Lessons in simplicity that should shape the future of drug delivery

VOLUME 33 NUMBER 10 OCTOBER 2015 NATURE BIOTECHNOLOGY Unfortunately, given the slow pace of drug delivery research breakthroughs in recent decades, the ability to exploit simple physiological aspects like pH in the gastrointestinal tract may be the exception rather than the rule. It seems that the complexity of the biological barriers faced by a drug on its way to its target site has repeatedly confounded attempts to achieve efficient delivery, particularly for intracellular targets and for complex and multifactorial pathologies like cancer, which are notorious for their interand intrapatient heterogeneity. One ubiquitous property associated with tumors, first described by Hiroshi Maeda in the 1980s, is the so-called enhanced permeation and retention (EPR) effect, which allows anti-cancer nanomedicines to accumulate in solid tumor tissue6. The attractiveness of EPR again lies within its simplicity, being the size-selective filtering through the fenestrated tumor endothelium. Unfortunately, some tumor types are not amenable to EPR-based targeting owing to pre-existing heterogeneity in their vasculature. Possibly this explains why 30 years after the discovery of this widespread biological mechanism, we have yet to witness its widespread translation into therapeutic products. Therefore, pharmacological approaches (e.g., antiangiogenic treatment) or physical strategies (e.g., ultrasound) that modulate the EPR effect, thereby rendering it more robust and generally applicable, could possibly rekindle EPR-based tumor targeting7–9. The Editorial1 declared that drug delivery research should evolve into a discipline more at the interface of material science and cell biology. In contrast to the enteric coating, PEGylation and sustained protein release, which mainly deal with drug delivery aspects at the extracellular level, the advent of therapeutics with intracellular targets imposes additional cellular barriers to efficient drug delivery. Studying these barriers in more detail could provide To the Editor: Your Editorial in the October 2014 issue argued that drug delivery researchers should adopt a new way of thinking1. Instead of pursuing safe and efficient drug delivery systems in a rather empirical way—as frequently occurs today—you suggested more emphasis should be placed on finding and understanding biological mechanisms that drive the delivery process. Although we agree this is an important aim, we believe it is of equal importance to stress some valuable lessons from the decades of drug delivery research that lie behind us2. Many successful delivery concepts from the past, which have instigated important breakthroughs, were largely based on simple, substantial and robust physicochemical or biological principles. In the late 1950s, enteric coating of capsules and tablets using pH-responsive polymers allowed protection of labile therapeutics in the harsh conditions of the stomach and site-specific delivery in the intestine2. Although merely based on a simple pH difference between the gastric and the enteric region, the principle is still employed today in pharmaceutical development of oral dosage forms. As another example, in the 1960s Frank Davis of Rutgers University (Piscataway, NJ, USA) almost accidentally stumbled upon a rather rudimentary hydrophilic polymer, polyethylene glycol (PEG), in pursuit of a strategy to mitigate adverse immunological responses to non-human pharmaceutical proteins3. He additionally observed that PEGylation of proteins could substantially increase their circulation time in the bloodstream. Again, albeit a relatively simple solution to bypass our body’s defenses, the effect of PEGylation appears to be substantial and robust, likely explaining why PEGylation continues to inspire researchers today in the design of long-circulating nanomedicines, and also partially explaining the success of Doxil (doxorubicin hydrochloride liposome), which was the first US Food and Drug Administration (FDA)-approved nanomedicine4. Similarly, in the 1970s, Bob Langer at the Massachusetts Institute of Technology (MIT; Cambridge, MA, USA) observed that labile proteins gradually leaked from hydrophobic polymer matrices while maintaining their activity: again, a simple observation that heralded the important concept of sustained protein release5. This discovery laid the foundations for the development of injectable microparticulate drug depots, which are in clinical use today. Although these technologies were considered cuttingedge at the time, they remain rather simple solutions to a drug delivery problem in our contemporary view. Importantly, however, we believe that the fact that these ideas were centered on generic, robust and reproducible traits largely accounts for their pervasive exploitation in clinically approved therapeutic products. Lessons in simplicity that should shape the future of drug delivery CORRESPONDENCE