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      Therapeutic Efficacy of Combining PEGylated Liposomal Doxorubicin and Radiofrequency (RF) Ablation: Comparison between Slow-Drug-Releasing, Non-Thermosensitive and Fast-Drug-Releasing, Thermosensitive Nano-Liposomes

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          Abstract

          Aims

          To determine how the accumulation of drug in mice bearing an extra-hepatic tumor and its therapeutic efficacy are affected by the type of PEGylated liposomal doxorubicin used, treatment modality, and rate of drug release from the liposomes, when combined with radiofrequency (RF) ablation.

          Materials and Methods

          Two nano-drugs, both long-circulating PEGylated doxorubicin liposomes, were formulated: (1) PEGylated doxorubicin in thermosensitive liposomes (PLDTS), having a burst-type fast drug release above the liposomes’ solid ordered to liquid disordered phase transition (at 42°C), and (2) non-thermosensitive PEGylated doxorubicin liposomes (PLDs), having a slow and continuous drug release. Both were administered intravenously at 8 mg/kg doxorubicin dose to tumor-bearing mice. Animals were divided into 6 groups: no treatment, PLD, RF, RF+PLD, PLDTS, and PLDTS+RF, for intra-tumor doxorubicin deposition at 1, 24, and 72 h post-injection (in total 41, mice), and 31 mice were used for randomized survival studies.

          Results

          Non-thermosensitive PLD combined with RF had the least tumor growth and the best end-point survival, better than PLDTS+RF (p<0.005) or all individual therapies (p<0.001). Although at 1 h post-treatment the greatest amount of intra-tumoral doxorubicin was seen following PLDTS+RF (p<0.05), by 24 and 72 h the greatest doxorubicin amount was seen for PLD+RF (p<0.05); in this group the tumor also has the longest exposure to doxorubicin.

          Conclusion

          Optimizing therapeutic efficacy of PLD requires a better understanding of the relationship between the effect of RF on tumor microenvironment and liposome drug release profile. If drug release is too fast, the benefit of changing the microenvironment by RF on tumor drug localization and therapeutic efficacy may be much smaller than for PLDs having slow and temperature-independent drug release. Thus the much longer circulation time of doxorubicin from PLD than from PLDTS may be beneficial in many therapeutic instances, especially in extra-hepatic tumors.

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          Most cited references52

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          Phosphorus assay in column chromatography.

          G BARTLETT (1959)
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            Error bars in experimental biology

            Error bars commonly appear in figures in publications, but experimental biologists are often unsure how they should be used and interpreted. In this article we illustrate some basic features of error bars and explain how they can help communicate data and assist correct interpretation. Error bars may show confidence intervals, standard errors, standard deviations, or other quantities. Different types of error bars give quite different information, and so figure legends must make clear what error bars represent. We suggest eight simple rules to assist with effective use and interpretation of error bars.
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              Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy.

              The results obtained in this study establish that liposome formulations incorporating a synthetic polyethylene glycol-derivatized phospholipid have a pronounced effect on liposome tissue distribution and can produce a large increase in the pharmacological efficacy of encapsulated antitumor drugs. This effect is substantially greater than that observed previously with conventional liposomes and is associated with a more than 5-fold prolongation of liposome circulation time in blood, a marked decrease in uptake by tissues such as liver and spleen, and a corresponding increased accumulation in implanted tumors. These and other properties described here have expanded considerably the prospects of liposomes as an effective carrier system for a variety of pharmacologically active macromolecules.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                1 May 2014
                : 9
                : 5
                : e92555
                Affiliations
                [1 ]Laboratory of Membrane and Liposome Research, Department of Biochemistry, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
                [2 ]Radiology Department, Hadassah Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel and Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
                Aristotle University of Thessaloniki, Greece
                Author notes

                Competing Interests: The authors have read the journal’s policy and have the following conflicts: Yechezkel Barenholz is one of the inventors on two already expired (March 2010) patents relevant to Doxil: 1. Yechezkel Barenholz and Gilad Haran: “Method of Amphipathic Drug Loading in Liposomes by pH Gradient”. U.S. Patent No. 5,192,549, March 9, 1993. on Water”. U.S. Patent 5,244,574, September 14, 1993 2. Yechezkel Barenholz and Gilad Haran: “Liposomes: Efficient Loading and Controlled Release of Amphipathic Molecules”. U.S. Patent 5,316,771, May 31, 1994. Yechezkel Barenholz is a stock holder of LipoCure Ltd., which prepared the DOX-NP (a Doxil-like PLD) for research applications, which is distributed by Avanti Polar lipids. S. Nahum Goldberg has unrelated sponsored research and consulting with Angiodynamics and Cosman Company, both of whom produce RF devices for tumor ablation. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: AVA EK YB SNG. Performed the experiments: AVA EK. Analyzed the data: AVA EK YB SNG. Contributed reagents/materials/analysis tools: AVA EK. Wrote the paper: AVA EK YB SNG.

                ¶ YB and SNG are joint senior authors on this work

                Article
                PONE-D-13-31894
                10.1371/journal.pone.0092555
                4006748
                24786533
                6c70cf91-1b62-4f88-8789-c17df584de52
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 31 July 2013
                : 25 February 2014
                Page count
                Pages: 12
                Funding
                This work was supported by NCI grant 5U54CA151881-04 to SNG, the Barenholz Fund, the Israel Ministry of Health, and the Israel Science Foundation. The Barenholz Fund is originated from royalties Hebrew University received from YB’s commercialized projects, and this money is used to support YB’s research activities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Trials
                Oncology
                Cancer Treatment
                Radiation Therapy
                Basic Cancer Research
                Oncology Agents
                Pharmacology
                Drug Research and Development
                Pharmacodynamics
                Pharmacokinetics
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Mouse Models
                Research Design
                Clinical Research Design

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