Light‐Triggered Drug Release from Red Blood Cells Suppresses Arthritic Inflammation

Abstract

Arthritis is a leading cause of disability in adults, which can be intensely incapacitating. The location and intensity of the pain is both subjective and challenging to manage. Consequently, patient-directed delivery of anti-inflammatories is an essential component of future therapeutic strategies for the management of this disorder. The design and application of a light-responsive red blood cell (RBC)-conveyed dexamethasone (Dex) construct that enables targeted drug delivery upon illumination of the inflamed site is described. The red wavelength (650 nm) responsive nature of the phototherapeutic is validated using tissue phantoms mimicking the light absorbing properties of various skin types. Furthermore, photoreleased Dex has the same impact on cellular responses as conventional Dex. Murine RBCs containing the photoactivatable therapeutic display comparable circulation properties as fluorescently labeled RBCs. In addition, a single dose of light-targeted Dex delivery is fivefold more effective in suppressing inflammation than the parent drug, delivered serially over multiple days. These results are consistent with the notion that the circulatory system be used as an on-command drug depot, providing the means to therapeutically target diseased sites both efficiently and effectively.

Assessment of Photoreleasable Linkers and Light-Capturing Antennas on a Photoresponsive Cobalamin Scaffold

“…The majority of these derivatives undergo efficient photolysis with high quantum yields. However, a few analogs, such as cyclopropyl-Cbl and decyl-Cbl, display a significant reduction in photolysis rate relative to the standard ligands utilized for Cbl-based phototherapeutics. ,, By contrast, the installation of fluorophores on the ribose 5′-hydroxyl moiety, in the form of photon-capturing “antennas,” enhances the photolysis rate of alkyl-Cbls under challenging tissue-mimetic conditions. In short, the ability to increase or decrease the photosensitivity of drug-linker-Cbl derivatives potentially enables phototherapeutics to be photochemically tuned to the required application (e.g., surface versus deep tissue therapy).…”

“…Alkyl substituents attached to Co of Cbl have long been known to be photolabile at wavelengths absorbed by the corrin ring of Cbl (i.e., 360–550 nm) . Furthermore, a variety of drugs have been covalently appended to short linkers attached to the corrin ring-constrained Co atom and subsequently photoreleased. − However, the range of photoreleasable linkers attached to Co has not been methodically investigated. The linkers assessed to date primarily include members of the standard methyl, ethyl, and propyl series − and, in the case of phototherapeutics, − ethyl and propyl linkers in drug-CO–HNCH 2 CH 2 –Co and drug-NH–COCH 2 CH 2 CH 2 –Co, respectively (Figure ).…”

“…Furthermore, a variety of drugs have been covalently appended to short linkers attached to the corrin ring-constrained Co atom and subsequently photoreleased. − However, the range of photoreleasable linkers attached to Co has not been methodically investigated. The linkers assessed to date primarily include members of the standard methyl, ethyl, and propyl series − and, in the case of phototherapeutics, − ethyl and propyl linkers in drug-CO–HNCH 2 CH 2 –Co and drug-NH–COCH 2 CH 2 CH 2 –Co, respectively (Figure ). In addition, although alkyl-Cbls undergo photolysis at the short wavelengths (<550 nm) absorbed by the corrin ring system, the extinction coefficients are modest (ε <10,000 M –1 cm –1 ).…”

Reaching new lights: a review on photo-controlled nanomedicines and theirin vivoevaluation

“…49,50 Notably, some of these advances have been made with body-native cells, employing them as tumor-targeted drug delivery vectors or as a circulatory dynamic drug depot. 51,52 In this review, we will discuss these recent advancements in the development of light-responsive DDS. As one of the major promises of DDS formulations entails improved pharmacokinetics and reduced systemic toxicity, we feel that a focus on photo-controllable DDS that have been evaluated in vivo is beneficial to provide a comprehensive overview.…”

“…49,50 Notably, some of these advances have been made with body-native cells, employing them as tumor-targeted drug delivery vectors or as a circulatory dynamic drug depot. 51,52…”