Abstract
Polymer-drug conjugates have demonstrated clinical potential in the context of anticancer therapy. However, such promising results have, to date, failed to translate into a marketed product. Polymer-drug conjugates rely on two factors for activity: (i) the presence of a defective vasculature, for passive accumulation of this technology into the tumour tissue (enhanced permeability and retention (EPR) effect) and (ii) the presence of a specific trigger at the tumour site, for selective drug release (e.g., the enzyme cathepsin B). Here, we retrospectively analyse literature data to investigate which tumour types have proved more responsive to polymer-drug conjugates and to determine correlations between the magnitude of the EPR effect and/or expression of cathepsin B. Lung, breast and ovarian cancers showed the highest response rate (30%, 47% and 41%, respectively for cathepsin-activated conjugates and 31%, 43%, 40%, across all conjugates). An analysis of literature data on cathepsin content in various tumour types showed that these tumour types had high cathepsin content (up to 3835 ng/mg for lung cancer), although marked heterogeneity was observed across different studies. In addition, these tumour types were also reported as having a high EPR effect. Our results suggest that a pre-screening of patient population could bring a more marked clinical benefit.
Highlights
Polymer-drug conjugates (PDCs) are nano-sized drug delivery systems, in which one or more chemotherapeutic agent is covalently linked to a water-soluble polymer (Figure 1a) [1,2]
Priority was given to articles related to PDCs, as the enhanced permeability and retention (EPR) effect is a phenomenon that applies to any macromolecular system, clinical and preclinical data relating to other such systems were included
The main clinical outcomes have been summarized in extensive reviews [55,56,57], but, as yet, a detailed analysis of which tumour types are proving more responsive to this type of drug delivery technology is still missing
Summary
Polymer-drug conjugates (PDCs) are nano-sized drug delivery systems, in which one or more chemotherapeutic agent is covalently linked to a water-soluble polymer (Figure 1a) [1,2]. The main rationale for PDCs stems from their ability to passively accumulate into the tumour tissue by means of the enhanced permeability and retention (EPR) effect (Figure 1b) [3]. Of greater significance, the anti-tumour activity of PDCs relies on two factors: (a) passive tumour accumulation via the EPR effect; (b) drug release following a biological stimulus (e.g., enzyme or pH) (Figure 1c). We retrospectively analyse data obtained from the literature concerning clinical trials carried out on PDCs in order to determine whether there is a connection between the clinical responses of various tumour types and the levels of enzyme expression/magnitude of the EPR effect in such tumour types. We determined the extent of the EPR effect, which has been, reported for these various tumour types
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