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Except for routine scaling and root planing, there are few effective nonsurgical therapeutic interventions for periodontitis and associated alveolar bone loss. Simvastatin (SIM), one of the 3-hydroxy-3-methylglutaryl-cosenzyme A reductase inhibitors, which is known for its capacity as a lipid-lowering medication, has been proven to be an effective anti-inflammatory and bone anabolic agent that has shown promising benefits in mitigating periodontal bone loss. The local delivery of SIM into the periodontal pocket, however, has been challenging due to SIM’s poor water-solubility and its lack of osteotropicity. To overcome these issues, we report a novel SIM formulation of a thermoresponsive, osteotropic, injectable hydrogel (PF127) based on pyrophosphorolated pluronic F127 (F127-PPi). After mixing F127-PPi with F127 at a 1:1 ratio, the resulting PF127 was used to dissolve free SIM in order to generate the SIM-loaded formulation. The thermoresponsive hydrogel’s rheologic behavior, erosion and SIM release kinetics, osteotropic property and biocompatibility were evaluated in vitro. Therapeutic efficacy of SIM-loaded PF127 hydrogel on periodontal bone preservation and inflammation resolution was validated in a ligature-induced periodontitis rat model. Given that SIM is already an approved medication for hyperlipidemia, the data presented here support the translational potential of the SIM-loaded PF127 hydrogel for better clinical management of periodontitis and associated pathologies.

Due to their potent immunosuppressive and anti-inflammatory effects, glucocorticoids (GCs) are the most widely used medications in treating lupus nephritis (LN). Long-term use of GCs, however, is associated with numerous off-target adverse effects. To reduce GCs' adverse effects, we previously developed two polymeric dexamethasone prodrug nanomedicines: N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based dexamethasone prodrug (P-Dex), and micelle-forming polyethylene glycol (PEG)-based dexamethasone prodrug (ZSJ-0228). Both P-Dex and ZSJ-0228 provided sustained amelioration of LN in lupus-prone NZB/W F1 mice with reduced GC-associated adverse effects. Here, we have extended our investigation to the MRL/lpr mouse model of LN. Compared to dose equivalent daily dexamethasone sodium phosphate (Dex) treatment, monthly P-Dex or ZSJ-0228 treatments were more effective in reducing proteinuria and extending the lifespan of MRL/lpr mice. Unlike the daily Dex treatment, ZSJ-0228 was not associated with measurable GC-associated adverse effects. In contrast, adrenal gland atrophy was observed in P-Dex treated mice.

We discovered tetrahydro-γ-carboline sulfonamides as a new antischistosomal chemotype. The aryl sulfonamide and tetrahydro–γ–carboline substructures were required for high antischistosomal activity. Increasing polarity improved solubility and metabolic stability but decreased antischistosomal activity. We identified two compounds with IC(50) values < 5 μM against ex vivo Schistosoma mansoni.

Intra-articular (IA) glucocorticoids (GC) are commonly used for clinical management of both osteoarthritis and rheumatoid arthritis, but their efficacy is limited by the relatively short duration of action and associated side effects. To provide sustained efficacy and to improve the safety of GCs, we previously developed a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrug. Serendipitously, we discovered that, by increasing the Dex content of the prodrug to unusually high levels, the aqueous solution of the polymeric prodrug becomes thermoresponsive, transitioning from a free-flowing liquid at 4 °C to a hydrogel at 30 °C or greater. Upon IA injection, the prodrug solution forms a hydrogel (ProGel-Dex) that is retained in the joint for more than 1 month, where it undergoes gradual dissolution, releasing the water-soluble polymeric prodrug. The released prodrug is swiftly internalized and intracellularly processed by phagocytic synoviocytes to release free Dex, resulting in sustained amelioration of joint inflammation and pain in rodent models of inflammatory arthritis and osteoarthritis. The low molecular weight (6.8 kDa) of the ProGel-Dex ensures rapid renal clearance once it escapes the joint, limiting systemic GC exposure and risk of potential off-target side effects. The present study illustrates the translational potential of ProGel-Dex as a potent opioid-sparing, locally delivered adjuvant analgesic for sustained clinical management of arthritis pain and inflammation. Importantly, the observed thermoresponsive properties of the prodrug establishes ProGel as a platform technology for the local delivery of a broad spectrum of therapeutic agents to treat a diverse array of pathological conditions.

HPMA copolymer-based dexamethasone prodrug (P-Dex) and PEG-based dexamethasone prodrug (PEG-Dex, ZSJ-0228) were previously found to passively target the inflamed kidney and provide potent and sustained resolution of nephritis in NZB/WF1 lupus-prone mice. While both prodrug nanomedicines effectively ameliorate lupus nephritis, they have demonstrated distinctively different safety profiles. To explore the underlining mechanisms of these differences, we conducted a head-to-head comparative PK/BD study of P-Dex and PEG-Dex on NZB/WF1 mice. Overall, the systemic organ/tissue exposures to P-Dex and Dex released from P-Dex were found to be significantly higher than those of PEG-Dex. The high prodrug concentrations were sustained in kidney for only 24 h, which cannot explain their lasting therapeutic efficacy (>1 month). P-Dex showed sustained presence in liver, spleen and adrenal gland, while the presence of PEG-Dex in these organs was transient. This difference in PK/BD profiles may explain PEG-Dex’ superior safety than P-Dex.

A general protocol for the challenging cyanofluoroalkylation of unactivated alkenes is disclosed. A broad range of synthetically useful di- and mono-fluorinated alkyl nitriles are readily obtained in good yields under mild reaction conditions. The efficient combination of intramolecular cyano migration and photoredox catalysis significantly expands the field of difunctionalization of olefins.

Periodontitis is a chronic inflammatory disease caused by complex interactions between the host immune system and pathogens that affect the integrity of periodontium. To prevent disease progression and thus preserve alveolar bone structure, simultaneous anti-inflammatory and osteogenic intervention are essential. Hence, a glycogen synthase kinase 3 beta inhibitor (BIO) was selected as a potent inflammation modulator and osteogenic agent to achieve this treatment objective. BIO's lack of osteotropicity, poor water solubility, and potential long-term systemic side effects, however, have hampered its clinical applications. To address these limitations, pyrophosphorylated Pluronic F127 (F127-PPi) was synthesized and mixed with regular F127 to prepare an injectable and thermoresponsive hydrogel formulation (PF127) of BIO, which could adhere to hard tissue and gradually release BIO to exert its therapeutic effects locally. Comparing to F127 hydrogel, PF127 hydrogels exhibited stronger binding to hydroxyapatite (HA). Additionally, BIO's solubility in PF127 solution was dramatically improved over F127 solution and the improvement was proportional to the polymer concentration. When evaluated on a rat model of periodontitis, PF127-BIO hydrogel treatment was found to be very effective in preserving alveolar bone and ligament, and preventing periodontal inflammation, as shown by the micro-CT and histological data, respectively. Altogether, these findings suggested that the thermoresponsive PF127 hydrogel is an effective local drug delivery system for better clinical management of periodontitis and associated pathologies.

The addictive potential of clinically used opioids as a result of their direct action on the dopaminergic reward system in the brain has limited their application. In an attempt to reduce negative side effects as well as to improve the overall effectiveness of these analgesics, we have designed, synthesized, and evaluated an N-(2-hydroxypropyl)methacrylamide (HPMA)-based macromolecular prodrug of hydromorphone (HMP), a commonly used opioid. To this end, P-HMP was synthesized via RAFT polymerization and a subsequent polymer analogous reaction. Its interaction with inflammatory cells in arthritic joints was evaluated in vitro using a RAW 264.7 cell culture, and subsequent confocal microscopy analysis confirmed that P-HMP could be internalized by the cells via endocytosis. In vivo imaging studies indicated that the prodrug can passively target the arthritic joint after systemic administration in a rodent model of monoarticular adjuvant-induced arthritis (MAA). The inflammatory pain-alleviating properties of the prodrug were assessed in MAA rats using the incapacitance test and were observed to be similar to dose-equivalent HMP. Analgesia through mechanisms at the spinal cord level was further measured using the tail flick test, and it was determined that the prodrug significantly reduced spinal cord analgesia versus free HMP, further validating the peripheral restriction of the macromolecular prodrug. Immunohistochemical analysis of cellular uptake of the P-HMP within the MAA knee joint proved the internalization of the prodrug by phagocytic synoviocytes, colocalized with HMP's target receptor as well as with pain-modulating ion channels. Therefore, it can be concluded that the novel inflammation-targeting polymeric prodrug of HMP (P-HMP) has the potential to be developed as an effective and safe analgesic agent for musculoskeletal pain.

We herein disclose an efficient manganese-promoted hydrazination of cyclobutanols through cyclic C-C bond cleavage. The ring opening occurs under mild reaction conditions, readily affording a variety of alkyl hydrazines in synthetically useful yields and exclusive regioselectivities. The chain reaction mechanism involving the addition of alkyl carbon radical to azodicarboxylate is proposed.

Cyclobutanols serve as privileged precursors for the preparation of γ-substituted ketones. We highlight recent advances in the radical-mediated ring-opening functionalization of cyclobutanols by fluorination, chlorination, bromination, or azidation, which open up a new vista for the synthesis of ketone derivatives. 1 Introduction 2 Silver-Catalyzed Fluorination, Chlorination, and Bromination of Cyclobutanols 3 Manganese-Catalyzed Azidation of Cyclobutanols 4 Conclusion

A manganese-catalyzed regioselective sp(3) C-S bond formation through C-C bond cleavage of cyclobutanols is described. A variety of primary and secondary alkyl thioethers are efficiently prepared under mild reaction conditions. The mechanistic pathways involving radical-mediated tandem C-C bond cleavage and C-S bond formation are proposed.

A conceptually new, efficient, and metal-free approach for the challenging azidocyanation of unactivated alkenes is presented. The strategy of intramolecular distal cyano migration is combined with alkene difunctionalization for the first time. A variety of useful azido-substituted alkyl nitriles are prepared in good yields and, most importantly, with exquisite regio- and stereo-selectivities.

Cyclobutanols serve as privileged precursors for the preparation of γ-substituted ketones. We highlight recent advances in the radical-mediated ring-opening functionalization of cyclobutanols by fluorination, chlorination, bromination, or azidation, which open up a new vista for the synthesis of ketone derivatives. 1 Introduction 2 Silver-Catalyzed Fluorination, Chlorination, and Bromination of Cyclobutanols 3 Manganese-Catalyzed Azidation of Cyclobutanols 4 Conclusion

A novel C-C bond-forming strategy employing manganese-catalyzed ring-opening of cyclobutanol substrates, followed by cyanation or ethynylation, is described. A cyano C1 unit and ethynyl C2 unit are regiospecifically introduced to the γ-position of ketones at room temperature, providing a mild yet powerful method for production of elusive aliphatic nitriles and alkynes. All transformations described are based on a common sequence: 1) oxidative ring-opening of cyclobutanol substrates by C-C bond cleavage; 2) radical addition to triple bonds bearing an arylsulfonyl group; and 3) radical-mediated C-S bond cleavage.

A conceptually new, efficient, and metal-free approach for the challenging azidocyanation of unactivated alkenes is presented. The strategy of intramolecular distal cyano migration is combined with alkene difunctionalization for the first time. A variety of useful azido-substituted alkyl nitriles are prepared in good yields and, most importantly, with exquisite regio- and stereo-selectivities.

This novel azidation method allows the synthesis of a wide range of primary, secondary, and tertiary alkyl azides with exclusive regioselectivity.

A novel C-C bond-forming strategy employing manganese-catalyzed ring-opening of cyclobutanol substrates, followed by cyanation or ethynylation, is described. A cyano C1 unit and ethynyl C2 unit are regiospecifically introduced to the γ-position of ketones at room temperature, providing a mild yet powerful method for production of elusive aliphatic nitriles and alkynes. All transformations described are based on a common sequence: 1) oxidative ring-opening of cyclobutanol substrates by C-C bond cleavage; 2) radical addition to triple bonds bearing an arylsulfonyl group; and 3) radical-mediated C-S bond cleavage.

A novel, manganese-catalyzed oxidative azidation of cyclobutanols is described. A wide range of primary, secondary, and tertiary alkyl azides were generated in synthetically useful yields and exclusive regioselectivity. Aside from linear alkyl azides, otherwise elusive medium-sized cyclic azides were also readily prepared. Preliminary mechanistic studies reveal that the reaction likely proceeds by a radical-mediated C-C bond cleavage/C-N3 bond formation pathway.