Doxorubicin and Paclitaxel-Loaded Lipid-Based Nanoparticles Overcome Multidrug Resistance by Inhibiting P-Glycoprotein and Depleting ATP

Dong, Xiaowei; Mattingly, Cynthia A.; Tseng, Michael T.; Cho, Moo J.; Liu, Yang; Adams, Val R.; Mumper, Russell J.

doi:10.1158/0008-5472.can-08-2747

Cited by 259 publications

(180 citation statements)

References 30 publications

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“…Certain NPs may overcome chemoresistance through the inhibition of multidrug resistance-1 (MDR-1) function in MDR-1-overexpressing cancer cells. 31 More PLGA-PEIOre TAX was taken up by both A549 and A549/T12 cells than free Oregon Green paclitaxel in the current study. Both cancer cells expressed a similar level of clathrin and caveolae ( Figure S1A); however, paclitaxel-resistant A549/T12 cells did not express MDR-1 ( Figure S1B).…”

Section: Discussionmentioning

confidence: 48%

PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells

Cheng

Shieh³

et al. 2012

IJN

127

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Background: Effective cancer chemotherapy remains an important issue in cancer treatment, and signal transducer and activator of transcription-3 (Stat3) activation leads to cellular resistance of anticancer agents. Polymers are ideal vectors to carry both chemotherapeutics and small interfering ribonucleic acid (siRNA) to enhance antitumor efficacy. In this paper, poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with paclitaxel and Stat3 siRNA were successfully synthesized, and their applications in cancer cells were investigated. Methods: Firstly, paclitaxel was enclosed by PLGA nanoparticles through solvent evaporation. They were then coated with cationic polyethylenimine polymer (PLGA-PEI-TAX), enabling it to carry Stat3 siRNA on its surface through electrostatic interactions (PLGA-PEI-TAX-S3SI). The size, zeta potential, deliver efficacy, and release profile of the PLGA nanocomplexes were characterized in vitro. The cellular uptake, intracellular nanoparticle trajectory, and subsequent cellular events were evaluated after treatment with various PLGA nanocomplexes in human lung cancer A549 cells and A549-derived paclitaxel-resistant A549/T12 cell lines with α-tubulin mutation. Results: A549 and A549/T12 cells contain constitutively activated Stat3, and silencing Stat3 by siRNA made both cancer cells more sensitive to paclitaxel. Therefore, PLGA-PEI-TAX-S3SI was synthesized to test its therapeutic role in A549 and A549/T12 cells. Transmission electron microscopy showed the size of PLGA-PEI-TAX-S3SI to be around 250 nm. PLGA-PEI nanoparticles were nontoxic. PLGA-PEI-TAX was taken up by A549 and A549/T12 cells more than free paclitaxel, and they induced more condensed microtubule bundles and had higher cytotoxicity in these cancer cells. Moreover, the yellowish fluorescence observed in the cytoplasm of the cancer cells indicates that the PLGA-PEI nanoparticles were still simultaneously delivering Oregon Green paclitaxel and cyanine-5-labeled Stat3 siRNA 3 hours after treatment. Furthermore, after the cancer cells were incubated with the synthesized PLGA nanocomplexes, PLGA-PEI-TAX-S3SI suppressed Stat3 expression and induced more cellular apoptosis in A549 and A549/T12 cells compared with PLGA-PEI-TAX. Conclusion:The PLGA-PEI-TAX-S3SI complex provides a new therapeutic strategy to control cancer cell growth.

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Section: Discussionmentioning

confidence: 48%

PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells

Cheng

Shieh³

et al. 2012

IJN

127

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“…There is high inherent toxicity of PGP inhibitors and altered pharmacokinetics and biodistribution of anticancer drugs when coadministered with PGP inhibitors (4,7). Not until recently a number of nanoparticle-based drug delivery systems such as polymer-drug conjugates, polymeric-micelles, and liposomes have been developed to overcome MDR (8).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Chemotherapy of Cancer Using pH-Sensitive Mesoporous Silica Nanoparticles to Antagonize P-Glycoprotein–Mediated Drug Resistance

Huang

Sun

Cheng

et al. 2011

Molecular Cancer Therapeutics

108

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Multidrug resistance (MDR) is the major clinical obstacle in the management of cancer by chemotherapy. Overexpression of ATP-dependent efflux transporter P-glycoprotein (PGP) is a key factor contributing to multidrug resistance of cancer cells. The purpose of the present study was to use the endosomal pH-sensitive MSN (mesoporous silica nanoparticles; MSN-Hydrazone-Dox) for controlled release of doxorubicin (Dox) in an attempt to overcome the PGP-mediated MDR. In vitro cell culture studies indicate that uptake of MSNHydrazone-Dox by the human uterine sarcoma MES-SA/Dox-resistant tumor (MES-SA/Dx-5) cell occurs through endocytosis, thus bypassing the efflux pump resistance. This improves the efficacy of the drug and leads to significant cytotoxicity and DNA fragmentation evidenced by terminal deoxynucleotidyl transferasemediated dUTP nick end labeling and DNA laddering assays. In vivo studies show that the intratumor injection of MSN-Hydrazone-Dox induces significant apoptosis of MES-SA/Dox-resistant cancer cells. This is validated by active caspase-3 immunohistochemical analysis. However, MSN-Hydrazone, without doxorubicin conjugation, cannot induce apoptosis in vitro and in vivo. In conclusion, both in vitro and in vivo studies show that MSN could serve as an efficient nanocarrier entering cell avidly via endocytosis, thus bypassing the PGP efflux pump to compromise the PGP-mediated MDR. MSN-Hydrazone-Dox could further respond to endosomal acidic pH to release doxorubicin in a sustained manner. Besides the cell study, this is the first report that successfully shows the therapeutic efficacy of using MSN against MDR cancer in vivo. Mol Cancer Ther; 10(5); 761-9. Ó2011 AACR.

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“…It was proved that the nanoparticle delivery system was able to bypass or inhibit P-glycoproteinmediated efflux and increase the internalization of drug into cells. [22][23][24] In addition, Tween 20 was also able to modulate multidrug resistance by inhibition of P-glycoproteinmediated efflux. 25 Therefore, the enhanced permeation of DTX-LNs may be the collective effects of both Tween 20 and nanoparticles.…”

mentioning

confidence: 99%

Enhanced oral bioavailability of docetaxel by lecithin nanoparticles: preparation, in vitro, and in vivo evaluation

Cao²,

Hu³

et al. 2012

IJN

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Abstract:The aim of this research work was to investigate the potential of lecithin nanoparticles (LNs) in improving the oral bioavailability of docetaxel. Docetaxel-loaded LNs (DTXLNs) were prepared from oil-in-water emulsions and characterized in terms of morphology, size, zeta potential, and encapsulation efficiency. The in vitro release of docetaxel from the nanoparticles was studied by using dialysis bag method. Caco-2 cell monolayer was used for the in vitro permeation study of DTX-LNs. Bioavailability studies were conducted in rats and different pharmacokinetic parameters were evaluated after oral administration of DTX-LNs. The results showed that DTX-LNs had a mean diameter of 360 ± 8 nm and exhibited spherical shape with smooth surface under transmission electron microscopy. The DTX-LNs showed a sustained-release profile, with about 80% of docetaxel released within 72 hours. The apical to basolateral transport of docetaxel across the Caco-2 cell monolayer from the DTX-LNs was 2.14 times compared to that of the docetaxel solution (0.15 × 10 −5 ± 0.016 × 10 −5 cm/second versus 0.07 × 10 −5 ± 0.003 × 10 −5 cm/second). The oral bioavailability of the DTX-LNs was 3.65 times that of docetaxel solution (8.75% versus 2.40%). These results indicate that DTX-LNs were valuable as an oral drug delivery system to enhance the absorption of docetaxel.

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Doxorubicin and Paclitaxel-Loaded Lipid-Based Nanoparticles Overcome Multidrug Resistance by Inhibiting P-Glycoprotein and Depleting ATP

Cited by 259 publications

References 30 publications

PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells

PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells

Enhanced Chemotherapy of Cancer Using pH-Sensitive Mesoporous Silica Nanoparticles to Antagonize P-Glycoprotein–Mediated Drug Resistance

Enhanced oral bioavailability of docetaxel by lecithin nanoparticles: preparation, in vitro, and in vivo evaluation

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