PEG-TRAIL-MMAE Conjugates with Optimized Ratio for Antitumor Application

TRAIL (tumor-necrosis-factor (TNF)-related apoptosis-inducing ligand) has been regarded as a promising broad-spectrum antitumor agent. However, its further application is limited by poor drug delivery and the tumors that has resistance to TRAIL.

To settle the problems, researchers applied a three-step drug delivery strategy in the form of PEG-TRAIL-MMAE (Monomethyl Auristatin E) to TRAIL. The first step is to proceed the PEGylation of TRAIL to improve its in vivo pharmacokinetics. Then, the second step is to activate the TRAIL extrinsic apoptosis pathway by the interaction between TRAIL conjugates with death receptors. The last step to overcome the TRAIL resistance in some tumors is to further release MMAE from the lysosome.

In order to balance the three steps, researchers optimized the PEG/MMAE ratio for PEG-TRAIL-MMAE conjugates. They prepared PEG-TRAIL-MMAE conjugates with various PEG/MMAE ratios and compared with each other according to their pharmacokinetics (PK) and pharmacodynamics (PD). The study proved the half-life of rats was prolonged by the conjugation of PEG-TRAIL-MMAE with a PEG/MMAE ratio of 1:2, with the best antitumor activity in vitro and in vivo and no sign of toxicity in xenograft models. It showed that the optimized PEG-TRAIL-MMAE conjugates is a promising multistep drug delivery and antitumor strategy.

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