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Reversal of P-glycoprotein-mediated multidrug resistance by CD44 antibody-targeted nanocomplexes for short hairpin RNA-encoding plasmid DNA delivery.

Abstract
Multidrug resistance (MDR) remains one of the major reasons for the reductions in efficacy of many chemotherapeutic agents in cancer therapy. As a classical MDR phenotype of human malignancies, the adenosine triphosphate binding cassette (ABC)-transporter P-glycoprotein (MDR1/P-gp) is an efflux protein with aberrant activity that has been linked to multidrug resistance in cancer. For the reversal of MDR by RNA interference (RNAi) technology, an U6-RNA gene promoter-driven expression vector encoding anti-MDR1/P-gp short hairpin RNA (shRNA) molecules was constructed (abbreviated pDNA-iMDR1-shRNA). This study explored the feasibility of using Pluronic P123-conjugated polypropylenimine (PPI) dendrimer (P123-PPI) as a carrier for pDNA-iMDR1-shRNA to overcome tumor drug resistance in breast cancer cells. P123-PPI functionalized with anti-CD44 monoclonal antibody (CD44 receptor targeting ligand) (anti-CD44-P123-PPI) can efficiently condense pDNA into nanocomplexes to achieve efficient delivery of pDNA, tumor specificity and long circulation. The in vitro studies methodically evaluated the effect of P123-PPI and anti-CD44-P123-PPI on pDNA-iMDR1-shRNA delivery and P-gp downregulation. Our in vitro results indicated that the P123-PPI/pDNA and anti-CD44-P123-PPI/pDNA nanocomplexes with low cytotoxicity revealed higher transfection efficiency compared with the PPI/pDNA nanocomplexes and Lipofectamine™ 2000 in the presence of serum. The nanocomplexes loaded with pDNA-iMDR1-shRNA against P-gp could reverse MDR accompanied by the suppression of MDR1/P-gp expression at the mRNA and protein levels and improve the internalization and cytotoxicity of Adriamycin (ADR) in the MCF-7/ADR multidrug-resistant cell line. BALB/c nude mice bearing MCF-7/ADR tumor were utilized as a xenograft model to assess antitumor efficacy in vivo. The results demonstrated that the administration of anti-CD44-P123-PPI/pDNA-iMDR1-shRNA nanocomplexes combined with ADR could inhibit tumor growth more efficiently than ADR alone. The enhanced therapeutic efficacy of ADR may be correlated with increased accumulation of ADR in drug-resistant tumor cells. Consequently, these results suggested that the use of pDNA-iMDR1-shRNA-loaded nanocomplexes may be a promising gene delivery strategy to reverse MDR and improve the effectiveness of chemotherapy.
AuthorsJijin Gu, Xiaoling Fang, Junguo Hao, Xianyi Sha
JournalBiomaterials (Biomaterials) Vol. 45 Pg. 99-114 (Mar 2015) ISSN: 1878-5905 [Electronic] Netherlands
PMID25662500 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibodies
  • Hyaluronan Receptors
  • Polypropylenes
  • RNA, Messenger
  • RNA, Small Interfering
  • poly(propyleneimine)
  • pluronic block copolymer P123
  • Doxorubicin
  • Poloxalene
  • DNA
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
  • Animals
  • Antibodies (metabolism)
  • Cell Death (drug effects)
  • DNA (metabolism)
  • Doxorubicin (pharmacology)
  • Drug Resistance, Multiple (drug effects)
  • Drug Resistance, Neoplasm (drug effects)
  • Endocytosis (drug effects)
  • Endosomes (drug effects, metabolism)
  • Female
  • Gene Silencing (drug effects)
  • Gene Transfer Techniques
  • Genes, Reporter
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hyaluronan Receptors (immunology)
  • Intracellular Space (metabolism)
  • MCF-7 Cells
  • Nanoparticles (chemistry)
  • Plasmids (metabolism)
  • Poloxalene (chemical synthesis, chemistry)
  • Polypropylenes (chemical synthesis, chemistry)
  • RNA, Messenger (genetics, metabolism)
  • RNA, Small Interfering (metabolism)
  • Tissue Distribution (drug effects)
  • Transfection

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