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.