Multiple myeloma (MM), a hematologic malignancy that preferentially colonizes the bone marrow, remains incurable with a survival rate of 3 to 6 mo for those with advanced disease despite great efforts to develop effective therapies. Thus, there is an urgent clinical need for innovative and more effective MM therapeutics. Insights suggest that endothelial cells within the bone marrow microenvironment play a critical role. Specifically, cyclophilin A (CyPA), a homing factor secreted by bone marrow endothelial cells (BMECs), is critical to MM homing, progression, survival, and chemotherapeutic resistance. Thus, inhibition of CyPA provides a potential strategy to simultaneously inhibit MM progression and sensitize MM to chemotherapeutics, improving therapeutic response. However, inhibiting factors from the bone marrow endothelium remains challenging due to delivery barriers. Here, we utilize both RNA interference (RNAi) and lipid–polymer nanoparticles to engineer a potential MM therapy, which targets CyPA within blood vessels of the bone marrow. We used combinatorial chemistry and high-throughput in vivo screening methods to engineer a nanoparticle platform for small interfering RNA (siRNA) delivery to bone marrow endothelium. We demonstrate that our strategy inhibits CyPA in BMECs, preventing MM cell extravasation in vitro. Finally, we show that siRNA-based silencing of CyPA in a murine xenograft model of MM, either alone or in combination with the Food and Drug Administration (FDA)-approved MM therapeutic bortezomib, reduces tumor burden and extends survival. This nanoparticle platform may provide a broadly enabling technology to deliver nucleic acid therapeutics to other malignancies that home to bone marrow.
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COoking with gas Low concentrations of carbon monoxide (CO) have shown therapeutic benefit in preclinical models, but safe delivery of appropriate dose has been challenging to achieve. Here, inspired by molecular gastronomy, Byrne et al . designed gas-entrapping materials (GEMs) using components generally recognized as safe, including xanthan gum, methylcellulose, maltodextrin, and corn syrup. Solid, hydrogel, and foam GEMs containing CO could deliver different concentrations of the gas to healthy rodents and pigs through noninhaled routes. In rodent models of colitis, acetaminophen overdose, and radiation-induced proctitis, rectally administered foam GEMs reduced tissue injury and inflammation. Foam GEMs could help achieve safe therapeutic CO delivery.more » « less
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Abstract Accurate medical recordkeeping is important for personal and public health. Conventional forms of on‐patient medical information, such as medical alert bracelets or finger‐markings, may compromise patient privacy because they are readily visible to other people. Here, the development of an invisible, temporary, and easily deployable on‐patient medical recordkeeping system is reported. Information is stored in unique patterns of spatially distributed near‐infrared (NIR) fluorescent quantum dots (QDs), which are delivered to the skin using dissolvable microneedle arrays. The patterns are invisible to the naked eye but detectable with an infrared camera, which can extract information with >98% accuracy using automated pattern recognition software. By encapsulating NIR QDs in an FDA‐approved biodegradable polymer, biodegradation rates can be tuned so that the encoded medical information can be conveyed in both a spatial and temporal manner, with some components fading within 100 days and others persisting for 6 months. This may be particularly useful for administering a series of vaccinations or treatments by indicating if enough time has passed for the patient to receive the next dose. Importantly, this system contains no personal information, does not require connection to a centralized database, and is not visible to the naked eye, ensuring patient privacy.
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Abstract The development of new material platforms can improve our ability to study biological processes. Here, we developed a water‐compatible variant of a click‐like polymerization between alkynoates and secondary amines to form β‐aminoacrylate synthetic polyethylene glycol (PEG) based hydrogels. These materials are easy to access—PEG alkynoate was synthesized on a 100 gram scale and the amines were available commercially; these materials are also operationally simple to formulate—gel formation occurred upon simple mixing of precursor solutions without the need for initiators, catalysts, nor specialized equipment. Three‐dimensional cell culture experiments also indicated cytocompatibility of these gels with >90 % viability retained in THP‐1 and NIH/3T3 cells after 72 hours in culture. This hydrogel system therefore represents an alternative platform to other click and click‐like hydrogels with improved accessibility and user‐friendliness for biomaterials application.
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Abstract Submucosal elevation, the process of instilling material in the submucosal space for separation of the surface mucosa and deeper muscularis layer, is a significant aspect of the endoscopic mucosal resection of large lesions performed to facilitate lesion removal and maximize safety. Submucosal injection, when applied, has historically been performed with normal saline, though this is limited by its rapid dissipation; solutions ideally need to be easily injectable, biocompatible, and provide a long‐lasting submucosal cushion with a desirable height. Here, reported is a new set of materials, endoscopically injectable shear‐thinning hydrogels, meeting these requirements because of their biocompatible components and ability to form a solid hydrogel upon injection. These findings are supported by evaluation in a large animal model and ultimately demonstrate the potential of these shear‐thinning hydrogels to serve as efficient submucosal injection fluids for cushion development. Given these unique characteristics, their broad application in mucosal resection techniques is anticipated.