Efficient megalin targeted delivery to renal proximal tubular cells mediated by modified-polymyxin B-polyethylenimine based nano-gene-carriers

Fatemeh Oroojalian, Ali Hossein Rezayan, Faramarz Mehrnejad, Azadeh Hashem Nia, Wayne Thomas Shier, Khalil Abnous, Mohammad Ramezani

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Non-viral vectors have attracted great interest, as they are simple to prepare, easy to modify and relatively safe, compared to viral vectors. Kidney-targeted gene delivery systems depict a promising technology to improve drug efficacy in renal diseases treatments. In order to develop a novel kidney-targeted gene delivery system, we synthesized polyamine-PEI conjugates using polymyxin B as ligand and investigated their potential targeting efficiency. After grafting either PEI25 kDa or PEI10 kDa with polymyxin B through amidation reaction, the modified-polymyxin-PEI/DNA-nanoplexes were produced via electrostatic attraction between the cationic polymers and EGFP plasmid. The properties of modified polymers including size, surface charge density, DNA condensation ability, buffering capacity and cytotoxicity were evaluated. Results revealed that the average size of -modified-polymyxin- PEI25 kDa was about 143–180 nm and modified-polymyxin-PEI10 kDa 115–194 nm. The zeta potentials were in the range of 16.4 ± 1.87 to 23.43 ± 1.25 mV and 11.3 ± 1.4 to 19.3 ± 2.1 mV for conjugates based on PEI25 and PEI10 respectively. The AFM images revealed that the complexes were spherical and nano-sized at C/P = 4. The buffering capacity of both PEI 10 and 25 kDa increased as the percentage of polymyxin B grafting increased. In vitro study demonstrated that modified-polymyxin-PEI conjugates could remarkably improve the gene transfection efficiency to kidney cells. The transfection efficiency of the polyplexes was dependent on the weight ratio of ligand in the formulation (~ 12 and 8 fold increase for PEI25 and PEI10 kDa, respectively) and was significantly higher than that of unmodified PEIs/DNA nanoparticles. These results suggest that modified-polymyxin-PEI /DNA nanoparticles can effectively target megalin-expressing kidney cells and show improved transfection efficiency and low cytotoxicity in In vitro and In vivo studies. Animal studies confirmed the in vivo study. Thus, these conjugates can be considered as a safe and efficient non-viral therapeutic therapy vector for kidney diseases.

Original languageEnglish (US)
Pages (from-to)770-782
Number of pages13
JournalMaterials Science and Engineering C
Volume79
DOIs
StatePublished - Oct 1 2017

Bibliographical note

Funding Information:
The authors would like to thank the Iran National Science Foundation (INFS) (Project 93027649) for the financial support of this research. Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences (Project 921689), Mashhad, Iran, Department of Medicinal Chemistry. This work was included in part in the PhD thesis of Fatemeh Oroojalian in University of Tehran (Project 28445/06/05).

Publisher Copyright:
© 2017 Elsevier B.V.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

  • Gene delivery
  • Megalin
  • Polyethylenimine
  • Polymyxin B
  • Renal targeting

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