Stimuli-responsive self-assembling materials comprising amphiphilic copolymers for localized remotely triggered therapeutic delivery

Abstract

The ability to introduce therapeutic at a specified location and time to a healing traumatic wound deep within the body by external non-invasive stimulus could provide great long-term benefit to patients. In this work, we have examined systems consisting of or including amphiphilic copolymers towards deep-tissue externally triggered localized therapeutic delivery applications. First, we probed a polyelectrolyte multilayer incorporating poly(L-glutamic acidtriethylene glycol-diclofenac) copolymer micellar aggregates for near-infrared responsive enhanced therapeutic delivery. It was discovered that the films released small-molecule non-steroidal anti-inflammatory drug diclofenac up to five-fold faster during remote irradiation with near-infrared. The near-infrared source was effective at generating more-rapid release from films with tissue mimic penetration depths of at least twelve centimeters. Irradiations in immediate succession produced diminishing rates of release. The highly near-infrared responsive behavior was attributed to a delayed-elution mechanism. In this mechanism, the diclofenac was first hydrolytically cleaved from unimers in the film and then resided within the hydrophobic cores of micellar aggregates until freed by energy imparted by the near-infrared irradiation. Gold nanorods were incorporated into the films to enhance the response of the films to near infrared above controls. Due to non-covalent suspension of the nanorods, aggregation led to a kinetically dependent enhancement of performance. Next, we improved the synthesis of a copolymer of 2-(dimethylamino)ethyl methacrylate with a spiropyran methacrylate by atom transfer radical polymerization for increased kinetic control. From there, we optimized the composition of this multiresponsive copolymer such that isomerization of the spiropyran moiety brought about a solubility transition surrounding 37°C. This property of the copolymer was designed such that the solubility shift by remote photo-trigger would bring about therapeutic release in a polymer multilayer system analogous to the diclofenac system. Overall, this work demonstrates the utility of engineering amphiphilic copolymers as a powerful approach to impart remotely triggerable therapeutic release properties for use with implants deeply located within the body.