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From Nano to Micro: Versatile Strategies for Near-Infrared Light-controlled Nitric Oxide Delivery and Their Therapeutic Applications


Nitric oxide (NO) has attracted considerable attention due to its promising applications in cancer treatment. The therapeutic effect of NO pro-drugs greatly depends on the concentration, duration and the specific site of NO delivered. Photochemical delivery can control the timing, dosage and location of NO release by administering the intensity and location of light irradiation. However, there are key challenges associated with using such photo-activated NO releasing molecules ("photoNORMs"). One is to activate these precursors with tissue penetrating near infrared (NIR) light, while another is to deliver these precursors directly to inflammatory sites, including tumors. Here, we describe two different NIR light-activated NO releasing composites with nano and micron size, and demonstrate their delivery strategies to cancer cells and tumor spheroids by using cell penetrating peptides (CPPs) and macrophages mediation respectively.

For the nano-delivery, we developed new nano-carriers with graphene quantum dots (GQDs) as photo-active cores, lipophilic domains and a surface modified with cell- penetrating peptides. The lipophilic domains in the CPP-nano-carriers can be loaded with hydrophobic photoNORMs. Such CPPs can overcome the barrier of cellular membranes and efficiently deliver our nano-carriers inside the cell. Moreover, GQD is able to absorb 794 nm photon and transfer energy to trigger NO release from the NO precursors in lipophilic domains. We showed NO photo-release in HeLa cancer cells under 794 nm laser irradiation can be visualized by using a fluorescent NO probe dye (DAF-FM-2DA).

For the micro-delivery, we applied bone marrow macrophages (BMMs) as "Trojan horses" to deliver biocompatible polymer micro-particles incorporating photoNORMs and upconversion nanoparticles (UCNPs) to breast cancer spheroids. Both components are activated by tissue penetrating NIR light allowing for simultaneous therapeutic NO delivery and photoluminescence (PL) imaging capabilities with a single NIR laser source. By varying light source intensity, we were able to garner control over NO release rates reducing hypoxia inducible factor 1 alpha (HIF-1α) levels with low doses of NO while demonstrating direct cytoxicity to spheroids with high doses of NO.

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