Cyclosporine A-loaded colon-targeted oral nanomicelles self-assembly by galactosylated carboxymethyl chitosan for efficient ulcerative colitis therapy.

An oral galactosylated carboxymethyl chitosan polymeric nanomicelles (Gal-N-CMCS NPs) embedded in chitosan-alginate hydrogel (CA-Gel) was developed to load cyclosporine A (CyA) as therapeutic agents against ulcerative colitis (UC). Galactose modified CMCS with macrophage targeting characteristic and CyA via a simple ultrasonication method to form Gal-N-CMCS/CyA NPs, and mixed CA-Gel to acquire the final formulation (Gal-N-CMCS/CyA Gel). The generated Gal-N-CMCS/CyA NPs displayed a desirable particle size (206.8 nm), negative surface charge (-19.5 mV), and high encapsulating efficiency (89.6 %). The morphology and release profiles were also charactered by transmission electron microscope [1] and dialysis method, respectively. Strikingly, the mucus penetration of Gal-N-CMCS/CyA NPs exceeded 90 % within 90 min. The Gal-N-CMCS NPs internalized by macrophages were 3.3-fold higher than CMCS-N NPs, thereby, enhancing the anti-inflammatory activities of NPs. Meanwhile, these NPs exhibited excellent biocompatibility, reduced the toxic effect of CyA, and targeting ability on inflammatory macrophages both in vitro and in vivo. Most importantly, in vivo studies revealed that CyA NPs could efficiently target the inflamed colon, remarkably alleviate inflammation, repair mucosal and reconstructed colonic epithelial barriers in UC mice induced by dextran sulfate sodium (DSS) via Toll-like receptor 4 -Nuclear factor kappa-B (TLR4-NF-κB) pathway. Our findings suggest that these high-performance and facilely fabricated Gal-N-CMCS/CyA NPs could be developed as a promising drug carrier for oral UC treatment.

Phenotypic variability of syndromic craniosynostosis caused by c.833G > T in FGFR2: Clinical and genetic evaluation of eight patients from a five-generation family.

OBJECTIVE: Craniosynostosis is the result of the early fusion of cranial sutures. Syndromic craniosynostosis includes but not limited by Crouzon syndrome and Pfeiffer syndrome. Considerable phenotypic overlap exists among these syndromes and mutations in FGFR2 may cause different syndromes. This study aims to investigate the explanation of the phenotypic variability via clinical and genetic evaluation for eight patients in a large pedigree. METHODS: For each patient, comprehensive physical examination, cranial plain CT scan with three-dimensional CT reconstruction (3D-CT), and eye examinations were conducted. Whole exome sequencing was applied for genetic diagnosis of the proband. Variants were analyzed and interpreted following the ACMG/AMP guidelines. Sanger sequencing was performed to reveal genotypes of all the family members. RESULTS: A pathogenic variant in the FGFR2 gene, c.833G > T (p.C278F), was identified and proved to be co-segregate with the disease. Some symptoms of head, hearing, vision, mouth, teeth expressed differently by affected individuals. Nonetheless, all the eight patients manifested core symptoms of Crouzon syndrome without abnormality in the limbs, which could exclude diagnosis of Pfeiffer syndrome. CONCLUSION: We have established clinical and genetic diagnosis of Crouzon syndrome for eight patients in a five-generation Chinese family. Variability of clinical features among these familial patients was slighter than that in previously reported sporadic cases.