Tumour endoproteases: the cutting edge of cancer drug delivery?

Abstract

Despite progression in anticancer drug development and improvements in the clinical utilization of therapies, current treatment regimes are still dependent upon the use of systemic antiproliferative cytotoxic agents. Although these agents are unquestionably potent, their efficacy is limited by toxicity towards 'normal' cells and a lack of tumour selective targeting, resulting in a therapeutic index which is modest at best. Consequently, the development of more tumour selective cancer treatments, with better discrimination between tumour and normal cells is unequivocally an important goal for cancer drug discovery. One such strategy is to exploit the tumour phenotype as a mechanism for tumour-selective delivery of potent therapeutics. An exciting approach in this area is to develop anticancer therapeutics as prodrugs, which are non-toxic until activated by enzymes localized specifically in the tumour. Enzymes suitable for tumour-activated prodrug development must have increased activity in the tumour relative to non-diseased tissue and an ability to activate the prodrug to its active form. One class of enzyme satisfying these criteria are the tumour endoproteases, particularly the serine- and metallo-proteases. These proteolytic enzymes are essential for tumour angiogenesis, invasion and metastasis, the major defining features of malignancy. This review describes the concept behind development of tumour-endoprotease activated prodrugs and discusses the various studies to date that have demonstrated the huge potential of this approach for improvement of cancer therapy.

Figure 1

Schematic representation of tumour endoprotease-activated prodrugs (TAPs). The prodrug is composed of three domains: a potent therapeutic agent (effector), an endoprotease-cleavable peptide sequence (trigger) and a linker to join the trigger to the effector. This TAP remains inactive until activation of the trigger. The presence of the endoprotease in the tumour but not in the ‘normal' tissues results in activation of the TAP trigger selectively in the tumour, causing the release of the potent effector and a subsequent therapeutic effect.

Figure 2

(a) Structure of tumour-activated prodrug incorporating the microtubule-targeted agent vinblastine targeted at the serine protease, prostate-specific antigen (PSA) (DeFeo-Jones et al., 2002). Vinblastine is attached at position 4 to an octapeptide incorporating a PSA-selective cleavage site. The prodrug is endcapped by acetylation to prevent nonspecific exopeptidase activation. (b) Schematic representation of prodrug activation by PSA. The cleavage site for PSA within the peptide is indicated by the arrow. Following the initial cleavage by PSA, the remaining amino-acid residues are removed rapidly by exopeptidases.

Figure 3

(a) Structure of matrix metalloproteinase (MMP)-targeted tumour-activated prodrug incorporating the cytotoxic agent doxorubicin (Albright et al., 2005). Doxorubicin is attached to a heptapeptide incorporating an MMP-selective cleavage site. The prodrug is endcapped by acetylation to prevent nonspecific exopeptidase activation and promote in vivo drug stability. (b) Schematic representation of prodrug activation by MMP with expected cleavage products. The cleavage site for MMP within the peptide is indicated by the arrow. Following the initial cleavage by MMP, the remaining amino-acid residues are removed rapidly by exopeptidases.