Reversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action

Verdière, Alain Colin de; Dubernet, Catherine; Némati, Fariba; Soma, Émilienne; Appel, M.; Ferté, Jacques; Bernard, S.M.; Puisieux, F.; Couvreur, Patrick

doi:10.1038/bjc.1997.362

Cited by 152 publications

(56 citation statements)

References 22 publications

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“…Moreover, nanoparticles are known to be more stable in the bloodstream, due to reduced interactions and exchanges with blood components (Lasic, 1998). Finally, cyanoacrylate nanoparticles were found to be able to reverse P-glycoprotein-mediated multidrug resistance by a specific mechanism (Colin de Verdière et al, 1997).…”

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confidence: 99%

Poly(ethylene glycol)-Coated Hexadecylcyanoacrylate Nanospheres Display a Combined Effect for Brain Tumor Targeting

Brigger

Morizet

Aubert

et al. 2002

J Pharmacol Exp Ther

221

128

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The aim of the present study was to evaluate the tumor accumulation of radiolabeled long-circulating poly(ethylene glycol) (PEG)-coated hexadecylcyanoacrylate nanospheres and non-PEG-coated hexadecylcyanoacrylate nanospheres (used as control), after intravenous injection in Fischer rats bearing intracerebrally well established 9L gliosarcoma. Both types of nanospheres showed an accumulation with a retention effect in the 9L tumor. However, long-circulating nanospheres concentrated 3.1 times higher in the gliosarcoma, compared with non-PEG-coated nanospheres. The tumor-to-brain ratio of pegylated nanospheres was found to be 11, which was in accordance with the ratios reported for other carriers tested for brain tumor targeting such as long-circulating liposomes or labels for magnetic resonance imaging. In addition, a 4-to 8-fold higher accumulation of the PEG-coated carriers was observed in normal brain regions, when compared with control nanospheres.Using a simplified pharmacokinetic model, two different mechanisms were proposed to explain this higher concentration of PEG-coated nanospheres in a tumoral brain. 1) in the 9L tumor, the preferential accumulation of pegylated nanospheres was attributable to their slower plasma clearance, relative to control nanospheres. Diffusion/convection was the proposed mechanism for extravasation of the nanospheres in the 9L interstitium, across the altered blood-brain barrier. 2) In addition, PEGcoated nanospheres displayed an affinity with the brain endothelial cells (normal brain region), which may not be considered as the result of a simple diffusion/convection process. The exact underlying mechanism of such affinity deserves further investigation, since it was observed to be as important as specific interactions described for immunoliposomes with the blood-brain barrier.

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mentioning

confidence: 99%

Poly(ethylene glycol)-Coated Hexadecylcyanoacrylate Nanospheres Display a Combined Effect for Brain Tumor Targeting

Brigger

Morizet

Aubert

et al. 2002

J Pharmacol Exp Ther

221

128

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“…Because cytotoxic drugs typically carry numerous dose-limiting normal tissue side effects (Tipton, 2003), it is generally impractical to overcome this form of drug resistance simply by increasing the drug dose. To improve the therapeutic ratio of cancer chemotherapy, it is critical to establish alternative approaches that may improve accumulation and prolong retention of cytotoxic drugs in drug-resistant cancer cells without causing additional normal tissue side effects.Particulate drug delivery systems such as polymeric microspheres (Liu et al, 2001), nanoparticles (de Verdiere et al 1997;Moghimi and Hunter, 2000), liposomes (Thierry et al, 1993;Romsicki and Sharom, 1999;Booser et al, 2002), and solid lipid nanoparticles (SLNs) (Wong et al, 2004(Wong et al, , 2005 offer great promise to achieve the aforementioned goal. Particulate systems are well known to be able to deliver drugs with higher efficiency with fewer adverse side effects (Booser et al, 2002;Lamprecht et al, 2005).…”

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confidence: 99%

A Mechanistic Study of Enhanced Doxorubicin Uptake and Retention in Multidrug Resistant Breast Cancer Cells Using a Polymer-Lipid Hybrid Nanoparticle System

Wong

Bendayan²,

Rauth³

et al. 2006

J Pharmacol Exp Ther

334

213

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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 Ͻ 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 DoxPLNs, 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.Chemotherapy with the use of cytotoxic drugs is commonly implemented in the management of many cancer types, e.g., breast cancers (Skeel, 2003;Tack et al., 2004). However, suboptimal therapeutic responses associated with multidrug resistance (MDR) frequently occur (Longley and Johnston, 2005). Overexpression of P-glycoprotein (Pgp) is one of the prominent mechanisms that contribute to the MDR phenotype (Endicott and Ling, 1989;Gottesman, 2002). Pgp is a 170-kDa membrane-associated glycoprotein that may actively extrude several substrates, including a variety of cytotoxic drugs such as doxorubicin (Dox), from cell cytoplasm to outside of plasma membrane, thus lowering the effective drug concentrations within the cells (Endicott and Ling, 1989;Gottesman, 2002). Because cytotoxic drugs typically carry numerous dose-limiting normal tissue side effects (Tipton, 2003), it is generally impractical to overcome this form of drug resistance simply by increasing the drug dose. To improve the therapeutic ratio of cancer chemotherapy, it is critical to establish alternative approaches that may improve accumulation and prolong retention of cytotoxic drugs in drug-resistant cancer cells without causing additional normal tissue side effects.Particulate drug delivery systems such as polymeric microspheres (...

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“…Doxorubicin is a well-known P-gp substrate (Vauthier et al 2003). Resistant cells treated with doxorubicin-loaded poly(alkyl cyanoacrylate) nanoparticles showed much higher sensitivity to the drug relative to the free doxorubicin (de Verdiere et al 1997). Degradation of the carrier was shown to play a key role in the mechanism of action.…”

Section: Drug Delivery To Resistant Tumour Cellsmentioning

confidence: 99%

Drug delivery to tumours: recent strategies

Reddy

2005

Journal of Pharmacy and Pharmacology

132

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Despite several advancements in chemotherapy, the real therapy of cancer still remains a challenge. The development of new anti-cancer drugs for the treatment of cancer has not kept pace with the progress in cancer therapy, because of the nonspecific drug distribution resulting in low tumour concentrations and systemic toxicity. The main hindrance for the distribution of anti-cancer agents to the tumour site is the highly disorganized tumour vasculature, high blood viscosity in the tumour, and high interstitial pressure within the tumour tissue. Recently, several approaches such as drug modifications and development of new carrier systems for anti-cancer agents have been attempted to enhance their tumour reach. Approaches such as drug delivery through enhanced permeability and retention (EPR) effect have resulted in a significant improvement in concentration in tumours, while approaches such as drug-carrier implants and microparticles have resulted in improvement in local chemotherapy of cancer. This review discusses different strategies employed for the delivery of anti-cancer agents to tumours, such as through EPR effect, local chemotherapeutic approaches using drug delivery systems, and special strategies such as receptor-mediated delivery, pH-based carriers, application of ultrasound and delivery to resistant tumour cells and brain using nanoparticles.

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Reversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action

Cited by 152 publications

References 22 publications

Poly(ethylene glycol)-Coated Hexadecylcyanoacrylate Nanospheres Display a Combined Effect for Brain Tumor Targeting

Poly(ethylene glycol)-Coated Hexadecylcyanoacrylate Nanospheres Display a Combined Effect for Brain Tumor Targeting

A Mechanistic Study of Enhanced Doxorubicin Uptake and Retention in Multidrug Resistant Breast Cancer Cells Using a Polymer-Lipid Hybrid Nanoparticle System

Drug delivery to tumours: recent strategies

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