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PEGylated Hyaluronic Acid-Modified Liposomal Delivery System with Anti-γ-Glutamylcyclotransferase siRNA for Drug-Resistant MCF-7 Breast Cancer Therapy

PEGylated hyaluronic acid (PEG–HA) was synthesized and employed to coat the cationic liposome-siRNA complex through electrostatic interaction to form PEG–HA–NP. Due to a reversed surface charge, PEG–HA–NP could keep stable in fetal bovine serum (FBS). In vitro studies demonstrated that PEG–HA–NP had... Full description

Journal Title: Journal of Pharmaceutical Sciences February 2015, Vol.104(2), pp.476-484
Main Author: Ran, Rui
Other Authors: Liu, Yayuan , Gao, Huile , Kuang, Qifang , Zhang, Qianyu , Tang, Jie , Fu, Han , Zhang, Zhirong , He, Qin
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0022-3549 ; E-ISSN: 1520-6017 ; DOI: 10.1002/jps.24163
Link: https://www.sciencedirect.com/science/article/pii/S002235491530201X
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recordid: elsevier_sdoi_10_1002_jps_24163
title: PEGylated Hyaluronic Acid-Modified Liposomal Delivery System with Anti-γ-Glutamylcyclotransferase siRNA for Drug-Resistant MCF-7 Breast Cancer Therapy
format: Article
creator:
  • Ran, Rui
  • Liu, Yayuan
  • Gao, Huile
  • Kuang, Qifang
  • Zhang, Qianyu
  • Tang, Jie
  • Fu, Han
  • Zhang, Zhirong
  • He, Qin
subjects:
  • Mcf-7
  • Gene Therapy
  • Non-Viral Gene Delivery
  • Liposome
  • Targeted Drug Delivery
  • Multidrug Resistance
  • Sirna
  • Γ-Glutamylcyclotransferase
  • Pharmacy, Therapeutics, & Pharmacology
ispartof: Journal of Pharmaceutical Sciences, February 2015, Vol.104(2), pp.476-484
description: PEGylated hyaluronic acid (PEG–HA) was synthesized and employed to coat the cationic liposome-siRNA complex through electrostatic interaction to form PEG–HA–NP. Due to a reversed surface charge, PEG–HA–NP could keep stable in fetal bovine serum (FBS). In vitro studies demonstrated that PEG–HA–NP had two cell internalization pathways and it had comparable P-glycoprotein downregulation efficacy with Lipofectamine RNAiMAX. In vivo experiments illustrated that PEG–HA–NP possessed the best tumor accumulation, cellular uptake, and P-glycoprotein downregulation capability in tumor bearing mice compared with naked NP and HA–NP after systemic administration. Overall, PEG–HA–NP proved itself an efficient siRNA carrier and the ability of downregulating P-glycoprotein made it a potential candidate to overcome multi-drug resistance. RNA interference is an effective method to achieve highly specific gene regulation. However, the commonly used cationic liposomes have poor biocompatibility, which may lead to systematic siRNA delivery of no avail. PEGylation is a good strategy in shielding the positive charge of cationic liposomes, but the enhanced serum stability is often in company with compromised cellular uptake and endosome escape. In this study, PEG was covalently linked to negatively charged hyaluronic acid and it was used to coat the liposome-siRNA nanoparticles. The resulting PEG–HA–NP complex had a diameter of 188.6±10.8nm and a dramatically declined zeta-potential from +34.9±4.0mV to −18.2±2.2mV. Owing to the reversed surface charge, PEG–HA–NP could remain stable in fetal bovine serum (FBS) to up to 24h. In contrast with normal PEGylation, hyaluronic acid and PEG co-modified PEG–HA–NP provided comparable cellular uptake and P-glycoprotein downregulation efficacy in MCF-7/ADR cells compared with Lipofectamine RNAiMAX and naked NP regardless of its anionic charged surface. Because of its good biocompatibility in serum, PEG–HA–NP possessed the best tumor accumulation, cellular uptake and subsequently the strongest P-glycoprotein silencing capability in tumor bearing mice compared with naked NP and HA–NP after i.v. injection, with a 34% P-glycoprotein downregulation. Therefore, PEG–HA coated liposomal complex was demonstrated to be a promising siRNA delivery system in adjusting solid tumor P-glycoprotein expression, which may become a potential carrier in reversing MDR for breast cancer therapy.
language: eng
source:
identifier: ISSN: 0022-3549 ; E-ISSN: 1520-6017 ; DOI: 10.1002/jps.24163
fulltext: fulltext
issn:
  • 0022-3549
  • 00223549
  • 1520-6017
  • 15206017
url: Link


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descriptionPEGylated hyaluronic acid (PEG–HA) was synthesized and employed to coat the cationic liposome-siRNA complex through electrostatic interaction to form PEG–HA–NP. Due to a reversed surface charge, PEG–HA–NP could keep stable in fetal bovine serum (FBS). In vitro studies demonstrated that PEG–HA–NP had two cell internalization pathways and it had comparable P-glycoprotein downregulation efficacy with Lipofectamine RNAiMAX. In vivo experiments illustrated that PEG–HA–NP possessed the best tumor accumulation, cellular uptake, and P-glycoprotein downregulation capability in tumor bearing mice compared with naked NP and HA–NP after systemic administration. Overall, PEG–HA–NP proved itself an efficient siRNA carrier and the ability of downregulating P-glycoprotein made it a potential candidate to overcome multi-drug resistance. RNA interference is an effective method to achieve highly specific gene regulation. However, the commonly used cationic liposomes have poor biocompatibility, which may lead to systematic siRNA delivery of no avail. PEGylation is a good strategy in shielding the positive charge of cationic liposomes, but the enhanced serum stability is often in company with compromised cellular uptake and endosome escape. In this study, PEG was covalently linked to negatively charged hyaluronic acid and it was used to coat the liposome-siRNA nanoparticles. The resulting PEG–HA–NP complex had a diameter of 188.6±10.8nm and a dramatically declined zeta-potential from +34.9±4.0mV to −18.2±2.2mV. Owing to the reversed surface charge, PEG–HA–NP could remain stable in fetal bovine serum (FBS) to up to 24h. In contrast with normal PEGylation, hyaluronic acid and PEG co-modified PEG–HA–NP provided comparable cellular uptake and P-glycoprotein downregulation efficacy in MCF-7/ADR cells compared with Lipofectamine RNAiMAX and naked NP regardless of its anionic charged surface. Because of its good biocompatibility in serum, PEG–HA–NP possessed the best tumor accumulation, cellular uptake and subsequently the strongest P-glycoprotein silencing capability in tumor bearing mice compared with naked NP and HA–NP after i.v. injection, with a 34% P-glycoprotein downregulation. Therefore, PEG–HA coated liposomal complex was demonstrated to be a promising siRNA delivery system in adjusting solid tumor P-glycoprotein expression, which may become a potential carrier in reversing MDR for breast cancer therapy.
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