← Back to Search
A Mechanistic Study Of Enhanced Doxorubicin Uptake And Retention In Multidrug Resistant Breast Cancer Cells Using A Polymer-Lipid Hybrid Nanoparticle System
H. L. Wong, R. Bendayan, A. M. Rauth, H. Xue, Karlo Babakhanian, X. Wu
Published 2006 · Medicine, Chemistry
Download PDFAnalyze on Scholarcy
The objectives of this study were to evaluate the potential of a polymer-lipid hybrid nanoparticle (PLN) system to enhance cellular accumulation and retention of doxorubicin (Dox), a widely used anticancer drug and an established P-glycoprotein (Pgp) substrate, in Pgp-overexpressing cancer cell lines and to explore the underlying mechanisms. Nanoparticles containing Dox complexed with a novel anionic polymer (Dox-PLN) were prepared using an ultrasound method. Two Pgp-overexpressing breast cancer cell lines (a human cell line, MDA435/LCC6/MDR1, and a mouse cell line, EMT6/AR1) were used to investigate the effect of nanoparticles on cellular uptake and retention of Dox. Endocytosis inhibition studies and fluorescence microscopic imaging were performed to elucidate the mechanisms of cellular drug uptake. Treatment of Pgp-overexpressing cell lines with Dox-PLNs resulted in significantly enhanced Dox uptake and more substantial increases in drug retention after the end of treatment compared with free Dox solutions (p < 0.05). Fluorescence microscopic images showed improved nuclear localization of Dox and uptake of lipid when the drug was delivered in the Dox-PLN form to MDA435/LCC6/MDR1 cells. Endocytosis inhibition studies revealed that phagocytosis is an important pathway in the membrane permeability of the nanoparticles. These findings suggest that some of the Dox physically associated with the nanoparticles bypass the membrane-associated Pgp when delivered as Dox-PLNs, and in this form, the drug is better retained within the Pgp-overexpressing cells than the free drug. The present study suggests a new mechanism for overcoming drug resistance in Pgp-overexpressing tumor cells using lipid-based nanoparticle formulations.
This paper references
The future direction of the Journal of Pharmacy and Pharmacology
D. Q. Craig (2001)
"Handbook of clinical drug data".
J. Knoben (1983)
Differential interactions of cytochalasins with P-glycoprotein
Zilfou Jt (1995)
Liposome-cell interactions in vitro: effect of liposome surface charge on the binding and endocytosis of conventional and sterically stabilized liposomes.
C. R. Miller (1998)
Nanoparticles Enhance Therapeutic Efficiency by Selectively Increased Local Drug Dose in Experimental Colitis in Rats
A. Lamprecht (2005)
Side Effects of Cancer Chemotherapy
M. Dodd (1993)
The membrane lipid environment modulates drug interactions with the P-glycoprotein multidrug transporter.
Y. Romsicki (1999)
Dynamics of Endocytosis and Exocytosis of Poly(D,L-Lactide-co-Glycolide) Nanoparticles in Vascular Smooth Muscle Cells
J. Panyam (2004)
Coformulated N-Octanoyl-glucosylceramide Improves Cellular Delivery and Cytotoxicity of Liposomal Doxorubicin
R. Veldman (2005)
Side effects of cancer chemotherapy, in Handbook of Cancer Chemotherapy
Jm Tipton (2003)
Antineoplastics, chemoprotectants and immunosuppressants, in Handbook of Clinical Drug Data (Anderson PO and Knoben JE eds) pp 157–212
RT Dorr (1998)
Novel solid lipid nanoparticles formulations increase the cytotoxicity and prolong the cellular accumulation of doxorubicin in human multidrug-resistant breast cancer cells (Abstract)
HL Wong (2005)
Drug export activity
R Evers (1998)
Side effects of cancer chemotherapy, in Handbook of Cancer Chemotherapy (Skeel RT ed) pp 561–580
JM Tipton (2003)
A new solid lipid nanoparticle formulation increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells
HL Wong (2006)
A New Polymer–Lipid Hybrid Nanoparticle System Increases Cytotoxicity of Doxorubicin Against Multidrug-Resistant Human Breast Cancer Cells
H. L. Wong (2006)
Cationic liposome-mediated gene delivery in vivo.
Y. Liu (2003)
Phase II study of liposomal annamycin in the treatment of doxorubicin-resistant breast cancer
D. Booser (2002)
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
M. M. Bradford (1976)
Reversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action.
A. C. de VerdiÃ¨re (1997)
Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA.
R. Evers (1998)
Characterization of nanostructure of stimuli-responsive polymeric composite membranes.
K. Zhang (2004)
Differential interactions of cytochalasins with P-glycoprotein.
J. T. Zilfou (1995)
Cellular localization and functional expression of P‐glycoprotein in rat astrocyte cultures
P. T. Ronaldson (2004)
Antineoplastics, chemoprotectants and immunosuppressants, in Handbook of Clinical Drug Data (Anderson PO and Knoben JE eds)
Rt Dorr (1998)
Toxicity and DNA binding of dextran-doxorubicin conjugates in multidrug-resistant KB-V1 cells: optimization of dextran size
W. Lam (2000)
Modulation of doxorubicin resistance in multidrug‐resistant cells by liposomes
A. Thierry (1993)
Anthracycline vs nonanthracycline adjuvant therapy for breast cancer.
Dina K Tack (2004)
Molecular mechanisms of drug resistance
D. Longley (2005)
The biochemistry of P-glycoprotein-mediated multidrug resistance.
J. A. Endicott (1989)
Selection of treatment for the patient with cancer
R T Skeel (2003)
Ability of Doxorubicin-Loaded Nanoparticles to Overcome Multidrug Resistance of Tumor Cells After Their Capture by Macrophages
C. E. Soma (2004)
A pharmacodynamic analysis method to determine the relative importance of drug concentration and treatment time on effect
N. Millenbaugh (2000)
Poloxamers and poloxamines in nanoparticle engineering and experimental medicine.
S. Moghimi (2000)
A Study of Alternative Delivery Strategies and Systems to Enhance the Therapeutic Effect and Cytotoxic Activity of Anticancer Agents
RY Cheung (2005)
Development of solid lipid nanoparticles containing ionically complexed chemotherapeutic drugs and chemosensitizers.
H. L. Wong (2004)
Fundamental Relationships Between the Composition of Pluronic Block Copolymers and Their Hypersensitization Effect in MDR Cancer Cells
E. Batrakova (2004)
Subcellular trafficking of HPMA copolymer-Tat conjugates in human ovarian carcinoma cells.
A. Nori (2003)
Triton‐X‐100‐modified polymer and microspheres for reversal of multidrug resistance
Z. Liu (2001)
Polysorbate‐80 coating enhances uptake of polybutylcyanoacrylate (PBCA)‐nanoparticles by human and bovine primary brain capillary endothelial cells
P. Ramge (2000)
Mechanisms of cancer drug resistance.
M. Gottesman (2002)
Handbook of Cancer Chemotherapy
R. Skeel (1995)
Selection of treatment for the patient with cancer, in Handbook of Cancer Chemotherapy
Rt Skeel (2003)
Recognition of liposomes by cells: in vitro binding and endocytosis mediated by specific lipid headgroups and surface charge density.
K. Lee (1992)
Interaction of cationic colloids at the surface of J774 cells: a kinetic analysis.
P. Chenevier (2000)
Antineoplastics, chemoprotectants and immunosuppressants
R T Dorr (1998)
In vitro toxicity to breast cancer cells of microsphere-delivered mitomycin C and its combination with doxorubicin.
R. Cheung (2006)
Pluronic block copolymers for overcoming drug resistance in cancer.
A. Kabanov (2002)
Nuclear immunolocalization of P-glycoprotein in multidrug-resistant cell lines showing similar mechanisms of doxorubicin distribution.
N. Baldini (1995)
The relative importance of passive and P-glycoprotein mediated anthracycline efflux from multidrug-resistant cells.
P. Wielinga (2000)
This paper is referenced by
HSA-based multi-target combination therapy: regulating drugs’ release from HSA and overcoming single drug resistance in a breast cancer model
Yi Gou (2018)
Molecular interactions, internal structure and drug release kinetics of rationally developed polymer-lipid hybrid nanoparticles.
Y. Li (2008)
Aspartate-modified doxorubicin on its N-terminal increases drug accumulation in LAT1-overexpressing tumors
W. Wu (2015)
Daunorubicin-loaded magnetic nanoparticles of Fe3O4 overcome multidrug resistance and induce apoptosis of K562-n/VCR cells in vivo
B. Chen (2009)
Overcoming doxorubicin resistance of cancer cells by Cas9-mediated gene disruption
Jong seong Ha (2016)
Interactions of amphiphilic block copolymers with lipid model membranes
E. Amado (2011)
Amphiphilic Polymers: Drug Delivery
Diana Rafael (2015)
Engineering RNA for Targeted siRNA Delivery and Medical Application☆
P. Guo (2010)
Chapter 11 - Solid lipid nanoparticles for brain tumors therapy: State of the art and novel challenges.
A. Brioschi (2009)
Dual redox/pH-responsive hybrid polymer-lipid composites: Synthesis, preparation, characterization and application in drug delivery with enhanced therapeutic efficacy
J. Li (2018)
A new nanostructured carrier design including oil to enhance the pharmaceutical properties of retinoid therapy and its therapeutic effects on chemo-resistant ovarian cancer.
M. Narvekar (2014)
Lipomers (Lipid-polymer Hybrid Particles) of Vardenafil Hydrochloride: a Promising Dual Platform for Modifying the Drug Release Rate and Enhancing Its Oral Bioavailability
M. A. Tawfik (2018)
In vivo evaluation of safety and efficacy of self-assembled nanoparticles for oral insulin delivery.
K. Sonaje (2009)
Multidrug Resistance in Cancer Circumvented Using a Cytosolic Drug Reservoir
L. Fan (2018)
Nanopartikel in biologischen Systemen
W. Stark (2011)
Reversal in multidrug resistance by magnetic nanoparticle of Fe 3 O 4 loaded with adriamycin and tetrandrine in K 562 / A 02 leukemic cells
B. Chen (2008)
Flower-like hierarchically nanostructured hydroxyapatite hollow spheres: facile preparation and application in anticancer drug cellular delivery.
Ke-wei Wang (2010)
Reducing Both Pgp Overexpression and Drug Efflux with Anti-Cancer Gold-Paclitaxel Nanoconjugates
Fei Li (2016)
A Precise Nanostructure of Folate-Overhung Mitoxantrone DNA Tetrahedron for Targeted Capture Leukemia
Ying-Zi Bu (2020)
Substrate stiffness orchestrates epithelial cellular heterogeneity with controlled proliferative pattern via E-cadherin/β-catenin mechanotransduction.
B. Wang (2016)
Enabling Anticancer Therapeutics by Nanoparticle Carriers: The Delivery of Paclitaxel
Yongjin Liu (2011)
nanoparticles loaded with cisplatin on sKOV3/DDP ovarian carcinoma cells
Z. Jiang (2009)
Doxorubicin and MBO-asGCS oligonucleotide loaded lipid nanoparticles overcome multidrug resistance in adriamycin resistant ovarian cancer cells (NCI/ADR-RES).
A. Siddiqui (2012)
Recent advances in ligand targeted therapy
G. Trapani (2012)
Resveratrol Modulates the Topoisomerase Inhibitory Potential of Doxorubicin in Human Colon Carcinoma Cells
Anika Schroeter (2014)
Covalent, Non-Covalent, Encapsulated Nanodrug Regulate the Fate of Intra- and Extracellular Trafficking: Impact on Cancer and Normal Cells
Sang-Woo Kim (2017)
PENGARUH p-HIDROKSI m-METOKSI KALKON (pHmMK) TERHADAP EKSPRESI PROTEIN Bcl-2 dan Bax PADA SEL KANKER PAYUDARA MCF-7
R. Arianingrum (2017)
Nanoparticle-assisted Therapeutic Strategies for Effective Cancer Management
D. Nandi (2020)
Chemoprotection Across the Tumor Border: Cancer Cell Response to Doxorubicin Depends on Stromal Fibroblast Ratios and Interstitial Therapeutic Transport
Daniel K. Logsdon (2017)
Pulmonary delivery of inhalable nanoparticles: dry powder inhalers.
M. AlHallak (2011)
CYTOTOXIC ACTIVITY OF BRAZILEIN ISOLATED FROM SECANG (CAESALPINIA SAPPAN L.) AGAINST MCF7/DOX CELLS BY INHIBITION OF P-GLYCOPROTEIN
N. P. L. Laksmiani (2017)
Chitosan/Sterculia striata polysaccharides nanocomplex as a potential chloroquine drug release device.
G. A. Magalhães (2016)See more