Introduction

This patent describes the synthesis of a polymeric conjugate of KillerTRAIL suitable for anti-cancer and anti-inflammatory therapies. The synthesis of therapeutic bio-macromolecules was carried out by conjugating thiol group (-SH) of cysteine 230 of KillerTRAIL with PEG maleimide and thus obtains mPEG-KillerTRAIL derivates. This approach synthesised stable bio-macromolecules which can increase the stability of the native KillerTRAIL, preventing its aggregation and improving KillerTRAIL shelf-life as well as other pharmacokinetic, biopharmaceutical parameters and its relative anti-cancer activity in vitro and in vivo.

Technical features

The invention has as its objective the synthesis of a KillerTRAIL polymer to be used in anti-tumor and / or anti-inflammatory therapy. The conjugation strategy of the mPEG-KillerTRAIL derivative was carried out by exploiting the conjugation reaction between the -SH group present in the cysteine ​​residue in position 230 of the protein and a maleimide derivative of the PEG, with a percentage yield of 79% and its greater stability compared to the starting KillerTRAIL. The experimental results on models of HCT 116 cells (colon carcinoma) show that mPEG-KillerTRAIL decreases the cell viability of HCT116 cells by 50% at a concentration equal to 1.5 ng / ml; while a reduction in cell viability of less than 20% was obtained by increasing the equivalent amount of KillerTRAIL in mPEG-KillerTRAIL to 2 ng / ml. The in vivo experimental results obtained on mouse models xenotransplanted with HCT-116 cells show that mPEG-KillerTRAIL reduces tumor growth by 74% compared to KillerTRAIL which, on the contrary, only reduces tumor mass by 37.5%. TRL-1; TRL-2; TRL-3; TRL-4.

Possible Applications

• Anti-tumor, anti-inflammatory therapy, neurodegenerative, metabolic and oxidative stress pathologies.

Advantages

• Increase the stability of KillerTRAIL.
• Improve pharmacokinetic, bio-distribution and biopharmaceutics of KillerTRAIL.
• Increase anti-cancer and anti-inflammatory in vitro and in vivo activities of KillerTRAIL.
• Synthesise a multifunctional derivative which has self-assembling properties or can be conjugated with other bio-macromolecules, drugs or make nanomedicine.