sTRAIL coupled to liposomes improves its pharmacokinetic profile and overcomes neuroblastoma tumour resistance in combination with Bortezomib

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 agains...

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Bibliographic Details
Published in:Journal of controlled release 2014-10, Vol.192, p.157-166
Main Authors: Loi, M., Becherini, P., Emionite, L., Giacomini, A., Cossu, I., Destefanis, E., Brignole, C., Di Paolo, D., Piaggio, F., Perri, P., Cilli, M., Pastorino, F., Ponzoni, M.
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - therapeutic use
Antineoplastic Combined Chemotherapy Protocols
Apoptosis - drug effects
Boronic Acids - administration & dosage
Boronic Acids - therapeutic use
Bortezomib
Cell Line, Tumor
Combination therapies
Female
Humans
Liposomes
Mice
Mice, Nude
Neuroblastoma
Neuroblastoma - drug therapy
Neuroblastoma - pathology
Pyrazines - administration & dosage
Pyrazines - therapeutic use
TNF-Related Apoptosis-Inducing Ligand - administration & dosage
TNF-Related Apoptosis-Inducing Ligand - pharmacokinetics
TNF-Related Apoptosis-Inducing Ligand - therapeutic use
TRAIL
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Summary: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. [Display omitted]
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2014.07.009