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| 2. |
- Ansari, Daniel, et al.
(författare)
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Comparison of MUC4 expression in primary pancreatic cancer and paired lymph node metastases.
- 2013
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 48:10, s. 1183-1187
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Objective. Mucin 4 (MUC4) is a transmembrane glycoprotein that is expressed in pancreatic ductal adenocarcinoma (PDAC), but not in normal pancreatic tissue. MUC4 has a proposed role in pancreatic tumor progression and metastasis. The purpose of this pilot study was to investigate MUC4 expression during PDAC metastasis by comparing the expression in the primary tumor and paired lymph node metastases from the same patient. Material and methods. Surgical specimens from 17 cases of primary PDAC and paired lymph node metastases were immunohistochemically analyzed for MUC4 expression. The modified histochemical score (H-score) was used for staining assessment. Results. Positive staining for MUC4 was detected in most primary and metastatic PDAC tumors (15/17 vs. 14/17). The concordance for MUC4 expression in primary tumors and corresponding lymph node metastases was 82%. In two cases, the primary tumor was MUC4-positive and the lymph node metastases were negative, while in one patient with a MUC4-negative primary tumor, the lymph node metastasis was positive. The distribution of H-score for expression of MUC4 significantly correlated (r = 0.615; p = 0.009) between primary tumors and paired metastatic lesions. Conclusions: MUC4 was observed in both primary and matched metastatic tumors with a high level of concordance, suggesting that MUC4 expression is retained following PDAC metastasis.
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| 3. |
- Urey, Carlos, et al.
(författare)
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Combining gas-phase electrophoretic mobility molecular analysis (GEMMA), light scattering, field flow fractionation and cryo electron microscopy in a multidimensional approach to characterize liposomal carrier vesicles
- 2016
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Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173. ; 513:1-2, s. 309-318
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Tidskriftsartikel (refereegranskat)abstract
- For drug delivery, characterization of liposomes regarding size, particle number concentrations, occurrence of low-sized liposome artefacts and drug encapsulation are of importance to understand their pharmacodynamic properties. In our study, we aimed to demonstrate the applicability of nano Electrospray Gas-Phase Electrophoretic Mobility Molecular Analyser (nES GEMMA) as a suitable technique for analyzing these parameters. We measured number-based particle concentrations, identified differences in size between nominally identical liposomal samples, and detected the presence of low-diameter material which yielded bimodal particle size distributions. Subsequently, we compared these findings to dynamic light scattering (DLS) data and results from light scattering experiments coupled to Asymmetric Flow-Field Flow Fractionation (AF4), the latter improving the detectability of smaller particles in polydisperse samples due to a size separation step prior detection. However, the bimodal size distribution could not be detected due to method inherent limitations. In contrast, cryo transmission electron microscopy corroborated nES GEMMA results. Hence, gas-phase electrophoresis proved to be a versatile tool for liposome characterization as it could analyze both vesicle size and size distribution. Finally, a correlation of nES GEMMA results with cell viability experiments was carried out to demonstrate the importance of liposome batch-to-batch control as low-sized sample components possibly impact cell viability.
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| 4. |
- Urey, Carlos, et al.
(författare)
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Development and In Vitro Characterization of a Gemcitabine-loaded MUC4-targeted Immunoliposome Against Pancreatic Ductal Adenocarcinoma
- 2017
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Ingår i: Anticancer research. - 1791-7530. ; 37:11, s. 6031-6039
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Tidskriftsartikel (refereegranskat)abstract
- CONCLUSION: Successful development and characterization of a MUC4-targeted immunoliposome shows promising results for a targeted treatment and improved retention of gemcitabine for treatment of PDAC.RESULTS: Development of a MUC4-targeted immunoliposome was confirmed and characterized by immunoblots and size characterization. The MUC4-targeted immunoliposome showed a significantly higher targeting affinity compared to the non-targeted liposomes and also showed an improved antiproliferative effect compared to free and non-targeted liposomal drug.BACKGROUND/AIM: Pancreatic Ductal adeno-carcinoma (PDAC) is a devastating disease. Gemcitabine is the standard chemotherapeutic agent against PDAC but has only limited effectiveness. The aim of the study was to develop and study the targeting affinity and in vitro antiproliferative effect of a MUC4-targeted gemcitabine-loaded immuno-liposome for treatment of PDAC.MATERIALS AND METHODS: Gemcitabine-loaded immunoliposomes were developed by grafting anti-MUC4 antibodies to the liposomal surface. Targeting affinity was compared in vitro between immunoliposomes and non-targeted liposomes and anti-proliferative effect was compared in vitro between free drug, non-targeted liposomal gemcitabine and MUC4-targeted immunoliposomal gemcitabine on a MUC4-positive pancreatic cancer cell line, Capan-1.
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| 5. |
- Urey, Carlos
(författare)
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Development of a targeted Drug Delivery System for treatment of Pancreatic Ductal Adenocarcinom
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pancreatic cancer is the fourth leading cause of cancer-related death with a 5-year survival of less than 6%. The only potential cure for pancreatic cancer is by surgical removal of the tumor. However, most patients present with an advanced and metastasized disease at the time of diagnosis, leaving only around 15% of patients eligible for surgery. For the majority of patients, palliative chemotherapeutic treatment is the only option.Gemcitabine, a nucleoside analogue, has been the standard chemotherapeutic treatment for pancreatic cancer in both the palliative and adjuvant settings. However, the use of gemcitabine is problematic, as it presents several drawbacks such as a short half-life (~15 min), drug resistance, deficient drug delivery, poorcellular uptake and hence, a suboptimal therapeutic response.The aim of this thesis was to develop a nanoparticle-based drug delivery system for a targeted and improved delivery of gemcitabine for treatment of pancreatic ductal adenocarcinoma. To address this issue, we used a liposomal drug delivery system as the delivery system of choice. In a first stage, we developed and extensively characterized the liposomal system by use of several measurement techniques, such as DLS, cryo-TEM, nES GEMMA and AF4, evaluated the system stability and studied thebiodistribution profile of the liposomal system by use of radiolabeled liposomes and SPECT/CT imaging. In a second stage, we proceeded to develop a targeted treatment. We first identified a potential targeting protein, MUC4, which is highly expressed in pancreatic cancer but not expressed in the healthy pancreas and studied its clinical impact on resected pancreatic cancer patients. Finally, we developed a MUC4-targeted immunoliposome (iGemLip). iGemLip showed a significantly higher binding affinity, cellular uptake and antiproliferative effect on a MUC4-positive pancreatic cancer cell line, Capan-1, compared to both free and liposomal gemcitabine.
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| 6. |
- Urey, Carlos, et al.
(författare)
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Low MUC4 expression is associated with survival benefit in patients with resectable pancreatic cancer receiving adjuvant gemcitabine
- 2017
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 52:5, s. 595-600
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous in vitro studies have shown that mucin 4 (MUC4) confers resistance toward gemcitabine in pancreatic cancer cells. To date, there are few clinical studies corroborating these findings. The aim of this study was to evaluate the predictive impact of MUC4 expression on survival in patients with resectable pancreatic cancer receiving adjuvant gemcitabine. Materials and methods: MUC4 expression was investigated by immunohistochemistry in 78 tissue sections from patients with pancreatic ductal adenocarcinoma undergoing Whipple resection. The H-score was used to evaluate MUC4 expression. The Kaplan–Meier method and Cox proportional hazards regression analysis were used to assess the predictive role of MUC4 expression. Results: The MUC4 protein was expressed in 93.6% (73/78) of pancreatic cancer tissue specimens. None of the normal control pancreatic tissues had any MUC4 expression. Low MUC4 expression (H-score ≤100) was detectable in 42 (53.8%) of tumors and high MUC4 expression (H-score >100) was detectable in 36 (46.2%) of tumors. Low expression of MUC4 was associated with favorable survival (p = .027), whereas high MUC4 expression did not correlate with survival (p = .87) in patients receiving adjuvant gemcitabine treatment. Conclusions: This is the first study indicating a predictive role of MUC4 expression for gemcitabine treatment in the clinical setting.
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| 7. |
- Weiss, Victor U., et al.
(författare)
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Nano electrospray gas-phase electrophoretic mobility molecular analysis (nES GEMMA) of liposomes : Applicability of the technique for nano vesicle batch control
- 2016
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Ingår i: Analyst. - : Royal Society of Chemistry (RSC). - 0003-2654. ; 141:21, s. 6042-6050
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Tidskriftsartikel (refereegranskat)abstract
- Liposomes are biodegradable nanoparticle vesicles consisting of a lipid bilayer encapsulating an aqueous core. Entrapped cargo material is shielded from the extra-vesicular medium and sustained release of encapsulated material can be achieved. However, application of liposomes as nano-carriers demands their characterization concerning size and size distribution, particle-number concentration, occurrence of vesicle building blocks in solution and determination of the resulting vesicle encapsulation capacity. These questions can be targeted via gas-phase electrophoretic mobility molecular analysis (GEMMA) based on a nano electrospray (nES) charge-reduction source. This instrument separates single-charged nanoparticles in the gas-phase according to size in a high-laminar sheath-flow by means of an orthogonal, tunable electric field. nES GEMMA analysis enables to confirm liposome integrity after passage through the instrument (in combination with atomic force microscopy) as well as to exclude vesicle aggregation. Additionally, nanoparticle diameters at peak apexes and size distribution data are obtained. Differences of hydrodynamic and dry particle diameter values, as well as the effect of number- and mass-based concentration data analysis on obtained liposome diameters are shown. Furthermore, the repeatability of liposome preparation is studied, especially upon incorporation of PEGylated lipids in the bilayer. Finally, the instruments applicability to monitor mechanical stress applied to vesicles is demonstrated.
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