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

Abstract

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.

Nanoformulation of the K-Ras(G12D)-inhibitory peptide KS-58 suppresses colorectal and pancreatic cancer-derived tumors

“…4 , various nanomedicines have shown pharmacological efficacy in subcutaneous tumor-bearing mouse models; however, there are few reports in pancreatic cancer models 28 , 29 . One of the reasons is that angiogenesis occurs in subcutaneously implanted tumors, which facilitates the EPR effect; however, tumors formed in the pancreas are covered with stroma and have few blood vessels making it difficult to demonstrate an EPR effect 28 , 29 . KS-58 NPs showed a clear pharmacological effect not only in subcutaneous tumor-bearing mice (Fig.…”

Multimodal Therapies against Pancreatic Ductal Adenocarcinoma: A Review on Synergistic Approaches toward Ultimate Nanomedicine Treatments

“…The application of nanotechnology to the medical field, termed nanomedicine, [31][32][33] is enabling novel treatments to enter preclinical and clinical trials, with the aim of overcoming the limitations shown by conventional therapies: to mention but a few, light-and ultrasound-triggered minimally invasive techniques such as sonodynamic and photodynamic therapy have recently been applied to PDAC. [34,35] In addition to that, an ever-increasing knowledge of this particularly resistant tumor and its hallmarks has progressively led to the adoption of innovative and smart approaches: targeted therapies to avoid multidrug resistance and systemic toxicity, [36,37] stromal therapies aimed at a TME and vessel normalization, [38][39][40][41] the use of exosomes as nanocarriers for gene therapy.…”

Nanotheranostics for Image-Guided Cancer Treatment

“…The concept of “targeted drug delivery” in cancer promises to focus the effects of anticancer agents onto the cancer cells themselves, avoiding, as much as possible, cytotoxic effects on healthy, non-cancerous cells. This would not only aim to minimize systemic side effects but could also enable the delivery of higher drug doses locally and help to act against mechanisms of drug resistance [ 1 , 2 ].…”