1. Codelivered Chemotherapeutic Doxorubicin via a Dual-Functional Immunostimulatory Polymeric Prodrug for Breast Cancer Immunochemotherapy
Yang Lan, Qiangwei Liang, Yue Sun, Aichen Cao, Lu Liu, Shuangyu Yu, Liyue Zhou, Jinxia Liu, Rongyue Zhu, Yanhua Liu ACS Appl Mater Interfaces. 2020 Jul 15;12(28):31904-31921. doi: 10.1021/acsami.0c06120. Epub 2020 Jul 2.
Immunochemotherapy is viewed as a promising approach for cancer therapy via combination treatment with immune-modulating drugs and chemotherapeutic drugs. A novel dual-functional immunostimulatory polymeric prodrug carrier PEG2k-Fmoc-1-MT was developed for simultaneously delivering 1-methyl tryptophan (1-MT) of an indoleamine 2,3-dioxygenase (IDO) inhibitor and chemotherapeutic doxorubicin (DOX) for breast cancer immunochemotherapy. DOX/PEG2k-Fmoc-1-MT micelles were more effective in cell proliferation inhibition and apoptosis induction in 4T1 cells. PEG2k-Fmoc-1-MT prodrug micelles presented enhanced inhibition ability of IDO with decreased kynurenine production and increased the proliferation in dose-dependent manners of effector CD4+ and CD8+ T cells. DOX/PEG2k-Fmoc-1-MT micelles exhibited prolonged blood circulation time and superior accumulation of DOX and 1-MT in tumors compared to that of DOX and 1-MT solutions. A significantly enhanced immune response of the DOX/PEG2k-Fmoc-1-MT micelles was observed with the decreasing tryptophan/kynurenine ratio in blood and tumor tissue, promoting effector CD4+ and CD8+ T cells while reducing regulatory T cell (Tregs) expression. Meanwhile, the coreleased DOX-triggered immunogenic cell death action combined with the cleaved 1-MT promoted the related cytokine secretion of tumor necrosis factor-α, interleukin-2, and interferon-γ, further facilitating the T cell-mediated immune responses. More importantly, the DOX-loaded micelles led to a significantly improved inhibition on tumor growth and prolonged animal survival rate in a 4T1 murine breast cancer model. In conclusion, DOX codelivered by a PEG2k-Fmoc-1-MT immunostimulatory polymeric prodrug showed a maximum immunochemotherapy efficacy against breast cancer.
2. Chemoenzymatic synthesis of diverse asparagine-linked alpha-(2,3)-sialyloligosaccharides
Kazuhiro Fukae, Naoki Yamamoto, Yuri Hatakeyama, Yasuhiro Kajihara Glycoconj J. 2004;21(5):243-50. doi: 10.1023/B:GLYC.0000045096.89408.50.
Partial sialyl transfer reaction by alpha-(2,3)-sialyltransferase toward (Gal-beta-1,4-GlcNAc-beta-1,2-Man-alpha-1,6/1,3-)(2)Man-beta-1,4-GlcNAc-beta-1,4-GlcNAc-beta-1-asparagine-Fmoc 1 was examined to obtain mono-alpha-(2,3)-sialyloligosaccharides and then branch-specific exo-glycosidase digestion (beta-D-galactosidase, N -acetyl-beta-D-glucosaminidase and alpha-D-mannosidase) toward the asialo-branch was performed to obtain diverse asparagine-linked complex type alpha-(2,3)-sialyloligosaccharides. In addition, two kinds of disialyloligosaccharides in which the sialyl linkage was a mixture of alpha-(2,3)- and alpha-(2,6)-types were also specifically prepared by an additional alpha-(2,6)-sialyltransferase reaction toward mono-alpha-(2,3)-sialyloligosaccharides thus obtained.
3. Enantioselective syntheses of alpha-Fmoc-Pbf-[2-(13)C]-L-arginine and Fmoc-[1,3-(13)C2]-L-proline and Incorporation into the neurotensin receptor 1 ligand, NT(8-13)
Chuanjun Song, Satita Tapaneeyakorn, Annabel C Murphy, Craig Butts, Anthony Watts, Christine L Willis J Org Chem. 2009 Dec 4;74(23):8980-7. doi: 10.1021/jo9014497.
Enantioselective syntheses of selectively labeled, orthogonally protected [2-(13)C]-L-arginine and [1,3-(13)C(2)]-L-proline are described from the commercially available precursors [2-(13)C]bromoacetic acid and potassium [(13)C]cyanide. Interestingly the enhanced signal assigned to C-2 in the (13)C NMR spectrum of alpha-Fmoc-Pbf-[2-(13)C]-L-arginine was very broad at room temperature. The two Fmoc-labeled amino acids were used to prepare [2-(13)C]-Arg9 and [1,3-(13)C(2)]-Pro10 labeled ligand (NT(8-13)) by manual Fmoc-SPSS.
