Evading P-glycoprotein mediated-efflux chemoresistance using Solid Lipid Nanoparticles

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• 作者：Marco C. Cavaco^b ; ¹ ; Carolina Pereira^a ; ¹ ; Bruna Kreutzer^b ; Luis F. Gouveia^a ; Beatriz Silva-Lima^b ; Alexandra M. Brito^c ; Mafalda Videira^a ; ^{mafaldavideira@campus.ul.pt}
• 关键词：ALDH1 ; aldehyde dehydrogenase 1 ; bp ; base pairs ; CME ; clathrin-mediated endocytosis ; CSC ; cancer stem cells ; ECM ; extracellular matrix ; EMT ; epithelial-mesenchymal transition ; HA ; hyaluronic acid ; MDR ; multidrug resistance ; PEG-PE ; polyethylene glycol-phosphatidylethanolamine ; P-gp ; P-glycoprotein ; Ptx ; paclitaxel ; SLN ; solid lipid nanoparticles ; SC ; stem cells ; TNBC ; triple negative breast cancer
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：110
• 期：Complete
• 页码：76-84
• 全文大小：1475 K
• 卷排序：110

文摘

Multidrug resistance (MDR), whereby cancer cells become resistant to the cytotoxic effects of various structurally and mechanistically unrelated chemotherapeutic agents, is a major problem in the clinical treatment of cancer. P-glycoprotein (P-gp) is a transmembrane protein responsible for drug efflux, which decreases drug intracellular bioavailability, consequently decreasing their efficacy against cancer. Solid Lipid Nanoparticles (SLNs) have not only the ability to protect the entrapped drug against proteolytic degradation, but also allow a selective intracellular targeting. Hypothetically, the entrapped drug enter the target cells by different uptake mechanisms, “nanocitose”, as compared to the free drug and may evade efflux-transporters, like P-gp. The functional role of P-gp in limiting the permeability of the anticancer drug paclitaxel (Ptx) was assessed in MDA-MB-436 cells. The observed increase in the pharmacologic efficacy of drug entrapped in SLN relatively to the free drug indicates that this system is shielding the drug. Therefore, “blinding” the nanoparticle from the efflux transporters. The effect was confirmed by the decrease expression of P-gp with loaded-SLNs and through the impact on cellular MDR1 expression. Besides the ability to prevent MDR events, functionalization of SLN with a specific antibody against membrane receptors (anti-CD44v6) improves the nanoparticle capability to target selectively malignant cells. This results allow to anticipate that poor clinical outcomes related to tumour P-gp overexpression might be overcome in a near future.