(28i) Versatile, Rapid, and Trackable Light-Activated Drug Release from Nanocarriers Using a Photo-Cleavable Prodrug Approach for Precise Immuno-Oncology.

Encapsulation of therapeutic agents into nanocarriers has the potential to improve the spatiotemporal control required for precise administration of immune agonist drugs for immuno-oncology. To control the release of such agents, nanocarriers have been designed with triggers responsive to various endogenous stimuli such as pH, oxidation potential, or enzymatic degradation. However, these systems lack the off-on ability required to selectively deliver therapeutic agents to a precise location, and often lead to off-target effects. Nanocarriers responsive to exogenous stimuli (i.e. sonication, light) are becoming increasingly popular because they offer a higher degree of spatiotemporal control as drug release can be manipulated by adjusting the wavelength, intensity, or duration of the external stimulus. Here, we present a versatile, trackable, and rapid light-triggered delivery system for controlled drug release from polymeric nanocarriers. This system uses a photo-cleavable prodrug approach based on the o-hydroxycinnamoyl (o-HA) moiety to obtain the off-on control necessary for spatiotemporal precision. First, we establish a set of photo-cleavable prodrug constructs by covalently linking the o-HA moiety to various parent compounds with different functional groups. We then demonstrate the light-activated cleaving of the prodrug construct to regenerate the parent compound, and an associated fluorescent reporter that enables tracking of the cleavage reaction. Chemically conjugating the parent compound to the o-HA moiety enhances the construct’s hydrophobicity and allows for encapsulation into PEG-PLA nanocarriers. Interestingly, we observe faster reaction kinetics of the light-activated cleavage occurring within the PEG-PLA nanocarriers than that of free construct in solution. Finally, we apply our photo-cleavable prodrug approach to an innate immune agonist and confirm the light-activated release of the drug in vitro. Ultimately, demonstrating the versatility of our light-activated nanocarrier system provides a valuable option to encapsulate therapeutic agents that require precise spatiotemporal drug administration like in immuno-oncology.