title: Enhanced anti-hyperproliferative activity of human thymidylate synthase inhibitor peptide by solid lipid nanoparticle delivery.
abstract: Recently, octapeptide LSCQLYQR (LRp), reducing growth of cis-platinum (cDDP) resistant ovarian carcinoma cells by inhibiting the monomer-monomer interface of the human enzyme thymidylate synthase, has been identified. As the peptide is not able to cross the cell membrane it requires an appropriate delivery system. In this work the application of SLNs, biocompatible and efficient tools for the intracellular drug transport, applied especially for lipophilic drugs, was exploited for the delivery of the hydrophilic peptide LRp. SLNs formulated in the absence/presence of small amount of squalene showed dimensions below 150 nm, negative zeta potential and good stability to the freeze-drying process. Even though the particles formulated with squalene exhibited a less ordered crystal lattice and a lower surface hydrophobicity, a rapid drug release from these nanocarriers occurred as a result of the relevant expulsion of the drug from the lipid core during lipid crystallization. On the contrary, SLNs formulated in the absence of squalene were able to incorporate more stably the peptide showing considerable cytotoxic effect on cDDP resistant C13* ovarian carcinoma cell line at concentration 50 times lower than that used previously with a marketed delivery system. From the cell cycle analysis by the propidium iodide test in SLNs-peptide treated cancer cells an increase of apoptosis percentage was observed, indicating that SLNs were able to carry efficiently the peptide until its enzymatic target.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 183, 41125 Modena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sacchetti
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 183, 41125 Modena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Marraccini
authors.affiliation: Department of Biomedical, Metabolical and Neural Sciences University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: D'Arca
authors.affiliation: Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Pelà
authors.affiliation: CIGS, University of Modena and R. Emilia, via Campi 213/A, 41125 Modena, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Pinetti
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 183, 41125 Modena, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Maretti
authors.affiliation: Department of Engineering Enzo Ferrari, University of Modena and R. Emilia, Strada Vignolese 905, 41125 Modena, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Hanuskova
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 183, 41125 Modena, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iannuccelli
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 183, 41125 Modena, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Costi
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 183, 41125 Modena, Italy. Electronic address: eliana.leo@unimore.it.
authors.forename: Eliana
authors.initials: E
authors.lastname: Leo
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008055:Lipids / Q000008:administration & dosage*; D053758:Nanoparticles; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D008055:Lipids; D013940:Thymidylate Synthase
keywords: Human thymidylate synthase; Ovarian cancer; Particle surface hydrophobicity; Peptide; Solid lipid nanoparticles; Squalene