Evading P-glycoprotein mediated-efflux chemoresistance using Solid Lipid Nanoparticles.
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.
Department of Pharmacological Sciences, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia Universidade de Lisboa, Lisbon, Portugal.
Marco C
MC
Cavaco
Department of Pharmaceutics, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia Universidade de Lisboa, Lisbon, Portugal.
Carolina
C
Pereira
Department of Pharmacological Sciences, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia Universidade de Lisboa, Lisbon, Portugal.
Bruna
B
Kreutzer
Department of Pharmaceutics, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia Universidade de Lisboa, Lisbon, Portugal.
Luis F
LF
Gouveia
Department of Pharmacological Sciences, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia Universidade de Lisboa, Lisbon, Portugal.
Beatriz
B
Silva-Lima
Department of Biochemistry and Human Biology, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia Universidade de Lisboa, Lisbon, Portugal.
Alexandra M
AM
Brito
Department of Pharmaceutics, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia Universidade de Lisboa, Lisbon, Portugal. Electronic address: mafaldavideira@campus.ul.pt.
Mafalda
M
Videira
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival; D004337:Drug Carriers; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000378:metabolism; D007150:Immunohistochemistry; D008055:Lipids / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage; D010316:Particle Size; D011485:Protein Binding; D012984:Software; D013696:Temperature
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C497483:CD44 protein, human; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D008055:Lipids; D017239:Paclitaxel
Breast cancer; CD44; Endocytosis; Multidrug resistance (MDR); P-glycoprotein (P-gp); Solid Lipid Nanoparticles (SLN)