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In Vivo Evaluation Of Doxorubicin-loaded Polymeric Micelles Targeting Folate Receptors And Early Endosomal PH In Drug-resistant Ovarian Cancer.
D. Kim, Z. G. Gao, E. Lee, Y. Bae
Published 2009 · Chemistry, Medicine
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The second generation of pH-sensitive micelles composed of poly(l-histidine-co-l-phenlyalanine(16 mol %))(MW:5K)-b-PEG(MW:2K) and poly(l-lactic acid)(MW:3K)-b-PEG(MW:2K)-folate (80/20 wt/wt %) was previously optimized by physicochemical and in vitro tests for both folate receptor and early endosomal pH targeting (pH approximately 6.0). In this study, the therapeutic efficacy of the doxorubicin (DOX)-loaded micelles (DOX loading content: 20 wt %) was evaluated using in vivo tests. Multidrug-resistant (MDR) ovarian tumor-xenografted mouse models were employed. The skin-fold dorsal window chamber model was applied for visualization of extravasation and drug retention for the initial one hour after iv injection. Noninvasive imaging followed, providing evidence of drug accumulation in the tumor after the first hour. The biodistribution study further supported the long circulation of the drug carrier, tumor-selective accumulation and intracellular drug delivery. Comprehensive tumor growth inhibition experiments examined the collective efficacy of the pH-sensitive micelles. The micelle formulation effectively suppressed the growth of existing MDR tumors in mice for at least 50 days by three iv injections at a 3-day interval at a dose of 10 mg of DOX/kg. The body weight of the animals treated with the test micelle formulation gradually increased over the experimental time period, rather than decreasing. The micelle formulation was superior to its first generation, which targeted pH 6.8 and folate receptor.
This paper references
Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein
B. Sikic (1997)
Anticancer prodrugs for application in monotherapy: targeting hypoxia, tumor-associated enzymes, and receptors.
F. M. D. de Groot (2001)
Role of P-glycoprotein in drug disposition.
Y. Tanigawara (2000)
Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review.
H. Maeda (2000)
The design and synthesis of polymers for eukaryotic membrane disruption.
N. Murthy (1999)
Enhanced Intercellular Retention Activity of Novel pH-sensitive Polymeric Micelles in Wild and Multidrug Resistant MCF-7 Cells
Ghazal Mohajer (2007)
Membrane Fusion Induced by Vesicular Stomatitis Virus Depends on Histidine Protonation*
F. A. Carneiro (2003)
Targeting multidrug resistance in cancer
G. Szakács (2006)
Cancer nanotechnology: opportunities and challenges
M. Ferrari (2005)
Long-circulating and target-specific nanoparticles: theory to practice.
S. Moghimi (2001)
PEGylated Nanoparticles for Biological and Pharmaceutical Applications
H. Otsuka (2003)
P-glycoprotein and multidrug resistance.
M. Gottesman (1996)
The cell biology of multiple drug resistance.
W. Beck (1987)
Liposome-based approaches to overcome anticancer drug resistance.
C. Mamot (2003)
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 (2006)
Poly(L-histidine)-PEG block copolymer micelles and pH-induced destabilization.
E. Lee (2003)
Doxorubicin Loaded pH-sensitive Micelle: Antitumoral Efficacy against Ovarian A2780/DOXR Tumor
D. Kim (2008)
Drug Delivery Systems: Entering the Mainstream
T. Allen (2004)
Prodrug chemotherapeutics bypass p-glycoprotein resistance and kill tumors in vivo with high efficacy and target-dependent selectivity
V. Guillemard (2004)
Differential macromolecular leakage from the vasculature of tumors
L. Heuser (1986)
Cell biological mechanisms of multidrug resistance in tumors.
S. Simon (1994)
Mechanisms of altered sequestration and efflux of chemotherapeutic drugs by multidrug-resistant cells
Z. Ouar (2004)
Multidrug resistance-associated protein (MRP) gene expression in human lung cancer.
F. Narasaki (1996)
Auxin induces exocytosis and the rapid synthesis of a high-turnover pool of plasma-membrane H+-ATPase
A. Hager (2004)
Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs.
R. Krishna (2000)
Doxorubicin-loaded polymeric micelle overcomes multidrug resistance of cancer by double-targeting folate receptor and early endosomal pH.
D. Kim (2008)
Nanoparticle and targeted systems for cancer therapy.
L. Brannon-Peppas (2004)
Pluronic block copolymers alter apoptotic signal transduction of doxorubicin in drug-resistant cancer cells.
T. Minko (2005)
Ligand-targeted liposomal anticancer drugs.
P. Sapra (2003)
Expression of MDR1/P-glycoprotein, the multidrug resistance protein MRP, and the lung-resistance protein LRP in multiple myeloma
H. Schwarzenbach (2002)
Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules.
H. Dvorak (1988)
Biodegradable thermo-sensitive nanoparticles from poly(L-lactic acid)/poly(ethylene glycol) alternating multi-block copolymer for potential anti-cancer drug carrier.
K. Na (2006)
Polymeric micelle for tumor pH and folate-mediated targeting.
E. Lee (2003)
Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes.
A. Gabizon (1992)
Physicochemical characteristics of pH-sensitive poly(L-histidine)-b-poly(ethylene glycol)/poly(L-lactide)-b-poly(ethylene glycol) mixed micelles.
Haiqing Yin (2008)
Susceptibility of nanoparticle-encapsulated paclitaxel to P-glycoprotein-mediated drug efflux.
M. Chavanpatil (2006)
Doxorubicin loaded pH-sensitive polymeric micelles for reversal of resistant MCF-7 tumor.
E. Lee (2005)
Nuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance efflux pump.
D. Goren (2000)
Multidrug resistance reversal agents.
J. Robert (2003)
Targeted drug delivery by thermally responsive polymers.
A. Chilkoti (2002)
HPMA-hydrogels result in prolonged delivery of anticancer drugs and are a promising tool for the treatment of sensitive and multidrug resistant leukaemia.
M. Stastny (2002)
Enzymatic activation of second-generation dendritic prodrugs: Conjugation of self-immolative dendrimers with poly(ethylene glycol) via click chemistry.
A. Gopin (2006)
Multidrug Resistance Associated with Increased Drug Efflux and Altered
L. Breuninger (1995)
Intracellular pH and the control of multidrug resistance.
S. Simon (1994)
This paper is referenced by
The achievement of ligand-functionalized organic/polymeric nanoparticles for treating multidrug resistant cancer
Wing-Hin Lee (2017)
Stimuli-responsive nanodrug self-assembled from amphiphilic drug-inhibitor conjugate for overcoming multidrug resistance in cancer treatment
Ping Huang (2019)
Enhanced synergism of thermo-chemotherapy by combining highly efficient magnetic hyperthermia with magnetothermally-facilitated drug release.
Y. Qu (2014)
Stimulus-responsive nanopreparations for tumor targeting.
Lin Zhu (2013)
Combinatorial delivery of superparamagnetic iron oxide nanoparticles (γFe2O3) and doxorubicin using folate conjugated redox sensitive multiblock polymeric nanocarriers for enhancing the chemotherapeutic efficacy in cancer cells.
Chetan Nehate (2017)
Immunomicelles for advancing personalized therapy.
R. Sawant (2012)
The challenges facing block copolymer micelles for cancer therapy: In vivo barriers and clinical translation.
S. Eetezadi (2015)
Nanotechnology to Combat Multidrug Resistance in Cancer
Sohail Akhter (2015)
Doxorubicin-loaded boron-rich polymer nanoparticles for orthotopically implanted liver tumor treatment
Luzhong Zhang (2013)
Development of nanoparticulate systems with action in breast and ovarian cancer: nanotheragnostics
Fabiana de Sousa Cunha (2019)
Photo-controlled metal-ion (Zn2+ and Cd2+) release in aqueous Tween-20 micelle solution.
X. Zhang (2012)
Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release
C. Oerlemans (2010)
Triglycerol-based hyperbranched polyesters with an amphiphilic branched shell as novel biodegradable drug delivery systems
S. Stefani (2016)
CO2 gas induced drug release from pH-sensitive liposome to circumvent doxorubicin resistant cells.
J. Liu (2012)
Surface-Eroding Poly(ortho ester amides) for Highly Efficient Oral Chemotherapy.
B. Wei (2015)
4.26 pH-Responsive Polymers for the Intracellular Delivery of Biomolecular Drugs
D. Benoit (2017)
Overcoming multidrug resistance (MDR) in cancer by nanotechnology
Huihui Bu (2010)
Anthracycline Nano-Delivery Systems to Overcome Multiple Drug Resistance: A Comprehensive Review.
P. Ma (2013)
Multifunctional hollow nanoparticles based on graft-diblock copolymers for doxorubicin delivery.
Pei-Lin Lu (2011)
Multifunctionality of lipid-core micelles for drug delivery and tumour targeting
R. Sawant (2010)
pH-sensitive drug-delivery systems for tumor targeting.
X. He (2013)
Role of non-covalent and covalent interactions in cargo loading capacity and stability of polymeric micelles.
Xiyu Ke (2014)
Self-assembly of folic acid dextran conjugates for cancer chemotherapy.
Y. Tang (2018)
Fundamentals and Applications of Controlled Release Drug Delivery
J. Siepmann (2012)
Targeted delivery of anticancer drugs: new trends in lipid nanocarriers
M. B. Oliveira (2017)
Overcoming multiple drug resistance in cancer using polymeric micelles
S. S. Kesharwani (2018)
Prevention of metastasis in a 4T1 murine breast cancer model by doxorubicin carried by folate conjugated pH sensitive polymeric micelles.
Z. Gao (2011)
Enhanced antitumor efficacy by cyclic RGDyK-conjugated and paclitaxel-loaded pH-responsive polymeric micelles.
Yajie Gao (2015)
Extracellular stability of nanoparticulate drug carriers
K. C. Liu (2014)
Size- and pathotropism-driven targeting and washout-resistant effects of boronic acid-rich protein nanoparticles for liver cancer regression.
Jing Wang (2013)
Fabrication and Intracellular Delivery of Doxorubicin/Carbonate Apatite Nanocomposites: Effect on Growth Retardation of Established Colon Tumor
S. Hossain (2013)
The delivery of doxorubicin to 3-D multicellular spheroids and tumors in a murine xenograft model using tumor-penetrating triblock polymeric micelles.
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