Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance.

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Simple SummaryDespite access to a vast arsenal of anticancer agents, many fail to realise their full therapeutic potential in clinical practice. One key determinant of this is the evolution of multifaceted resistance mechanisms within the tumour that may either pre-exist or develop during the course of therapy. This is particularly evident in pancreatic cancer, where limited responses to treatment underlie dismal survival rates, highlighting the urgent need for new therapeutic approaches. Here, we discuss the major features of pancreatic tumours that contribute to therapy resistance, and how they may be alleviated through exploitation of the mounting and exciting promise of nanomedicines; a unique collection of nanoscale platforms with tunable and multifunctional capabilities that have already elicited a widespread impact on cancer management.The development of drug resistance remains one of the greatest clinical oncology challenges that can radically dampen the prospect of achieving complete and durable tumour control. Efforts to mitigate drug resistance are therefore of utmost importance, and nanotechnology is rapidly emerging for its potential to overcome such issues. Studies have showcased the ability of nanomedicines to bypass drug efflux pumps, counteract immune suppression, serve as radioenhancers, correct metabolic disturbances and elicit numerous other effects that collectively alleviate various mechanisms of tumour resistance. Much of this progress can be attributed to the remarkable benefits that nanoparticles offer as drug delivery vehicles, such as improvements in pharmacokinetics, protection against degradation and spatiotemporally controlled release kinetics. These attributes provide scope for precision targeting of drugs to tumours that can enhance sensitivity to treatment and have formed the basis for the successful clinical translation of multiple nanoformulations to date. In this review, we focus on the longstanding reputation of pancreatic cancer as one of the most difficult-to-treat malignancies where resistance plays a dominant role in therapy failure. We outline the mechanisms that contribute to the treatment-refractory nature of these tumours, and how they may be effectively addressed by harnessing the unique capabilities of nanomedicines. Moreover, we include a brief perspective on the likely future direction of nanotechnology in pancreatic cancer, discussing how efforts to develop multidrug formulations will guide the field further towards a therapeutic solution for these highly intractable tumours.