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Temperature-sensitive magnetic drug carriers for concurrent gemcitabine chemohyperthermia.

ABSTRACT: To improve the efficacy of gemcitabine (GEM) for the treatment of advanced pancreatic cancer via local hyperthermia potentiated via a multi-functional nanoplatform permitting both in vivo heating and drug delivery is the goal of this study. Here, a chemohyperthermia approach to synergistically achieve high intra-tumoral drug concentrations, while permitting concurrent hyperthermia for more effective tumor cell kill and growth inhibition, is proposed. Drug delivery and hyperthermia are achieved using a hydroxypropyl cellulose (HPC)-grafted porous magnetic drug carrier that is MRI visible to permit in vivo visualization of the biodistribution. These synthesized magnetic drug carriers produce strong T2 -weighted image contrast and permit efficient heating using low-magnetic-field intensities. The thermomechanical response of HPC permits triggered GEM release confirmed during in vitro drug release studies. During in vitro studies, pancreatic cancer cell growth is significantly inhibited (?82% reduction) with chemohyperthermia compared to chemotherapy or hyperthermia alone. Using PANC-1 xenografts in nude mice, the delivery of injected GEM-loaded magnetic carriers (GEM-magnetic carriers) is visualized with both MRI and fluorescent imaging techniques. Chemohyperthermia with intra-tumoral injections of GEM-magnetic carriers (followed by heating) results in significant increases in apoptotic cell death compared to tumors treated with GEM-magnetic carriers injections alone. Chemohyperthermia with GEM-magnetic carriers offers the potential to significantly improve the therapeutic efficacy of GEM for the treatment of pancreatic cancer. In vivo delivery confirmation with non-invasive imaging techniques could permit patient-specific adjustments therapeutic regimens for improve longitudinal outcomes.

SUBMITTER: Kim DH

PROVIDER: S-EPMC4008717 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Temperature-sensitive magnetic drug carriers for concurrent gemcitabine chemohyperthermia.

Kim Dong-Hyun DH Guo Yang Y Zhang Zhuoli Z Procissi Daniel D Nicolai Jodi J Omary Reed A RA Larson Andrew C AC

Advanced healthcare materials 20131021 5

To improve the efficacy of gemcitabine (GEM) for the treatment of advanced pancreatic cancer via local hyperthermia potentiated via a multi-functional nanoplatform permitting both in vivo heating and drug delivery is the goal of this study. Here, a chemohyperthermia approach to synergistically achieve high intra-tumoral drug concentrations, while permitting concurrent hyperthermia for more effective tumor cell kill and growth inhibition, is proposed. Drug delivery and hyperthermia are achieved u ...[more]

PMID: 24574255

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Project description:Magnetic and temperature-sensitive solid lipid particles (mag. SLPs) were prepared in the presence of oleic acid-coated iron oxide (IO-OA) nanoparticles with 1-tetradecanol and poly(ethylene oxide)-block-poly(?-caprolactone) as lipid and stabilizing surfactant-like agents, respectively. The particles, typically ~850 nm in hydrodynamic size, showed heat dissipation under the applied alternating magnetic field. Cytotoxic activity of the mag.SLPs, non-magnetic SLPs, and iron oxide nanoparticles was compared concerning the mammalian cancer cell lines and their drug-resistant counterparts using trypan blue exclusion test and MTT assay. The mag.SLPs exhibited dose-dependent cytotoxicity against human leukemia cell lines growing in suspension (Jurkat and HL-60/wt), as well as the doxorubicin (Dox)- and vincristine-resistant HL-60 sublines. The mag.SLPs showed higher cytotoxicity toward drug-resistant sublines as compared to Dox. The human glioblastoma cell line U251 growing in a monolayer culture was also sensitive to mag.SLPs cytotoxicity. Staining of U251 cells with the fluorescent dyes Hoechst 33342 and propidium iodide (PI) revealed that mag.SLPs treatment resulted in an increased number of cells with condensed chromatin and/or fragmented nuclei as well as with blebbing of the plasma membranes. While the Hoechst 33342 staining of cell suggested the pro-apoptotic activity of the particles, the PI staining indicated the pro-necrotic changes in the target cells. These conclusions were confirmed by Western blot analysis of apoptosis-related proteins, study of DNA fragmentation (DNA laddering due to the inter-nucleosomal cleavage and DNA comets due to single strand breaks), as well as by FACS analysis of the patterns of cell cycle distribution (pre-G1 phase) and Annexin V/PI staining of the treated Jurkat cells. The induction of apoptosis or necrosis by the particles used to treat Jurkat cells depended on the dose of the particles. Production of the reactive oxygen species (ROS) was proposed as a potential mechanism of mag.SLPs-induced cytotoxicity. Accordingly, hydrogen peroxide and superoxide radical levels in mag.SLPs-treated Jurkat leukemic cells were increased by ~20-40 and ~70%, respectively. In contrast, the non-magnetic SLPs and neat iron oxides did not influence ROS levels significantly. Thus, the developed mag.SLPs can be used for effective killing of human tumor cells, including drug-resistant ones.

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Temperature-sensitive magnetic drug carriers for concurrent gemcitabine chemohyperthermia.

Publications

Temperature-sensitive magnetic drug carriers for concurrent gemcitabine chemohyperthermia.

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