title: sTRAIL coupled to liposomes improves its pharmacokinetic profile and overcomes neuroblastoma tumour resistance in combination with Bortezomib.
abstract: Neuroblastoma (NB), the most common and deadly extracranial solid tumour of childhood, represents a challenging in paediatric oncology. Soluble tumour necrosis factor (TNF)-related apoptosis-inducing ligand (sTRAIL) is a cancer cell-specific molecule exerting remarkable anti-tumour activities against paediatric malignancies both in vitro and in preclinical settings. However, due to its too fast elimination and to the undesired related side effects, the improvement of sTRAIL in vivo bioavailability and the specific delivery to the tumour is mandatory for increasing its therapeutic efficacy. In this manuscript, we developed an innovative pegylated liposomal formulation carrying the sTRAIL at the outer surface (sTRAIL-SL) with the intent to improve its serum half-life and increase its efficacy in vivo, while reducing side effects. Furthermore, the possibility to combine sTRAIL-SL with the proteasome inhibitor Bortezomib (BTZ) was investigated, being BTZ able to sensitize tumour cells toward TRAIL-induced apoptosis. We demonstrated that sTRAIL preserved and improved its anti-tumour activity when coupled to nanocarriers. Moreover, sTRAIL-SL ameliorated its PK profile in blood allowing sTRAIL to exert a more potent anti-tumour activity, which led, upon BTZ priming, to a statistically significant enhanced life spans in two models of sTRAIL-resistant NB-bearing mice. Finally, mechanistic studies indicated that the combination of sTRAIL with BTZ sensitized sTRAIL-resistant NB tumour cells to sTRAIL-induced cell death, both in vitro and in vivo, through the Akt/GSK3/β-catenin axis-dependent mechanism. In conclusion, our results suggest that sTRAIL-SL might be an efficient vehicle for sTRAIL delivery and that its use in clinic, in combination with BTZ, might represent an adjuvant strategy for the treatment of stage IV, sTRAIL-resistant, NB patients.
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Loi
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Becherini
authors.affiliation: Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Emionite
authors.affiliation: Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Giacomini
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Cossu
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Destefanis
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Brignole
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Di Paolo
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Piaggio
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Perri
authors.affiliation: Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cilli
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy. Electronic address: fabiopastorino@ospedale-gaslini.ge.it.
authors.forename: F
authors.initials: F
authors.lastname: Pastorino
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova 16148, Italy. Electronic address: mircoponzoni@ospedale-gaslini.ge.it.
authors.forename: M
authors.initials: M
authors.lastname: Ponzoni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage* / Q000627:therapeutic use*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines / Q000008:administration & dosage* / Q000627:therapeutic use*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D008081:Liposomes; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; D000069286:Bortezomib
keywords: Bortezomib; Combination therapies; Liposomes; Neuroblastoma; TRAIL