The enhanced permeability and retention (EPR) effect constitutes the rationale by which nanotechnologies selectively target drugs to tumors. Despite promising preclinical and clinical results, these technologies have, in our view, underachieved compared to their potential, possibly due to a suboptimal exploitation of the EPR effect. Here, we have systematically analyzed clinical data to identify key parameters affecting the extent of the EPR effect. An analysis of 17 clinical studies showed that the magnitude of the EPR effect was varied and was influenced by tumor type and size. Pancreatic, colon, breast, and stomach cancers showed the highest levels of accumulation of nanomedicines. Tumor size also had an effect on the accumulation of nanomedicines, with large-size tumors having higher accumulation than both medium- and very large-sized tumors. However, medium tumors had the highest percentage of cases (100% of patients) with evidence of the EPR effect. Moreover, tumor perfusion, angiogenesis, inflammation in tumor tissues, and other factors also emerged as additional parameters that might affect the accumulation of nanomedicines into tumors. At the end of the commentary, we propose 2 strategies for identification of suitable patient subpopulations, with respect to the EPR effect, in order to maximize therapeutic outcome.

Prototype drug eluting implants have been 3D printed using a supramolecular polyurethane-PEG formulation. The implants are capable of releasing a pharmaceutical active with effective drug release over a period of up to 8.5 months.

We have previously reported the synthesis of a poly(ethylene glycol)-haloperidol (PEGhaloperidol) conjugate that retained affinity for its target D2 receptor and was stable in simulated physiological conditions. We hypothesised that this polymer-drug conjugate would localise haloperidol's activity either centrally or peripherally, dependent on the location of administration, due to the polymer preventing penetration through the blood-brain barrier (BBB). Herein, we validate this hypothesis using in vitro and in vivo studies. We first demonstrate, via a [ 35 S]GTPγS-binding assay, that drug activity is retained after conjugation to the polymer, supportive of retention of effective therapeutic ability. Specifically, the PEGhaloperidol conjugate (at 10 and 100 nM) was able to significantly inhibit dopamine-induced G-protein activation via D2 receptors, albeit with a loss of potency compared to the free haloperidol (~18-fold at 10 nM). This loss of potency was further probed and rationalised using molecular docking experiments, which indicated that conjugated haloperidol can still bind to the D2 receptors, albeit with a flipped orientation in the biding pocket within the receptor, which may explain the reduced activity. Finally, rat catalepsy studies confirmed the restricted permeation of the conjugate through the BBB in vivo. Rats treated intravenously with free haloperidol became cataleptic, whereas normal behaviour was observed in rats that received the PEG-haloperidol conjugate, suggesting that conjugation can effectively prevent unwanted central effects. Taken together these results demonstrate that conjugating small

Polymer-drug conjugates have been intensely studied in the context of improving cancer chemotherapy and yet the only polymer-drug conjugate on the market (Movantik Ò) has a different therapeutic application (relieving opioid-induced constipation). In parallel, a number of studies have recently been published proposing the use of this approach for treating diseases other than cancer. In this commentary, we analyse the many and very diverse applications that have been proposed for polymer-drug conjugates (ranging from inflammation, to cardiovascular diseases) and the rationales underpinning them. We also highlight key design features to be considered when applying polymer-drug conjugates to these new therapeutic areas.