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  •   صفحه اصلی مخزن دانش
  • School of Pharmacy
  • Theses(P)
  • مشاهده آیتم
  •   صفحه اصلی مخزن دانش
  • School of Pharmacy
  • Theses(P)
  • مشاهده آیتم
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Preparation and characterization of peptide-modified vincristine liposomes for enhanced BBB penetration

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نمایش/بازکردن
سولماز مجردجبلی (بعددفاع).pdf (4.381Mb)
تاریخ
2022
نویسنده
Mojarad-Jabali, Solmaz
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نمایش پرونده کامل آیتم
چکیده
Itroduction: In recent years, peptide-modified liposomal formulations have been considered as a promising drug delivery systems to deliver therapeutic agents across the BBB for glioma treatment. Object: The aim of this study was to prepare of vincristine liposomes (LS/VCR) functionalized with three transferrin receptor-targeted peptides including T12, B6 and T7 and to evaluate their ability to cross the BBB and target glioma cells in vitro and in vivo. Method: In the first step, Brij 56-Mal was synthesized in 5 steps using Brij 56, which is a non-ionic surfactant. To confirm the synthesis of Brij 56-Mal, Fourier transform infrared (FT-IR) spectroscopy at each stage of synthesis and elemental analysis (CHNS) and nuclear magnetic resonance spectroscopy (13C NMR and 1H NMR) on the final product was done. In the next step, FMOC solid-phase peptide synthesis was carried out manually with Rink amide resin for synthesis of T12, B6 and T7 and then they were conjugated to Brij 56-Mal and 1H NMR analysis was performed to confirm the conjugaation. The peptide-modified liposomes were prepared by combination of a thin film hydration method and a pre-insertion method. VCR was loaded in peptide-modified liposomes with pH gradient active loading method and characterized. The hydrodynamic diameter, polydispersity index and zeta potential of liposomes were measured by dynamic light scattering (DLS), and their morphology was characterized by transmission electron microscopy (TEM). The storage stability of VCR-loaded liposomes was further evaluated by monitoring the variation in particle size and PDI values after one-month storage at 4 ◦C. The in vitro release of VCR from different formulations was evaluated in a neutral condition and 37 °C in the presence of 10% bovine fetal serum (FBS) for 48 h. The cellular uptake of different liposomal formulations was evaluated in GL261 and hCMEC/D3 cells by fluorescent microscopy and flow cytometry. The hCMEC/D3 cell monolayers were established using hanging cell culture inserts to evaluate the in vitro BBB penetration of different liposomal formulations. MTT assay was conducted to evaluate the in vitro cytotoxicity of free VCR and different VCR-loaded liposomes in GL261 cells and Annexin V/PI dual staining was utilized to evaluate the apoptotic behavior of different VCR formulations. Finally, in vivo biodistribution and brain targeting efficiency of obtained liposomes was investigated in NMRI mice and the ex vivo imaging was carried out in the major organs (brain, heart, liver, spleen, lung, and kidney) 24 h after intravenous administration. Conclusion: Among all TfR targeting or non-targeting groups, T7-modified liposomes (T7-LS) showed the highest BBB penetration capacity and brain distribution and displayed an enhanced accumulation in glioma cells. When loaded with vincristine (VCR), as a model chemotherapeutic, T7-LS/VCR could achieve the best anti-glioma outcome by means of targeted cytotoxicity and apoptosis in vitro. The obtained results suggested T7-LS as a potential platform for effective brain targeted delivery and glioma therapy in clinic
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http://dspace.tbzmed.ac.ir:8080/xmlui/handle/123456789/66308
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