There is still an urgent need for improved treatments for metastatic cancer. Although the phospholipase A(2) (PLA(2)) 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-PLA(2) Conjugate that would reduce PLA(2) systemic toxicity but retain antitumor activity following alpha-amylase triggered degradation of dextrin in the tumor interstitium. Dextrin (M-w similar to 60000 g/mol; similar to 22 mol % succinoylation) and PLA(2) (from honey bee venom) were chosen as models for these initial studies, and the conjugates synthesized contained 6.1 wt % PLA(2), with <1% free enzyme. The conjugate showed decreased (similar to 36%) enzyme activity compared to native PLA(2), but activity was restored to similar to 100% following incubation with alpha-amylase. Whereas dextrin conjugation caused a marked reduction in PLA(2)'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 PLA(2). In these cell lines, cytotoxicity showed partial correlation with the level of EGFR expression. The reduced toxicity and alpha-amylase triggered activity of the dextrin-PLA(2) conjugate confirmed the potential of this approach for further development as a novel anticancer treatment.