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Shuaijun Zou,1,* Qian He,2,* Qianqian Wang,1,* Bo Wang,1 Guoyan Liu,1 Fuhai Zhang,1 Xi Cheng,3 Beilei Wang,1 Liming Zhang1 1Department of Marine Biomedicine and Polar Medicine, Naval Special Medical Center, Naval Medical University, Shanghai, 200433, People’s Republic of China; 2The Third Affiliated Hospital of Naval Medical University, Shanghai, 200433, People’s Republic of China; 3The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Beilei Wang; Liming ZhangDepartment of Marine Biomedicine and Polar Medicine, Naval Special Medical Center, Naval Medical University, Shanghai, 200433, People’s Republic of ChinaTel +8621-81871129; +8621-81871128Email lilly_wang@126.com; lmzhang@smmu.edu.cnPurpose: Pore-forming toxins (PFTs) perform important functions during bacterial infections. Among various virulence-targeting therapies, nanosponges (NSs) have excellent neutralization effects on multiple PFTs. To enhance treatment efficacy, NSs tend to be incorporated into other biomaterials, such as hydrogels.Methods: In the present work, red blood cell (RBC) vesicles were harvested to wrap polymer nanoparticles, leading to the formation of NSs, and the optimal Pluronic F127 hydrogel concentration was determined for gelation. Then, a novel detoxification system was constructed by incorporating NSs into an optimized Pluronic F127 hydrogel (NS-pGel). Next, the system was characterized by rheological and sustained release behavior as well as micromorphology. Then, the in vitro neutralization effect of NS-pGel on various PFTs was examined by a hemolysis protocol. Finally, therapeutic and prophylactic detoxification efficiency was evaluated in a mouse subcutaneous infection model in vivo.Results: A thermosensitive, injectable detoxification system was successfully constructed by loading NSs into a 30% Pluronic F127 hydrogel. Characteri

Shuaijun Zou,1,* Qian He,2,* Qianqian Wang,1,* Bo Wang,1 Guoyan Liu,1 Fuhai Zhang,1 Xi Cheng,3 Beilei Wang,1 Liming Zhang1 1Department of Marine Biomedicine and Polar Medicine, Naval Special Medical Center, Naval Medical University, Shanghai, 200433, People’s Republic of China; 2The Third Affiliated Hospital of Naval Medical University, Shanghai, 200433, People’s Republic of China; 3The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Beilei Wang; Liming ZhangDepartment of Marine Biomedicine and Polar Medicine, Naval Special Medical Center, Naval Medical University, Shanghai, 200433, People’s Republic of ChinaTel +8621-81871129; +8621-81871128Email lilly_wang@126.com; lmzhang@smmu.edu.cnPurpose: Pore-forming toxins (PFTs) perform important functions during bacterial infections. Among various virulence-targeting therapies, nanosponges (NSs) have excellent neutralization effects on multiple PFTs. To enhance treatment efficacy, NSs tend to be incorporated into other biomaterials, such as hydrogels.Methods: In the present work, red blood cell (RBC) vesicles were harvested to wrap polymer nanoparticles, leading to the formation of NSs, and the optimal Pluronic F127 hydrogel concentration was determined for gelation. Then, a novel detoxification system was constructed by incorporating NSs into an optimized Pluronic F127 hydrogel (NS-pGel). Next, the system was characterized by rheological and sustained release behavior as well as micromorphology. Then, the in vitro neutralization effect of NS-pGel on various PFTs was examined by a hemolysis protocol. Finally, therapeutic and prophylactic detoxification efficiency was evaluated in a mouse subcutaneous infection model in vivo.Results: A thermosensitive, injectable detoxification system was successfully constructed by loading NSs into a 30% Pluronic F127 hydrogel. Characteri

Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain metal-based PARP-1 inhibitors with enhanced biological activities by conjugating platinum moiety with an original inhibitor, e.g., benzonaphthyridone. Based on the structure activity relationship analysis of PARP-1 inhibitors, three platinated PARP-1 inhibitors were designed, and the complexes were synthesized and characterized. Complex 3 presented significantly enhanced cytotoxicity against a panel of human cancer cells and a 10-fold increased inhibitory effect against recombinant PARP-1 compared with the original PARP-1 inhibitor. Complex 3 was as cytotoxic as cisplatin and its spectrum of anticancer activity was identical to that of cisplatin. The complex was able to enter into cancer cells efficiently, bind to DNA well, and block cell cycle at G(2)/M phase, indicating that complex 3 is an effective anticancer agent with a distinct mechanism of action. Our study implies that the conjugation of platinum with PARP-1 inhibitors could be a valid strategy to obtain more potent anticancer agents with improved biological activities. (C) 2013 Elsevier Masson SAS. All rights reserved.

Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain metal-based PARP-1 inhibitors with enhanced biological activities by conjugating platinum moiety with an original inhibitor, e.g., benzonaphthyridone. Based on the structure activity relationship analysis of PARP-1 inhibitors, three platinated PARP-1 inhibitors were designed, and the complexes were synthesized and characterized. Complex 3 presented significantly enhanced cytotoxicity against a panel of human cancer cells and a 10-fold increased inhibitory effect against recombinant PARP-1 compared with the original PARP-1 inhibitor. Complex 3 was as cytotoxic as cisplatin and its spectrum of anticancer activity was identical to that of cisplatin. The complex was able to enter into cancer cells efficiently, bind to DNA well, and block cell cycle at G(2)/M phase, indicating that complex 3 is an effective anticancer agent with a distinct mechanism of action. Our study implies that the conjugation of platinum with PARP-1 inhibitors could be a valid strategy to obtain more potent anticancer agents with improved biological activities. (C) 2013 Elsevier Masson SAS. All rights reserved.

Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain metal-based PARP-1 inhibitors with enhanced biological activities by conjugating platinum moiety with an original inhibitor, e.g., benzonaphthyridone. Based on the structure activity relationship analysis of PARP-1 inhibitors, three platinated PARP-1 inhibitors were designed, and the complexes were synthesized and characterized. Complex 3 presented significantly enhanced cytotoxicity against a panel of human cancer cells and a 10-fold increased inhibitory effect against recombinant PARP-1 compared with the original PARP-1 inhibitor. Complex 3 was as cytotoxic as cisplatin and its spectrum of anticancer activity was identical to that of cisplatin. The complex was able to enter into cancer cells efficiently, bind to DNA well, and block cell cycle at G(2)/M phase, indicating that complex 3 is an effective anticancer agent with a distinct mechanism of action. Our study implies that the conjugation of platinum with PARP-1 inhibitors could be a valid strategy to obtain more potent anticancer agents with improved biological activities. (C) 2013 Elsevier Masson SAS. All rights reserved.

Starting from three achiral compounds, the title reaction provides rapid access to a variety of molecules that contain indoline, tetrahydroquinoline, and tetrahydroisoquinoline moieties (see scheme). The process features the efficient formation of multiple new bonds and chiral centers, excellent stereoselectivity, oxetane desymmetrization, and easy product purification through filtration. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Starting from three achiral compounds, the title reaction provides rapid access to a variety of molecules that contain indoline, tetrahydroquinoline, and tetrahydroisoquinoline moieties (see scheme). The process features the efficient formation of multiple new bonds and chiral centers, excellent stereoselectivity, oxetane desymmetrization, and easy product purification through filtration. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.