Stimuli-Responsive Nanocarriers as Next-Generation on-Demand Drug Delivery Systems for Cancer Therapy: Mechanistic Insights, Trigger Modalities, and Translational Challenges

Chemotherapy has been used in cancer treatment for decades; however, standard chemotherapy treatments still have significant weaknesses, including collateral damage to healthy tissue, rapid development of drug resistance, and dose-limiting toxicity that limits therapeutic value. There is now an alternative approach using polymer materials that are responsive to biological stimuli that will allow for improved treatment of cancer while avoiding the limitations. Responsive polymer materials are designed to be inert during circulation until they reach their site of action; then, they will respond to specific triggers. These smart carriers respond to stimuli present in the tumor microenvironment (e.g., low pH, high glutathione levels, and increased proteolytic activity) or external stimuli applied at the bedside (e.g., localized heat, light, ultrasound, and applied magnetic fields). In both cases, there is a consistent pattern where the drug is released exactly where/when it is needed, with minimal drug release occurring outside that location and timeframe. Therefore, it is theorized that the use of polymeric-based delivery systems with stimuli-regulated drug release will significantly increase the concentration of drug delivered intratumorally, decrease the drug toxicity, and provide a potential mechanism to overcome the development of multidrug resistance from a variety of cancer treatments. To date, various types of responsive polymers have been developed and could be combined to give rise to a wide variety of different vehicle systems (e.g., micelles, nanogels, hydrogels, and hybrid delivery systems), with many of these carriers designed to respond to multiple stimuli simultaneously. Nonetheless, significant challenges remain in the clinical application of these materials due to tumor heterogeneity, immune system interactions, reproducibility issues, polymer chemistry advances, surface chemistry, and other interaction mechanisms. As a result of all of these evolving regulatory systems, as well as some of the emerging areas of polymer chemistry and surface engineering, theranostic integration will allow for new routes to provide therapy for patients with cancer. Additionally, because of these scientific advances, there will also be more opportunities to provide targeted, controllable, and on-demand treatments to patients using stimuli-responsive polymers.