įree radicals are highly reactive molecules with an unpaired electron, and reactive oxygen species (ROS) and reactive nitrogen species (RNS) are critical mediators in vivo. We have previously demonstrated that polymer crosslinking can be initiated by naturally occurring free radical species to drive the immobilization and accumulation of a coupled payload in situ. For example, pH, redox status, or enzyme expression are commonly dysregulated in disease. Stimuli-responsive systems are an intriguing alternative strategy that leverage physiological characteristics to initiate drug accumulation or release. Although this approach has high specificity, the ligand-receptor pairs are unique and the receptors are heterogeneously expressed within diseased tissues, reducing the widespread efficacy of antibody-mediated targeting. Antibody-drug conjugates have been approved by the US Food and Drug Administration (FDA) for certain cancer indications, and targeting is achieved through antibodies that bind upregulated receptors on disease cells. Two-phase delivery combined with a library of radical-sensitive chemistries can enhance the versatility and flexibility of this free radical-initiated platform delivery system.ĭrug targeting approaches are increasingly investigated to promote drug accumulation within diseased tissues and reduce side and off-target effects. Delivering thiolated payloads in a second phase, after the initial polymer net formation, allowed greater control over the payload dosing and timing. Thiols were especially reactive and even reacted with acrylates in the absence of free radicals, and this motivated us to explore a two-phase targeting approach. Both the alkene and thiol chemistries crosslinked in the presence of ROS, generating high molecular weight polymer networks that immobilized fluorescent payloads in tissue mimics. The reactivity, toxicity, crosslinking kinetics, and immobilization potential of PEG dialkenes and dithiols were characterized. To build on these promising results, we evaluated PEG dialkenes and dithiols as alternative polymer chemistries for targeting. We have previously demonstrated that native ROS are capable of crosslinking and immobilizing acrylated polyethylene glycol diacrylate (PEGDA) networks and coupled payloads in tissue mimics, providing evidence for a potential targeting mechanism. Native free radicals, such as reactive oxygen species (ROS), are widely upregulated in many pathological states. Stimuli-responsive biomaterials are an emerging strategy that leverage common pathophysiological triggers to target drug delivery to limit or avoid toxic side effects.
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