Doxorubicin and siRNA Codelivery via Chitosan-Coated pH-Responsive Mixed Micellar Polyplexes for Enhanced Cancer Therapy in Multidrug-Resistant Tumors

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

This study investigated the potential of chitosan-coated mixed micellar nanocarriers (polyplexes) for codelivery of siRNA and doxorubicin (DOX). DOX-loaded mixed micelles (serving as cores) were prepared by thin film hydration method and coated with chitosan (CS, serving as outer shell), and complexed with multidrug resistance (MDR) inhibiting siRNA. Selective targeting was achieved by folic acid conjugation. The polyplexes showed pH-responsive enhanced DOX release in acidic tumor pH, resulting in higher intracellular accumulation, which was further augmented by downregulation of mdr-1 gene after treatment with siRNA-complexed polyplexes. In vitro cytotoxicity assay demonstrated an enhanced cytotoxicity in native 4T1 and multidrug-resistant 4T1-mdr cell lines, compared to free DOX. Furthermore, in vivo, polyplexes codelivery resulted in highest DOX accumulation and significantly reduced the tumor volume in mice with 4T1 and 4T1-mdr tumors as compared to the free DOX groups, leading to improved survival times in mice. In conclusion, codelivery of siRNA and DOX via polyplexes has excellent potential as targeted drug nanocarriers for treatment of MDR cancers.

Original languageEnglish
Pages (from-to)4179-4190
Number of pages12
JournalMolecular Pharmaceutics
Volume13
Issue number12
DOIs
Publication statusPublished - 5 Dec 2016

Fingerprint

Chitosan
Doxorubicin
Small Interfering RNA
Neoplasms
Multiple Drug Resistance
Therapeutics
Micelles
Tumor Burden
Folic Acid
Down-Regulation
Cell Line
Pharmaceutical Preparations
Genes

Keywords

  • breast cancer
  • cytotoxicity
  • doxorubicin siRNA codelivery
  • multidrug resistance
  • nanoparticles
  • polymeric micelles
  • simultaneous delivery

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

@article{a4590ed8186f4b078f7a1e0de7730840,
title = "Doxorubicin and siRNA Codelivery via Chitosan-Coated pH-Responsive Mixed Micellar Polyplexes for Enhanced Cancer Therapy in Multidrug-Resistant Tumors",
abstract = "This study investigated the potential of chitosan-coated mixed micellar nanocarriers (polyplexes) for codelivery of siRNA and doxorubicin (DOX). DOX-loaded mixed micelles (serving as cores) were prepared by thin film hydration method and coated with chitosan (CS, serving as outer shell), and complexed with multidrug resistance (MDR) inhibiting siRNA. Selective targeting was achieved by folic acid conjugation. The polyplexes showed pH-responsive enhanced DOX release in acidic tumor pH, resulting in higher intracellular accumulation, which was further augmented by downregulation of mdr-1 gene after treatment with siRNA-complexed polyplexes. In vitro cytotoxicity assay demonstrated an enhanced cytotoxicity in native 4T1 and multidrug-resistant 4T1-mdr cell lines, compared to free DOX. Furthermore, in vivo, polyplexes codelivery resulted in highest DOX accumulation and significantly reduced the tumor volume in mice with 4T1 and 4T1-mdr tumors as compared to the free DOX groups, leading to improved survival times in mice. In conclusion, codelivery of siRNA and DOX via polyplexes has excellent potential as targeted drug nanocarriers for treatment of MDR cancers.",
keywords = "breast cancer, cytotoxicity, doxorubicin siRNA codelivery, multidrug resistance, nanoparticles, polymeric micelles, simultaneous delivery",
author = "Butt, {Adeel Masood} and {Mohd Amin}, {Mohd Cairul Iqbal} and Haliza Katas and {Abdul Murad}, {Nor Azian} and {A. Jamal}, {A. Rahman} and Prashant Kesharwani",
year = "2016",
month = "12",
day = "5",
doi = "10.1021/acs.molpharmaceut.6b00776",
language = "English",
volume = "13",
pages = "4179--4190",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
number = "12",

}

TY - JOUR

T1 - Doxorubicin and siRNA Codelivery via Chitosan-Coated pH-Responsive Mixed Micellar Polyplexes for Enhanced Cancer Therapy in Multidrug-Resistant Tumors

AU - Butt, Adeel Masood

AU - Mohd Amin, Mohd Cairul Iqbal

AU - Katas, Haliza

AU - Abdul Murad, Nor Azian

AU - A. Jamal, A. Rahman

AU - Kesharwani, Prashant

PY - 2016/12/5

Y1 - 2016/12/5

N2 - This study investigated the potential of chitosan-coated mixed micellar nanocarriers (polyplexes) for codelivery of siRNA and doxorubicin (DOX). DOX-loaded mixed micelles (serving as cores) were prepared by thin film hydration method and coated with chitosan (CS, serving as outer shell), and complexed with multidrug resistance (MDR) inhibiting siRNA. Selective targeting was achieved by folic acid conjugation. The polyplexes showed pH-responsive enhanced DOX release in acidic tumor pH, resulting in higher intracellular accumulation, which was further augmented by downregulation of mdr-1 gene after treatment with siRNA-complexed polyplexes. In vitro cytotoxicity assay demonstrated an enhanced cytotoxicity in native 4T1 and multidrug-resistant 4T1-mdr cell lines, compared to free DOX. Furthermore, in vivo, polyplexes codelivery resulted in highest DOX accumulation and significantly reduced the tumor volume in mice with 4T1 and 4T1-mdr tumors as compared to the free DOX groups, leading to improved survival times in mice. In conclusion, codelivery of siRNA and DOX via polyplexes has excellent potential as targeted drug nanocarriers for treatment of MDR cancers.

AB - This study investigated the potential of chitosan-coated mixed micellar nanocarriers (polyplexes) for codelivery of siRNA and doxorubicin (DOX). DOX-loaded mixed micelles (serving as cores) were prepared by thin film hydration method and coated with chitosan (CS, serving as outer shell), and complexed with multidrug resistance (MDR) inhibiting siRNA. Selective targeting was achieved by folic acid conjugation. The polyplexes showed pH-responsive enhanced DOX release in acidic tumor pH, resulting in higher intracellular accumulation, which was further augmented by downregulation of mdr-1 gene after treatment with siRNA-complexed polyplexes. In vitro cytotoxicity assay demonstrated an enhanced cytotoxicity in native 4T1 and multidrug-resistant 4T1-mdr cell lines, compared to free DOX. Furthermore, in vivo, polyplexes codelivery resulted in highest DOX accumulation and significantly reduced the tumor volume in mice with 4T1 and 4T1-mdr tumors as compared to the free DOX groups, leading to improved survival times in mice. In conclusion, codelivery of siRNA and DOX via polyplexes has excellent potential as targeted drug nanocarriers for treatment of MDR cancers.

KW - breast cancer

KW - cytotoxicity

KW - doxorubicin siRNA codelivery

KW - multidrug resistance

KW - nanoparticles

KW - polymeric micelles

KW - simultaneous delivery

UR - http://www.scopus.com/inward/record.url?scp=85002805034&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85002805034&partnerID=8YFLogxK

U2 - 10.1021/acs.molpharmaceut.6b00776

DO - 10.1021/acs.molpharmaceut.6b00776

M3 - Article

C2 - 27934479

AN - SCOPUS:85002805034

VL - 13

SP - 4179

EP - 4190

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 12

ER -