The integration of triggered drug delivery with real time quantification using FRET; creating a super ‘smart’ drug delivery system

Abstract

The ability to control drug release at a specific physiological target enables the possibility of an enhanced therapeutic effect with reduced off-target toxic side effects. The discipline of controlled drug release has grown to include most areas of medicine with examples in the literature of targeted drug delivery to the majority of organs within the human body. In addition, a variety of external stimuli used to meditate the drug release process have also been investigated. Nonetheless, the concurrent real time monitoring of drug release has not been widely studied. In this manuscript, we present a novel micellar drug delivery system that is not only capable of releasing its cargo when stimulated by light but also provides a real time analysis of the amount of cargo remaining. Controlled drug release from the delivery system was mediated by physicochemical changes of a spiropyran-merocyanine photochromic dyad, while drug quantification was enabled using a Förster Resonance Energy Transfer (FRET) relationship between the photochrome and a co-encapsulated BODIPY fluorophore. The percentage of drug released from the delivery system was significantly greater (24%) when exposed to light irradiation compared to an analogous control maintained in the dark (5%). Furthermore, the fluorescence read-out capability also enabled the drug-release process to be followed in living cells with a significantly reduced fluorescence emission observed for those cells incubated with the delivery system and exposed to light irradiation compared to control cells maintained in the dark. Combined, these results highlight the utility of this approach to theranostic drug delivery with the potential of light-triggered released together with a fluorescence read-out to enable quantification of the drug release process.

Remote Light‐Responsive Nanocarriers for Controlled Drug Delivery: Advances and Perspectives

“…The cis ‐to‐ trans isomerization can be achieved by illumination with Vis light (λ > 400 nm) or heating ( Scheme a) . SP is a hydrophobic moiety and able to isomerize to hydrophilic trans conformation, merocyanine (MC), under UV irradiation via intramolecular carbon–oxygen bond breakage (Scheme b) . Similar to AZO, Vis light or heating can induce the trans ‐to‐ cis isomerization.…”

Spiropyran-Based Drug Delivery Systems

“…In 2017, Aibani et al investigated a novel light-responsive DDS, which showed both controlled release of the loaded therapeutic agent and simultaneous real-time analysis of the quantity of therapeutic remaining in the micellar nanocarrier ( Aibani et al, 2017 ). The micellar drug carrier was composed of an amphiphilic copolymer, which consisted of a hydrophilic PEG monomer and a hydrophobic C10 decyl chain monomer, both containing a methacrylate functional group; this amphiphilic copolymer was previously shown to be biocompatible ( Yildiz et al, 2011 ).…”

“…Overall, this system shows promise for its ability to incorporate various hydrophobic APIs, thus offering a route for solubilising them. Also, drug release can be monitored by taking advantage of FRET communication between two different chromophores in the micelles’ hydrophobic core ( Aibani et al, 2017 ).…”

Recent advances in drug release monitoring

“…These two polymer nanoassemblies were used to monitor the amount of drug remaining in the hydrophobic core in real time and detect metastatic tumors in a tissue pH-dependent manner. Aibani et al [57] exploited differences in the hydrophobic/hydrophilic balance between two isomers, spiropyran and merocyanine, to mediate drug release from a polymer micelle. The stable spiropyran with closed hydrophobic four-ring system preferentially favors a non-polar environment, whereas light irradiation can convert to its zwittrionic merocyanine counterpart with open ring, which prefers a more hydrophilic environment.…”