Nano-encapsulation of a novel anti-Ran-GTPase peptide for blockade of regulator of chromosome condensation 1 (RCC1) function in MDA-MB-231 breast cancer cells.

Autor: Haggag YA; School of Pharmacy and Pharmaceutical Sciences, Saad Centre for Pharmacy and Diabetes, Ulster University, Cromore Road, Coleraine, Co. Londonderry, BT52 1SA, UK; Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Tanta, Tanta, Egypt., Matchett KB; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, UK., Dakir el-H; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, UK; Institute of Cancer Therapeutics, University of Bradford, Bradford, UK., Buchanan P; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, UK., Osman MA; Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Tanta, Tanta, Egypt., Elgizawy SA; Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Tanta, Tanta, Egypt., El-Tanani M; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, UK; Institute of Cancer Therapeutics, University of Bradford, Bradford, UK; IDT (Imhotep Diagnostics and Therapeutics), Europa Tool House, Springbank, Industrial Estate, Dunmurry, Northern Ireland, UK., Faheem AM; Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Tanta, Tanta, Egypt; Sunderland Pharmacy School, Department of Pharmacy, Health and Well Being, University of Sunderland, Sunderland SR1 3SD, UK., McCarron PA; School of Pharmacy and Pharmaceutical Sciences, Saad Centre for Pharmacy and Diabetes, Ulster University, Cromore Road, Coleraine, Co. Londonderry, BT52 1SA, UK. Electronic address: p.mccarron@ulster.ac.uk.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2017 Apr 15; Vol. 521 (1-2), pp. 40-53. Date of Electronic Publication: 2017 Feb 02.
DOI: 10.1016/j.ijpharm.2017.02.006
Abstrakt: Ran is a small ras-related GTPase and is highly expressed in aggressive breast carcinoma. Overexpression induces malignant transformation and drives metastatic growth. We have designed a novel series of anti-Ran-GTPase peptides, which prevents Ran hydrolysis and activation, and although they display effectiveness in silico, peptide activity is suboptimal in vitro due to reduced bioavailability and poor delivery. To overcome this drawback, we delivered an anti-Ran-GTPase peptide using encapsulation in PLGA-based nanoparticles (NP). Formulation variables within a double emulsion solvent evaporation technique were controlled to optimise physicochemical properties. NP were spherical and negatively charged with a mean diameter of 182-277nm. Peptide integrity and stability were maintained after encapsulation and release kinetics followed a sustained profile. We were interested in the relationship between cellular uptake and poly(ethylene glycol) (PEG) in the NP matrix, with results showing enhanced in vitro uptake with increasing PEG content. Peptide-loaded, pegylated (10% PEG)-PLGA NP induced significant cytotoxic and apoptotic effects in MDA-MB-231 breast cancer cells, with no evidence of similar effects in cells pulsed with free peptide. Western blot analysis showed that encapsulated peptide interfered with the proposed signal transduction pathway of the Ran gene. Our novel blockade peptide prevented Ran activation by blockage of regulator of chromosome condensation 1 (RCC1) following peptide release directly in the cytoplasm once endocytosis of the peptide-loaded nanoparticle has occurred. RCC1 blockage was effective only when a nanoparticulate delivery approach was adopted.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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