Dextrin−Phospholipase A₂: Synthesis and Evaluation as a Bioresponsive Anticancer Conjugate

Current address: Wound Biology Group, Tissue Engineering & Reparative Dentistry, School of Dentistry, Cardiff University, Heath Park, Cardiff, CF14 4XY, U.K.

There is still an urgent need for improved treatments for metastatic cancer. Although the phospholipase A₂ (PLA₂) crotoxin, an antitumor protein that appears to act by interaction with epidermal growth factor receptors (EGFR), has recently shown activity in breast cancer in phase I clinical trials, it also displayed nonspecific neurotoxicity. Therefore, the aim of this study was to apply a novel concept called polymer-masked-unmasked-protein therapy (PUMPT) to give a bioresponsive dextrin−PLA₂ conjugate that would reduce PLA₂ systemic toxicity but retain antitumor activity following α-amylase triggered degradation of dextrin in the tumor interstitium. Dextrin (M_w 60000 g/mol; 22 mol % succinoylation) and PLA₂ (from honey bee venom) were chosen as models for these initial studies, and the conjugates synthesized contained 6.1 wt % PLA₂, with <1% free enzyme. The conjugate showed decreased (36%) enzyme activity compared to native PLA₂, but activity was restored to 100% following incubation with α-amylase. Whereas dextrin conjugation caused a marked reduction in PLA₂’s hemolytic activity, the conjugate was cytotoxic toward MCF-7, HT29, and B16F10 cells at a level that was comparable to, or greater than, that seen for free PLA₂. In these cell lines, cytotoxicity showed partial correlation with the level of EGFR expression. The reduced toxicity and α-amylase triggered activity of the dextrin−PLA₂ conjugate confirmed the potential of this approach for further development as a novel anticancer treatment.