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

J Control Release. 2014 Oct 28:192:157-66. doi: 10.1016/j.jconrel.2014.07.009. Epub 2014 Jul 17.

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.

Keywords: Bortezomib; Combination therapies; Liposomes; Neuroblastoma; TRAIL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Female
  • Humans
  • Liposomes
  • Mice
  • Mice, Nude
  • 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*

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • Liposomes
  • Pyrazines
  • TNF-Related Apoptosis-Inducing Ligand
  • Bortezomib