title: Doxorubicin-Hyaluronan Conjugated Super-Paramagnetic Iron Oxide Nanoparticles (DOX-HA-SPION) Enhanced Cytoplasmic Uptake of Doxorubicin and Modulated Apoptosis, IL-6 Release and NF-kappaB Activity in Human MDA-MB-231 Breast Cancer Cells.
abstract: Triple negative breast cancer exhibit increased IL-6 expression compared with matched healthy breast tissue and a strong link between inflammation and cancer progression and metastasis has been reported. We investigated whether doxorubicin-hyaluronan-super-paramagnetic iron oxide nanoparticles (DOX-HA-SPION) would show greater therapeutic efficacy in human triple negative breast cancer cells (TNBC) MDA-MB-231, as was recently shown in drug-sensitive and multi-drug-resistant ovarian cancer cells. Therefore, we measured cellular DOX uptake via confocal microscopy; observed morphologic changes: mitochondrial and nuclear changes with electron microscopy, and quantitated apoptosis using FACS analysis after Annexin V and PI staining in MDA-MB-231 cells treated with either DOX alone or DOX-HA-SPION. We also measured both proinflammatory and anti-inflammatory cytokines; IL-6, IL-10 respectively and also measured nitrate levels in the conditioned medium by ELISA. Inaddition, NF-κB activity was measured by luciferase assay. Confocal microscopy demonstrated greater cytoplasmic uptake of DOX-HA-SPION than free DOX. We also demonstrated reduction of Vimentin with DOX-HA-SPION which is significantly less than both control and DOX. DOX-HA-SPION enhanced apoptosis and significantly down regulated both pro-inflammatory mediators IL-6 and NF-κB in comparison to DOX alone. The secretion levels of anti-inflammatory mediators IL-10 and nitrate was not decreased in the DOX or DOX-HA-SPION treatment groups. Our data suggest that DOX-HA-SPION nanomedicine-based drug delivery could have promising potential in treating metastasized and chemoresistant breast cancer by enhancing the drug efficacy and minimizing off-target effects.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Vyas
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lopez-Hisijos
authors.forename: Sulakshana
authors.initials: S
authors.lastname: Gandhi
authors.forename: M
authors.initials: M
authors.lastname: El-Dakdouki
authors.forename: Marc D
authors.initials: MD
authors.lastname: Basson
authors.forename: Mary F
authors.initials: MF
authors.lastname: Walsh
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.forename: Arpita K
authors.initials: AK
authors.lastname: Vyas
authors.forename: Lakshmi S
authors.initials: LS
authors.lastname: Chaturvedi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000493:pharmacokinetics; D015850:Interleukin-6 / Q000378:metabolism*; D058185:Magnetite Nanoparticles / Q000737:chemistry* / Q000633:toxicity; D016328:NF-kappa B / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; D058185:Magnetite Nanoparticles; D016328:NF-kappa B; D004317:Doxorubicin; D006820:Hyaluronic Acid