RESUMO
The clinical benefits of diquafosol tetrasodium (DQS), a hydrophilic P2Y2 receptor agonist for dry eye, have been hindered by a demanding dosing regimen. Nevertheless, it is challenging to achieve sustained release of DQS with conventional drug delivery vehicles which are mainly designed for hydrophobic small molecule drugs. To address this, we developed an affinity hydrogel for DQS by taking advantage of borate-mediated dynamic covalent complexation between DQS and hydroxypropyl guar. The resultant formulation (3% DQS Gel) was characterized by sustained release, low corneal permeation, and extended ocular retention, which were desirable attributes for ocular surface drug delivery. Both in vitro and in vivo studies had been carried out to verify the biocompatibility of 3% DQS Gel. Using corneal fluorescein staining, the Schirmer's test, PAS staining, quantitative PCR and immunohistological analyses as outcome measures, the superior therapeutic effects of 3% DQS Gel over PBS, the hydrogel vehicle and free DQS were demonstrated in a mouse dry eye model. Our DQS delivery strategy reported herein is readily applicable to other hydrophilic small molecule drugs with cis-diol moieties, thus providing a general solution to improve clinical outcomes of numerous diseases.
Assuntos
Síndromes do Olho Seco , Lágrimas , Animais , Camundongos , Disponibilidade Biológica , Preparações de Ação Retardada/uso terapêutico , Soluções Oftálmicas , Síndromes do Olho Seco/tratamento farmacológico , Polifosfatos/farmacologia , Polifosfatos/uso terapêuticoRESUMO
Lung cancer is the most prevalent and observed type of cancer in Xuanwei County, Yunnan, South China. Lung cancer in this area is called Xuanwei lung cancer. However, its pathogenesis remains largely unknown. To date, a number of studies have shown that microRNA (miR)218 functions as a tumor suppressor in multiple types of cancer. However, the role of miR218 and its regulatory gene network in Xuanwei lung cancer have yet to be investigated. The current study identified that the expression levels of miR218 in XWLC05 cells were markedly lower compared with those in immortalized lung epithelial BEAS2B cells. The present study also demonstrated that overexpression of miR218 could decrease cell proliferation, invasion, viability and migration in Xuanwei lung cancer cell line XWLC05 and NSCLC cell line NCIH157. Additionally, the results revealed that overexpression of miR218 could induce XWLC05 and NCIH157 cell apoptosis by arresting the cell cycle at G2/M phase. Finally, the present study demonstrated that overexpression of miR218 could lead to a significant increase in phosphatase and tensin homolog (PTEN) and YY1 transcription factor (YY1), and a decrease in Bcell lymphoma 2 (BCL2) and BMI1 protooncogene, polycomb ring finger (BMI1) at the mRNA and protein level in XWLC05 and NCIH157 cell lines. However, we did not observe any remarkable difference in the roles of miR218 and miR218mediated regulation of BCL2, BMI1, PTEN and YY1 expression in the progression of Xuanwei lung cancer. In conclusion, miR218 could simultaneously suppress cell proliferation and tumor invasiveness and induce cell apoptosis by increasing PTEN and YY1 expression, while decreasing BCL2 and BMI1 in Xuanwei lung cancer. The results demonstrated that miR218 might serve a vital role in tumorigenesis and progression of Xuanwei lung cancer and overexpression of miR218 may be a novel approach for the treatment of Xuanwei lung cancer.