilic macromolecule, reaching a good loading (2.42% respect to the theoretical 4.00% w/w) and a prolonged release over 60days. GE11-PLGA/PEG-PLGA blend nanoparticles showed good in vitro stability for 30days in physiological saline solution at 4°C and for 24h in pH 7.4 or pH 5.0 buffer at 37°C respectively, giving indications about potential storage and administration conditions. Furthermore ex vivo stability study in human plasma using fluorescence Single Particle Tracking (fSPT) assessed good GE11-PLGA/PEG-PLGA nanoparticles dimensional stability after 1 and 4h. Thanks to the versatility in polymeric composition and relative tunable nanoparticles features in terms of drug incorporation and release, GE11-PLGA/PEG-PLGA blend NPs can be considered highly promising as smart nanoparticulate platforms for the treatment of diseases characterized by EGFR overexpression by parenteral administration .
authors: Department of Drug Sciences, University of Pavia, 12, Viale Taramelli, 27100, Pavia, Italy.
authors: Barbara
authors: B
authors: Colzani
authors: Department of Chemistry, University of Milan, 19, Via Golgi, 20130, Milano, Italy.
authors: Giovanna
authors: G
authors: Speranza
authors: Department of Drug Sciences, University of Pavia, 12, Viale Taramelli, 27100, Pavia, Italy.
authors: Rossella
authors: R
authors: Dorati
authors: Department of Drug Sciences, University of Pavia, 12, Viale Taramelli, 27100, Pavia, Italy.
authors: Bice
authors: B
authors: Conti
authors: Department of Drug Sciences, University of Pavia, 12, Viale Taramelli, 27100, Pavia, Italy.
authors: Tiziana
authors: T
authors: Modena
authors: Department of Chemistry, University of Pavia, 12, Viale Taramelli, 27100, Pavia, Italy.
authors: Giovanna
authors: G
authors: Bruni
authors: Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, Ghent Research Group on Nanomedicines, Harelbekestraat 72, 9000, Ghent, Belgium.
authors: Elisa
authors: E
authors: Zagato
authors: Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, Ghent Research Group on Nanomedicines, Harelbekestraat 72, 9000, Ghent, Belgium.
authors: Lotte
authors: L
authors: Vermeulen
authors: Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, Ghent Research Group on Nanomedicines, Harelbekestraat 72, 9000, Ghent, Belgium.
authors: George R
authors: GR
authors: Dakwar
authors: Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, Ghent Research Group on Nanomedicines, Harelbekestraat 72, 9000, Ghent, Belgium.
authors: Kevin
authors: K
authors: Braeckmans
authors: Department of Drug Sciences, University of Pavia, 12, Viale Taramelli, 27100, Pavia, Italy. Electronic address: ida.genta@unipv.it.
authors: Ida
authors: I
authors: Genta
mesh_terms: D000072283:A549 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007263:Infusions, Parenteral; D019344:Lactic Acid / Q000008:administration & dosage / Q000138:chemical synthesis*; D046911:Macromolecular Substances / Q000008:administration & dosage / Q000138:chemical synthesis; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000138:chemical synthesis*; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000138:chemical synthesis*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: C572557:GE11 peptide; D046911:Macromolecular Substances; D010455:Peptides; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols
keywords: EGFR-targeted nanoparticles; GE11 peptide; GE11 targeted PLGA nanoplatforms; Macromolecular hydrophilic drugs nanoencapsulation; Smart PLGA nanoparticles