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Designing the new generation of intelligent biocompatible carriers for protein and peptide delivery

Acta Pharmaceutica Sinica B 2018年第2期8卷 147-164页

作者： Angela M.Wagner Margaret P.gran Nicholas A.Peppas McKetta Department of Chemical Engineering The University of Texas at Austin Institute for Biomaterials Drug Delivery and Regenerative Medicine The University of Texas at Austin Department of Biomedical Engineering The University of Texas at Austin Department of Pediatrics Dell Medical School The University of Texas at Austin Department of Surgery and Perioperative Care Dell Medical School The University of Texas at Austin Division of Pharmaceutics College of Pharmacy The University of Texas at Austin

Therapeutic proteins and peptides have revolutionized treatment for a number of diseases, and the expected increase in macromolecule-based therapies brings a new set of challenges for the pharmaceutics field. Due to their poor stability, large molecular weight, and poor transport properties,therapeutic proteins and peptides are predominantly limited to parenteral administration. The short serum half-lives typically require frequent injections to maintain an effective dose, and patient compliance is a growing issue as therapeutic protein treatments become more widely available. A number of studies have underscored the relationship of subcutaneous injections with patient non-adherence, estimating that over half of insulin-dependent adults intentionally skip injections. The development of oral formulations has the potential to address some issues associated with non-adherence including the interference with daily activities, embarrassment, and injection pain. Oral delivery can also help to eliminate the adverse effects and scar tissue buildup associated with repeated injections. However, there are several major challenges associated with oral delivery of proteins and peptides, such as the instability in the gastrointestinal(GI)tract, low permeability, and a narrow absorption window in the intestine. This review provides a detailed overview of the oral delivery route and associated challenges. Recent advances in formulation and drugdelivery technologies to enhance bioavailability are discussed, including the co-administration of compounds to alter conditions in the GI tract, the modification of the macromolecule physicochemical properties, and the use of improved targeted and controlled release carriers.

关键词： Oral delivery Hydrogels Protein delivery Peptide delivery Carbohydrates Mucoadhesion

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Science Letters:A novel way of liver preservation improves rat liver viability upon reperfusion

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2007年第5期8卷 289-295页

作者： KEBIS Anton KUKAN Marián granI Peter JAKUBOVSK■ Ján Laboratory of Perfused Organs Slovak Center for Organ TransplantationSlovak Medical UniversityLimbová 1283303 BratislavaSlovakia Department of Pathology School of MedicineComenius University81372 BratislavaSlovakia

Background/aim： Currently, the liver is cold-preserved at 0-4 ℃ for experimental and clinical purposes. Here, we investigated whether milder hypothermia during the initial phase of the preservation period was beneficial for liver viability upon reperfusion. Methods： In the first set of experiments, rat livers were preserved either conventionally in clinically used histidine-trypthopan-ketoglutarate （HTK） solution （Group A： 45 min and Group B： 24 h） or by slow cooling HTK solution （from 13 ℃ to 3 ℃） during the initial 45 min of preservation （Group C： 24 h）. In the second set of experiments, additional groups of livers were evaluated： Group BB-preservation according to Group B and Group CC-preservation according to Group C. Further, some livers were preserved at 13 ℃ for 24 h. Livers were then reperfused using a blood-free perfusion model. Results： Bile production was approximately 2-fold greater in Group C compared to Group B. Alanine transaminase （ALT） and aspartate transaminase （AST） release into perfusate were 2-3-fold higher in Group B compared to Group C. No significant differences were found in ALT and AST release between Group C and Group A. Livers in Group CC compared to Group BB exhibited significantly lower portal resistance, greater oxygen consumption and bromosulfophthalein excretion into bile and lower lactate dehydrogenase （LDH） release into perfusate. Histological evaluation of tissue sections in Group BB showed parenchymal dystrophy of hepatocytes, while dystrophy ofhepatocytes was absent in Group CC. Livers preserved at 13 ℃ for 24 h exhibited severe ischemic injury Conclusion： These results suggest that the conventional way of liver preservation is not suitable at least for rat livers and that slow cooling of HTK solution during the initial phase of cold storage can improve liver viability during reperfusion.

关键词： Rat Hepatic graft Cold ischemia Liver protection Histidine-trypthopan-ketoglutarate solution (HTK)

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Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein

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World Journal of Gastroenterology 2016年第48期22卷 10680-10686页

作者： Francois Ghiringhelli Corentin Richard Sandy Chevrier Frédérique Végran Romain Boidot Department of Medical Oncology Center GF Leclerc21000 DijonFrance Platform of Transfer in Oncology Center GF Leclerc21000 DijonFrance INSERM UMR866 21000 DijonFrance University of Bourgogne Franche Comte 21000 DijonFrance

Precision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer(CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase(PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients(Check2 for the first patient and RAD51 C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency.

关键词： Colorectal cancer Exome analysis Genetic aberrations Homologous repair deficiency Precision medicine

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Conversion of Existing Roundabouts into Turbo-Roundabouts： Case Studies from Real World

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Journal of Civil Engineering and Architecture 2012年第8期6卷 953-962页

作者： Orazio Giuffrè Marco Guerrieri Anna granà Department of Civil Environmental Aerospace Materials Engineering Università degli Studi di Palermo Palermo90128 Italy

Compared with roundabouts the main advantages of turbo-roundabouts are the reduction in the number of potential conflicting points and the lower speed of vehicles passing through the intersection, they both can improve safety conditions at the .junction. Moreover, the physical delimitation among lanes limits the side-by-side accident risk. These aspects make turbo-roundabouts more appropriate than roundabouts when a higher level of safety has to be guaranteed, particularly in presence of relevant pedestrian and two-wheels traffic volumes. The present paper has three main objectives：（1） to discuss general design criteria and functional principles of turbo roundabouts, （2） to give the geometric design principles of the central island and circulating lanes and （3） to present three case studies from real world concerning the conversion of existing roundabouts into turbo roundabouts.

关键词： Roundabout turbo roundabout capacity.

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小像幅微型飞机测量

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测绘译丛 1990年第2期 26-31页

作者： gran.,RW 张晓航

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Helicobacter pyloripromote gastric cancer cells invasion through a NF-κB and COX-2-mediated pathway

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World Journal of Gastroenterology 2005年第21期11卷 3197-3203页

作者： Chun-YingWu Chau-JongWang Chi-ChuanTseng Hsiao-PingChen Ming-ShingWu Jaw-TownLin HiroyasuInoue gran-HumChen GraduateInstituteofClinicalMedicine CollegeofMedicineNationalTaiwanUniversityTaiwanChina InstituteofBiochemistry CollegeofMedicineChung-ShanMedicalUniversityTaiwanChina DivisionofGastroenterology DepartmentofInternalMedicineNationalTaiwanUniversityHospitalTaiwanChina DivisionofGastroenterology DepartmentofInternalMedicineNationalTaiwanUniversityHospitalTaiwanChina DepartmentofPharmacology NationalCardiovascularCenterResearchInstituteJapan

AIM: To examine the effects of Helicobacter pylori(Hpylori) infection on the invasiveness of gastric cancer cells,and to elucidate its mechanism. METHODS: Gastric carcinoma cells, MKN-45, were incubated with CagA-positive H pylori, and cell invasion was determined by Matrigel *** expression of matrix metallopr-oteinase-9 (MMP-9),vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) were assessed by Western-blot analysis, and transcriptional activation of the COX-2 promoter was examined by measuring luciferase and β-galactosidase activities. Lastly,the proteinDNA interaction was confirmed by an electrophoretic mobility shift assay. RESULTS: The current studies showed that: (1) incubation of CagA-positive H pylori with MKN-45 cells significantly promotes gastric cancer cells invasion, and this effect is attenuated by pre-treatment with NS-398, a COX-2 inhibitor, or PDTC,a nuclear factor κB (NF-κB) inhibitor;(2) the induction of MKN-45 cells invasion by Hpylori is associated with increases in COX-2, MMP-9, and VEGF protein expression, and co-incubation of NS-398 or PDTC significantly reduces these effects;(3) H pylori infection transactivates COX-2 promoter activity and increases the binding of NF-κB to this promoter. CONCLUSION: Our data demonstrate that H pylori infection promotes gastric epithelial cells invasion by activating MMP-9 and VEGF expression. These effects appear to be mediated through a NF-κB and COX-2 mediated pathway, as COX-2 or NF-κB inhibitor significantly attenuate the invasiveness of gastric cancer cells and the expressions of MMP-9 and VEGF protein.

关键词： H pylori Gastric cancer Invasion MMP-9 VEGF COX-2 NF-κB

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干扰素是如何发挥细胞生长抑制作用的？

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国外学者来访报告 1998年第3期18卷 8-13页

作者： gran.,D Karolinska医院肿瘤病理科

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用于向量计算机的快速分解和求解算法

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电力情报 1992年第4期 19-28页

作者： gran.,GP 傅松

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上颌窦底抬高植骨一期种植术的临床研究

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中国口腔种植学杂志 1999年第1期4卷 27-30页

作者：李祖兵 gran.,AN 湖北医科大学口腔医学院美国纽约大学Brookdale医院牙种植中心

介绍和评价上颌后牙区牙槽骨吸收患者行上颌窦底抬高植骨一期种植术的方法和效果。６例（共９侧）Ⅰ～Ⅱ型上颌牙槽骨吸收患者，行上颌窦前外侧壁开窗后，分离并抬高窦底粘膜，常规植入２～３颗种植体，其中部分种植体用小型夹板固定，... 详细信息

介绍和评价上颌后牙区牙槽骨吸收患者行上颌窦底抬高植骨一期种植术的方法和效果。６例（共９侧）Ⅰ～Ⅱ型上颌牙槽骨吸收患者，行上颌窦前外侧壁开窗后，分离并抬高窦底粘膜，常规植入２～３颗种植体，其中部分种植体用小型夹板固定，再于窦底种植体周充填自体骨、冻干骨、ＨＡ复合物。术后８～９月，Ｘ线检查骨生长愈合情况及种植体动度。结果８侧手术区一期愈合；８～９月后，种植体动度为０～－８，５例种植体与骨结合良好，３例牙槽骨质吸收２～３ｍｍ。结论上颌窦底抬高植骨一期种植术较好解决了上颌后牙区牙槽骨严重吸收而不宜种植的难题，值得临床推广应用。

关键词：上颌窦底牙种植颌骨移植

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世界上首例小肠与肝脏同时移植获得成功

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浙江医学情报 1991年第2期3卷 46-47页

作者： gran,D 高惠荣

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