title: Translocator protein ligand-PLGA conjugated nanoparticles for 5-fluorouracil delivery to glioma cancer cells.
abstract: Translocator protein 18 kDa (TSPO) is a promising target for molecular imaging and for targeted drug delivery to tumors overexpressing TSPO. In our previous work, new macromolecular conjugates with a high affinity and selectivity for TSPO were prepared by conjugating the biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) polymer with two potent and selective TSPO ligands, namely, compounds 1 and 2. Based on this, nanoparticle delivery systems (NPs), employing TSPO ligand-PLGA conjugated (PLGA-TSPO) polymers, were prepared. Furthermore, to evaluate the ability of the new NPs to be used as a drug delivery systems for anticancer therapy, PLGA-TSPO NPs were loaded with 5-fluorouracil (5-FU), chosen as a model hydrophilic anticancer drug. The main goal of this work was to investigate the synergistic potential of using NP conjugates PLGA-TSPO, TSPO ligands being pro-apoptotic agents, to simultaneously deliver a cytotoxic anticancer drug. To better highlight the occurrence of synergistic effects, dual drug loaded PLGA NPs (PLGA NPs/5-FU/1) and dual drug loaded PLGA-TSPO NPs (PLGA-TSPO NPs/5-FU/1), with 5-FU and TSPO ligand 1 physically incorporated together, were also prepared and characterized. The particle size and size distribution, surface morphology, and drug encapsulation efficiency, as well as the drug release kinetics, were investigated. In vitro cytotoxicity studies were carried out on C6 glioma cells overexpressing TSPO, and to evaluate the potential uptake of these nanoparticulate systems, the internalization of fluorescent labeled PLGA-TSPO NPs (FITC-PLGA-TSPO NPs) was also investigated by fluorescence microscopy. Results demonstrated that PLGA-TSPO NPs/5-FU and dual drug loaded PLGA NPs/5-FU/1 and PLGA-TSPO NPs/5-FU/1 could significantly enhance toxicity against human cancer cells due to the synergistic effect of the TSPO ligand 1 with the anticancer drug 5-FU.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro" , via Orabona 4, 70125 Bari, Italy.
authors.forename: Valentino
authors.initials: V
authors.lastname: Laquintana
authors.forename: Nunzio
authors.initials: N
authors.lastname: Denora
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopalco
authors.forename: Angela
authors.initials: A
authors.lastname: Lopedota
authors.forename: Annalisa
authors.initials: A
authors.lastname: Cutrignelli
authors.forename: Francesco Massimo
authors.initials: FM
authors.lastname: Lasorsa
authors.forename: Giulia
authors.initials: G
authors.lastname: Agostino
authors.forename: Massimo
authors.initials: M
authors.lastname: Franco
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis; D002152:Calorimetry, Differential Scanning; D002352:Carrier Proteins / Q000008:administration & dosage / Q000378:metabolism*; D049109:Cell Proliferation; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011963:Receptors, GABA-A / Q000008:administration & dosage / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D004337:Drug Carriers; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005472:Fluorouracil
keywords: 5-fluorouracil; conjugates; intracellular drug delivery; nanoparticles; poly(d,l-lactide-co-glycolide); translocator protein