Pol-Edern LE RENARD | Chester Beatty Library, Dublin (original) (raw)
Papers by Pol-Edern LE RENARD
Pol-Edern Le Renard. Injectable formulations forming an implant in situ as vehicle of silica micr... more Pol-Edern Le Renard. Injectable formulations forming an implant in situ as vehicle of silica microparticles embedding superparamagnetic iron oxide nanoparticles for the local, magnetically mediated hyperthermia treatment of solid tumors. Galenic pharmacology.
Geburtshilfe Und Frauenheilkunde, Apr 23, 2018
2018 EMF-Med 1st World Conference on Biomedical Applications of Electromagnetic Fields (EMF-Med), 2018
In the present work, we investigate the influence of concomitant exposure to a clinical magnetic ... more In the present work, we investigate the influence of concomitant exposure to a clinical magnetic resonance imaging (MRI) electromagnetic environment together with cisplatin (CDDP) on the in-vitro chemosensitivity of cell lines from the ovarian cancer panel (SW626, PA-1, Caov3, SK-OV-3). CDDP treatment concentration was close to half of the maximal inhibitory concentration (IC50). We used a MRI-compatible incubation set-up for applying electromagnetic exposures consisting in three different imaging sequences generated by a 3-T clinical instrument: a T2-weighted 2D turbo-spin echo (TSE), a 3D TSE, and, a gradient-recalled echo (GRE). We assessed cell viability at 68-h after the joint chemical and electromagnetic treatment. Overall, our results do not show significant impact of simultaneous MRI and CDDP exposure on the in-vitro activity in various ovarian cancer cell lines, suggesting that it is pharmacologically safe. Overall, the implemented set-up revealed high performances.
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit:
Local moderate magnetically induced hyperthermia using an implant formed in situ in a mouse tumor... more Local moderate magnetically induced hyperthermia using an implant formed in situ in a mouse tumor model LE RENARD, Pol-Edern, et al. Purpose: We investigate a new heat delivery technique for the local treatment of solid tumors. The technique involves injecting a formulation that solidifies to form an implant in situ. This implant entraps superparamagnetic iron oxide nanoparticles (SPIONs) embedded in silica microbeads for magnetically induced moderate hyperthermia. Particle entrapment prevents phagocytosis and distant migration of SPIONs. The implant can be repeatedly heated by magnetic induction. Methods: We evaluated heating and treatment efficacies by means of thermometry and survival studies in nude mice carrying subcutaneous human colocarcinomas. At day 1, we injected the formulation into the tumor. At day 2, a single 20-min hyperthermia treatment was delivered by 141-kHz magnetic induction using field strengths of 9 to 12 mT under thermometry. Results: SPIONs embedded in silic...
ABSTRACT In this chapter we review both preformulation and formulation efforts relevant to magnet... more ABSTRACT In this chapter we review both preformulation and formulation efforts relevant to magnetically-induced hyperthermia as a new and attractive modality for the treatment of cancer lesions eligible for a thermotherapy. Also addressed are the efforts to apply this method to de novo indications in specific clinical situations. Following a pharmaceutical approach, we first introduce the general biological rationale for the use of hyperthermia, considering the techniques available to generate hyperthermia. We then detail several different magnetically-induced heating modalities and review the literature on formulations in an attempt to compare their specificities, advantages and shortcomings. First, we consider the formulation of glass ceramics and cement biomaterials for magnetically mediated hyperthermia with respect to the biological specificities in the treatment of solid bone tumors. Secondly, formulations intended for magnetically mediated hyperthermia are considered for soft tissue solid tumors, emphasizing the potential for pharmacological modulation. In the final section, we consider magnetic liposome formulations that can be equally administrated in various types of tumors. We do not detail magnetic fluid hyperthermia that uses suspensions of magnetic nanoparticles stabilized by various coatings. Biological and immunological considerations revealed by liposomes are outlined. This chapter focuses on the importance of the formulation and on the highly complex interactions between formulation and hyperthermia that should be considered with respect to various medical applications.
International Journal of Molecular Sciences, 2021
Over-expression of fluorescently-labeled markers for extracellular vesicles is frequently used to... more Over-expression of fluorescently-labeled markers for extracellular vesicles is frequently used to visualize vesicle up-take and transport. EVs that are labeled by over-expression show considerable heterogeneity regarding the number of fluorophores on single particles, which could potentially bias tracking and up-take studies in favor of more strongly-labeled particles. To avoid the potential artefacts that are caused by over-expression, we developed a genome editing approach for the fluorescent labeling of the extracellular vesicle marker CD63 with green fluorescent protein using the CRISPR/Cas9 technology. Using single-molecule sensitive fluorescence microscopy, we quantitatively compared the degree of labeling of secreted small extracellular vesicles from conventional over-expression and the CRISPR/Cas9 approach with true single-particle measurements. With our analysis, we can demonstrate a larger fraction of single-GFP-labeled EVs in the EVs that were isolated from CRISPR/Cas9-mo...
In this chapter we review both preformulation and formulation efforts relevant to magnetically-in... more In this chapter we review both preformulation and formulation efforts relevant to magnetically-induced hyperthermia as a new and attractive modality for the treatment of cancer lesions eligible for a thermotherapy. Also addressed are the efforts to apply this method to de novo indications in specific clinical situations. Following a pharmaceutical approach, we first introduce the general biological rationale for the use of hyperthermia, considering the techniques available to generate hyperthermia. We then detail several different magnetically-induced heating modalities and review the literature on formulations in an attempt to compare their specificities, advantages and shortcomings. First, we consider the formulation of glass ceramics and cement biomaterials for magnetically mediated hyperthermia with respect to the biological specificities in the treatment of solid bone tumors. Secondly, formulations intended for magnetically mediated hyperthermia are considered for soft tissue s...
Dans ce travail, nous passons en revue les efforts de formulation et de preformulation pharmaceut... more Dans ce travail, nous passons en revue les efforts de formulation et de preformulation pharmaceutiques pertinentes pour les nouvelles modalites d'hyperthermie magnetiquement induite dans le traitement des lesions cancereuses pour lesquelles une thermotherapie est indiquee, ou pour des indications de novo dans certaines situations cliniques. Nous introduirons d'abord les principes biologiques generaux sous-jacents a l'utilisation de l'hyperthermie, compte tenu des moyens techniques pour generer l'hyperthermie actuellement accessibles, nous detaillerons plus precisement differentes modalites magnetiques de chauffage. Nous presenterons alors une synthese des formulations decrites dans la litterature, en comparant leurs specificites, avantages et inconvenients. Premierement, nous considererons les biomateriaux bases sur les ceramiques, les verres et les ciments, pour hyperthermie a mediation magnetique dans le traitement des tumeurs solides de l'os, tenant compte...
ANZ Journal of Surgery
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Biomaterials, 2010
We investigated the use of in situ implant formation that incorporates superparamagnetic iron oxi... more We investigated the use of in situ implant formation that incorporates superparamagnetic iron oxide nanoparticles (SPIONs) as a form of minimally invasive treatment of cancer lesions by magnetically induced local hyperthermia. We developed injectable formulations that form gels entrapping magnetic particles into a tumor. We used SPIONs embedded in silica microparticles to favor syringeability and incorporated the highest proportion possible to allow large heating capacities. Hydrogel, single-solvent organogel and cosolvent (low-toxicity hydrophilic solvent) organogel formulations were injected into human cancer tumors xenografted in mice. The thermoreversible hydrogels (poloxamer, chitosan), which accommodated 20% w/v of the magnetic microparticles, proved to be inadequate. Alginate hydrogels, however, incorporated 10% w/v of the magnetic microparticles, and the external gelation led to strong implants localizing to the tumor periphery, whereas internal gelation failed in situ. The organogel formulations, which consisted of precipitating polymers dissolved in single organic solvents, displayed various microstructures. A 8% poly(ethylene-vinyl alcohol) in DMSO containing 40% w/v of magnetic microparticles formed the most suitable implants in terms of tumor casting and heat delivery. Importantly, it is of great clinical interest to develop cosolvent formulations with up to 20% w/v of magnetic microparticles that show reduced toxicity and centered tumor implantation.
Biomaterials, 2010
We investigated the use of in situ implant formation that incorporates superparamagnetic iron oxi... more We investigated the use of in situ implant formation that incorporates superparamagnetic iron oxide nanoparticles (SPIONs) as a form of minimally invasive treatment of cancer lesions by magnetically induced local hyperthermia. We developed injectable formulations that form gels entrapping magnetic particles into a tumor. We used SPIONs embedded in silica microparticles to favor syringeability and incorporated the highest proportion possible to allow large heating capacities. Hydrogel, single-solvent organogel and cosolvent (low-toxicity hydrophilic solvent) organogel formulations were injected into human cancer tumors xenografted in mice. The thermoreversible hydrogels (poloxamer, chitosan), which accommodated 20% w/v of the magnetic microparticles, proved to be inadequate. Alginate hydrogels, however, incorporated 10% w/v of the magnetic microparticles, and the external gelation led to strong implants localizing to the tumor periphery, whereas internal gelation failed in situ. The organogel formulations, which consisted of precipitating polymers dissolved in single organic solvents, displayed various microstructures. A 8% poly(ethylene-vinyl alcohol) in DMSO containing 40% w/v of magnetic microparticles formed the most suitable implants in terms of tumor casting and heat delivery. Importantly, it is of great clinical interest to develop cosolvent formulations with up to 20% w/v of magnetic microparticles that show reduced toxicity and centered tumor implantation.
ABSTRACT Purpose: We investigate a new heat delivery technique for the local treatment of solid t... more ABSTRACT Purpose: We investigate a new heat delivery technique for the local treatment of solid tumors. The technique involves injecting a formulation that solidifies to form an implant in situ. This implant entraps superparamagnetic iron oxide nanoparticles (SPIONs) embedded in silica microbeads for magnetically induced moderate hyperthermia. Particle entrapment prevents phagocytosis and distant migration of SPIONs. The implant can be repeatedly heated by magnetic induction. Methods: We evaluated heating and treatment efficacies by means of thermometry and survival studies in nude mice carrying subcutaneous human colocarcinomas. At day 1, we injected the formulation into the tumor. At day 2, a single 20-min hyperthermia treatment was delivered by 141-kHz magnetic induction using field strengths of 9 to 12 mT under thermometry. Results: SPIONs embedded in silica microbeads were effectively confined within the implant at the injection site. Heat-induced necro-apoptosis was assessed by histology on day 3. On average, 12 mT resulted in tumor temperature of 47.8o C, and over 70% tumor necrosis that correlated to the heat dose (AUC ¼ 282o C•min). In contrast, a 9-mT field strength induced tumoral temperature of 40o C (AUC ¼ 131o C•min) without morphologically identifiable necrosis. Survival after treatment with 10.5 or 12 mT fields was significantly improved compared to non-implanted and implanted controls. Median survival times were 27 and 37 days versus 12 and 21 days respectively. Conclusion: Five of eleven mice (45%) of the 12 mT group survived one year without any tumor recurrence, holding promise for tumor therapy using magnetically induced moderate hyperthermia through injectable implants. https://drive.google.com/file/d/0BwRd6ZCsN5WWRjRUMWtRVTJ0ZVU/edit?usp=sharing
Intensive Care Medicine, 2005
To analyze the pattern of cell-surface expression of the triggering receptor expressed on myeloid... more To analyze the pattern of cell-surface expression of the triggering receptor expressed on myeloid cells (TREM) 1 during septic shock. Prospective clinical study in an adult 16-bed medical ICU. 25 septic shock patients, 15 patients with shock of noninfectious origin and 7 healthy volunteers. Arterial blood was drawn within 12 h of admission and subjected to flow cytometry analysis after staining with anti-TREM-1 and anti-CD14 antibodies. Repeated sampling was performed on days 2, 3, 5, 7, and 14 in septic shock patients. Monocytic TREM-1 expression was significantly higher in septic shock patients (mean fluorescence intensity 2.3+/-0.2) than in nonseptic patients (1.0+/-0.1), and healthy volunteers (1.0+/-0.1). There was no difference in monocytic TREM-1 expression between nonseptic patients and healthy volunteers or between any of the three groups with respect to TREM-1 expression on neutrophils. The time course of TREM-1 expression on monocytes diverged significantly by day 3 between survivors and ns. The specificity of TREM-1 regulation by infection is highlighted. Moreover, surface TREM-1 expression on monocytes may prove useful in allowing the follow-up of septic patients during the course of the disease.
Critical Care Medicine, 2005
To examine the expression patterns of the triggering receptor expressed on myeloid cells (TREM)-1... more To examine the expression patterns of the triggering receptor expressed on myeloid cells (TREM)-1 during experimental septic shock. Animal study. Animal research laboratory. Male BALB/c mice, 7-9 wks of age. Septic shock was induced by cecal ligation and puncture in eight mice. Eight additional animals were sham-operated and served as a control group. All animals were resuscitated by fluid infusion and administered antibiotics. Kill was performed under anesthesia 12, 24, or 48 hrs later. Surface expression of TREM-1 was analyzed using flow cytometry on peripheral blood cells, peritoneal macrophages and neutrophils, splenic macrophages, and Kupffer cells. Gene expression was also studied in these same cells using reverse transcription-polymerase chain reaction. Tumor necrosis factor-alpha, interleukin-1beta, and soluble TREM-1 concentrations were determined in plasma and peritoneal lavage fluid. Sepsis strongly induced TREM-1 gene expression, which translated into an up-regulation of TREM-1 surface expression on neutrophils and monocytes/macrophages both at the focus on infection as well as distally. Moreover, sepsis induced the release of significant levels of soluble TREM-1. Plasma soluble TREM-1 concentrations negatively correlated with tumor necrosis factor-alpha and interleukin-1beta levels at 12 hrs. These results provide new information as to the regulation of TREM-1 during sepsis. Considering that both cell-surface and soluble TREM-1 were strongly up-regulated during infection, this study may add support to the putative usefulness of TREM-1 as a diagnostic tool.
Cette thèse présente les travaux de développement de formulations injectables capables de se soli... more Cette thèse présente les travaux de développement de formulations injectables capables de se solidifier in situ, formant ainsi un implant piégeant des microparticules magnétiques en vue du traitement de tumeurs par induction magnétique d'une hyperthermie locale modérée. Nous exposons tout d'abord le contexte physique, biologique et clinique de l'hyperthermie comme traitement anticancéreux, particulièrement des modalités électromagnétiques. Les performances in vitro et in vivo des matériaux et formulations ...
In this chapter we review both preformulation and formulation efforts relevant to magnetically-in... more In this chapter we review both preformulation and formulation efforts relevant to magnetically-induced hyperthermia as a new and attractive modality for the treatment of cancer lesions eligible for a thermotherapy. Also addressed are the efforts to apply this method to de novo indications in specific clinical situations. Following a pharmaceutical approach, we first introduce the general biological rationale for the use of hyperthermia, considering the techniques available to generate hyperthermia. We then detail several different magnetically-induced heating modalities and review the literature on formulations in an attempt to compare their specificities, advantages and shortcomings. First, we consider the formulation of glass ceramics and cement biomaterials for magnetically mediated hyperthermia with respect to the biological specificities in the treatment of solid bone tumors. Secondly, formulations intended for magnetically mediated hyperthermia are considered for soft tissue solid tumors, emphasizing the potential for pharmacological modulation. In the final section, we consider magnetic liposome formulations that can be equally administrated in various types of tumors. We do not detail magnetic fluid hyperthermia that uses suspensions of magnetic nanoparticles stabilized by various coatings. Biological and immunological considerations revealed by liposomes are outlined. This chapter focuses on the importance of the formulation and on
Pol-Edern Le Renard. Injectable formulations forming an implant in situ as vehicle of silica micr... more Pol-Edern Le Renard. Injectable formulations forming an implant in situ as vehicle of silica microparticles embedding superparamagnetic iron oxide nanoparticles for the local, magnetically mediated hyperthermia treatment of solid tumors. Galenic pharmacology.
Geburtshilfe Und Frauenheilkunde, Apr 23, 2018
2018 EMF-Med 1st World Conference on Biomedical Applications of Electromagnetic Fields (EMF-Med), 2018
In the present work, we investigate the influence of concomitant exposure to a clinical magnetic ... more In the present work, we investigate the influence of concomitant exposure to a clinical magnetic resonance imaging (MRI) electromagnetic environment together with cisplatin (CDDP) on the in-vitro chemosensitivity of cell lines from the ovarian cancer panel (SW626, PA-1, Caov3, SK-OV-3). CDDP treatment concentration was close to half of the maximal inhibitory concentration (IC50). We used a MRI-compatible incubation set-up for applying electromagnetic exposures consisting in three different imaging sequences generated by a 3-T clinical instrument: a T2-weighted 2D turbo-spin echo (TSE), a 3D TSE, and, a gradient-recalled echo (GRE). We assessed cell viability at 68-h after the joint chemical and electromagnetic treatment. Overall, our results do not show significant impact of simultaneous MRI and CDDP exposure on the in-vitro activity in various ovarian cancer cell lines, suggesting that it is pharmacologically safe. Overall, the implemented set-up revealed high performances.
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit:
Local moderate magnetically induced hyperthermia using an implant formed in situ in a mouse tumor... more Local moderate magnetically induced hyperthermia using an implant formed in situ in a mouse tumor model LE RENARD, Pol-Edern, et al. Purpose: We investigate a new heat delivery technique for the local treatment of solid tumors. The technique involves injecting a formulation that solidifies to form an implant in situ. This implant entraps superparamagnetic iron oxide nanoparticles (SPIONs) embedded in silica microbeads for magnetically induced moderate hyperthermia. Particle entrapment prevents phagocytosis and distant migration of SPIONs. The implant can be repeatedly heated by magnetic induction. Methods: We evaluated heating and treatment efficacies by means of thermometry and survival studies in nude mice carrying subcutaneous human colocarcinomas. At day 1, we injected the formulation into the tumor. At day 2, a single 20-min hyperthermia treatment was delivered by 141-kHz magnetic induction using field strengths of 9 to 12 mT under thermometry. Results: SPIONs embedded in silic...
ABSTRACT In this chapter we review both preformulation and formulation efforts relevant to magnet... more ABSTRACT In this chapter we review both preformulation and formulation efforts relevant to magnetically-induced hyperthermia as a new and attractive modality for the treatment of cancer lesions eligible for a thermotherapy. Also addressed are the efforts to apply this method to de novo indications in specific clinical situations. Following a pharmaceutical approach, we first introduce the general biological rationale for the use of hyperthermia, considering the techniques available to generate hyperthermia. We then detail several different magnetically-induced heating modalities and review the literature on formulations in an attempt to compare their specificities, advantages and shortcomings. First, we consider the formulation of glass ceramics and cement biomaterials for magnetically mediated hyperthermia with respect to the biological specificities in the treatment of solid bone tumors. Secondly, formulations intended for magnetically mediated hyperthermia are considered for soft tissue solid tumors, emphasizing the potential for pharmacological modulation. In the final section, we consider magnetic liposome formulations that can be equally administrated in various types of tumors. We do not detail magnetic fluid hyperthermia that uses suspensions of magnetic nanoparticles stabilized by various coatings. Biological and immunological considerations revealed by liposomes are outlined. This chapter focuses on the importance of the formulation and on the highly complex interactions between formulation and hyperthermia that should be considered with respect to various medical applications.
International Journal of Molecular Sciences, 2021
Over-expression of fluorescently-labeled markers for extracellular vesicles is frequently used to... more Over-expression of fluorescently-labeled markers for extracellular vesicles is frequently used to visualize vesicle up-take and transport. EVs that are labeled by over-expression show considerable heterogeneity regarding the number of fluorophores on single particles, which could potentially bias tracking and up-take studies in favor of more strongly-labeled particles. To avoid the potential artefacts that are caused by over-expression, we developed a genome editing approach for the fluorescent labeling of the extracellular vesicle marker CD63 with green fluorescent protein using the CRISPR/Cas9 technology. Using single-molecule sensitive fluorescence microscopy, we quantitatively compared the degree of labeling of secreted small extracellular vesicles from conventional over-expression and the CRISPR/Cas9 approach with true single-particle measurements. With our analysis, we can demonstrate a larger fraction of single-GFP-labeled EVs in the EVs that were isolated from CRISPR/Cas9-mo...
In this chapter we review both preformulation and formulation efforts relevant to magnetically-in... more In this chapter we review both preformulation and formulation efforts relevant to magnetically-induced hyperthermia as a new and attractive modality for the treatment of cancer lesions eligible for a thermotherapy. Also addressed are the efforts to apply this method to de novo indications in specific clinical situations. Following a pharmaceutical approach, we first introduce the general biological rationale for the use of hyperthermia, considering the techniques available to generate hyperthermia. We then detail several different magnetically-induced heating modalities and review the literature on formulations in an attempt to compare their specificities, advantages and shortcomings. First, we consider the formulation of glass ceramics and cement biomaterials for magnetically mediated hyperthermia with respect to the biological specificities in the treatment of solid bone tumors. Secondly, formulations intended for magnetically mediated hyperthermia are considered for soft tissue s...
Dans ce travail, nous passons en revue les efforts de formulation et de preformulation pharmaceut... more Dans ce travail, nous passons en revue les efforts de formulation et de preformulation pharmaceutiques pertinentes pour les nouvelles modalites d'hyperthermie magnetiquement induite dans le traitement des lesions cancereuses pour lesquelles une thermotherapie est indiquee, ou pour des indications de novo dans certaines situations cliniques. Nous introduirons d'abord les principes biologiques generaux sous-jacents a l'utilisation de l'hyperthermie, compte tenu des moyens techniques pour generer l'hyperthermie actuellement accessibles, nous detaillerons plus precisement differentes modalites magnetiques de chauffage. Nous presenterons alors une synthese des formulations decrites dans la litterature, en comparant leurs specificites, avantages et inconvenients. Premierement, nous considererons les biomateriaux bases sur les ceramiques, les verres et les ciments, pour hyperthermie a mediation magnetique dans le traitement des tumeurs solides de l'os, tenant compte...
ANZ Journal of Surgery
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Biomaterials, 2010
We investigated the use of in situ implant formation that incorporates superparamagnetic iron oxi... more We investigated the use of in situ implant formation that incorporates superparamagnetic iron oxide nanoparticles (SPIONs) as a form of minimally invasive treatment of cancer lesions by magnetically induced local hyperthermia. We developed injectable formulations that form gels entrapping magnetic particles into a tumor. We used SPIONs embedded in silica microparticles to favor syringeability and incorporated the highest proportion possible to allow large heating capacities. Hydrogel, single-solvent organogel and cosolvent (low-toxicity hydrophilic solvent) organogel formulations were injected into human cancer tumors xenografted in mice. The thermoreversible hydrogels (poloxamer, chitosan), which accommodated 20% w/v of the magnetic microparticles, proved to be inadequate. Alginate hydrogels, however, incorporated 10% w/v of the magnetic microparticles, and the external gelation led to strong implants localizing to the tumor periphery, whereas internal gelation failed in situ. The organogel formulations, which consisted of precipitating polymers dissolved in single organic solvents, displayed various microstructures. A 8% poly(ethylene-vinyl alcohol) in DMSO containing 40% w/v of magnetic microparticles formed the most suitable implants in terms of tumor casting and heat delivery. Importantly, it is of great clinical interest to develop cosolvent formulations with up to 20% w/v of magnetic microparticles that show reduced toxicity and centered tumor implantation.
Biomaterials, 2010
We investigated the use of in situ implant formation that incorporates superparamagnetic iron oxi... more We investigated the use of in situ implant formation that incorporates superparamagnetic iron oxide nanoparticles (SPIONs) as a form of minimally invasive treatment of cancer lesions by magnetically induced local hyperthermia. We developed injectable formulations that form gels entrapping magnetic particles into a tumor. We used SPIONs embedded in silica microparticles to favor syringeability and incorporated the highest proportion possible to allow large heating capacities. Hydrogel, single-solvent organogel and cosolvent (low-toxicity hydrophilic solvent) organogel formulations were injected into human cancer tumors xenografted in mice. The thermoreversible hydrogels (poloxamer, chitosan), which accommodated 20% w/v of the magnetic microparticles, proved to be inadequate. Alginate hydrogels, however, incorporated 10% w/v of the magnetic microparticles, and the external gelation led to strong implants localizing to the tumor periphery, whereas internal gelation failed in situ. The organogel formulations, which consisted of precipitating polymers dissolved in single organic solvents, displayed various microstructures. A 8% poly(ethylene-vinyl alcohol) in DMSO containing 40% w/v of magnetic microparticles formed the most suitable implants in terms of tumor casting and heat delivery. Importantly, it is of great clinical interest to develop cosolvent formulations with up to 20% w/v of magnetic microparticles that show reduced toxicity and centered tumor implantation.
ABSTRACT Purpose: We investigate a new heat delivery technique for the local treatment of solid t... more ABSTRACT Purpose: We investigate a new heat delivery technique for the local treatment of solid tumors. The technique involves injecting a formulation that solidifies to form an implant in situ. This implant entraps superparamagnetic iron oxide nanoparticles (SPIONs) embedded in silica microbeads for magnetically induced moderate hyperthermia. Particle entrapment prevents phagocytosis and distant migration of SPIONs. The implant can be repeatedly heated by magnetic induction. Methods: We evaluated heating and treatment efficacies by means of thermometry and survival studies in nude mice carrying subcutaneous human colocarcinomas. At day 1, we injected the formulation into the tumor. At day 2, a single 20-min hyperthermia treatment was delivered by 141-kHz magnetic induction using field strengths of 9 to 12 mT under thermometry. Results: SPIONs embedded in silica microbeads were effectively confined within the implant at the injection site. Heat-induced necro-apoptosis was assessed by histology on day 3. On average, 12 mT resulted in tumor temperature of 47.8o C, and over 70% tumor necrosis that correlated to the heat dose (AUC ¼ 282o C•min). In contrast, a 9-mT field strength induced tumoral temperature of 40o C (AUC ¼ 131o C•min) without morphologically identifiable necrosis. Survival after treatment with 10.5 or 12 mT fields was significantly improved compared to non-implanted and implanted controls. Median survival times were 27 and 37 days versus 12 and 21 days respectively. Conclusion: Five of eleven mice (45%) of the 12 mT group survived one year without any tumor recurrence, holding promise for tumor therapy using magnetically induced moderate hyperthermia through injectable implants. https://drive.google.com/file/d/0BwRd6ZCsN5WWRjRUMWtRVTJ0ZVU/edit?usp=sharing
Intensive Care Medicine, 2005
To analyze the pattern of cell-surface expression of the triggering receptor expressed on myeloid... more To analyze the pattern of cell-surface expression of the triggering receptor expressed on myeloid cells (TREM) 1 during septic shock. Prospective clinical study in an adult 16-bed medical ICU. 25 septic shock patients, 15 patients with shock of noninfectious origin and 7 healthy volunteers. Arterial blood was drawn within 12 h of admission and subjected to flow cytometry analysis after staining with anti-TREM-1 and anti-CD14 antibodies. Repeated sampling was performed on days 2, 3, 5, 7, and 14 in septic shock patients. Monocytic TREM-1 expression was significantly higher in septic shock patients (mean fluorescence intensity 2.3+/-0.2) than in nonseptic patients (1.0+/-0.1), and healthy volunteers (1.0+/-0.1). There was no difference in monocytic TREM-1 expression between nonseptic patients and healthy volunteers or between any of the three groups with respect to TREM-1 expression on neutrophils. The time course of TREM-1 expression on monocytes diverged significantly by day 3 between survivors and ns. The specificity of TREM-1 regulation by infection is highlighted. Moreover, surface TREM-1 expression on monocytes may prove useful in allowing the follow-up of septic patients during the course of the disease.
Critical Care Medicine, 2005
To examine the expression patterns of the triggering receptor expressed on myeloid cells (TREM)-1... more To examine the expression patterns of the triggering receptor expressed on myeloid cells (TREM)-1 during experimental septic shock. Animal study. Animal research laboratory. Male BALB/c mice, 7-9 wks of age. Septic shock was induced by cecal ligation and puncture in eight mice. Eight additional animals were sham-operated and served as a control group. All animals were resuscitated by fluid infusion and administered antibiotics. Kill was performed under anesthesia 12, 24, or 48 hrs later. Surface expression of TREM-1 was analyzed using flow cytometry on peripheral blood cells, peritoneal macrophages and neutrophils, splenic macrophages, and Kupffer cells. Gene expression was also studied in these same cells using reverse transcription-polymerase chain reaction. Tumor necrosis factor-alpha, interleukin-1beta, and soluble TREM-1 concentrations were determined in plasma and peritoneal lavage fluid. Sepsis strongly induced TREM-1 gene expression, which translated into an up-regulation of TREM-1 surface expression on neutrophils and monocytes/macrophages both at the focus on infection as well as distally. Moreover, sepsis induced the release of significant levels of soluble TREM-1. Plasma soluble TREM-1 concentrations negatively correlated with tumor necrosis factor-alpha and interleukin-1beta levels at 12 hrs. These results provide new information as to the regulation of TREM-1 during sepsis. Considering that both cell-surface and soluble TREM-1 were strongly up-regulated during infection, this study may add support to the putative usefulness of TREM-1 as a diagnostic tool.
Cette thèse présente les travaux de développement de formulations injectables capables de se soli... more Cette thèse présente les travaux de développement de formulations injectables capables de se solidifier in situ, formant ainsi un implant piégeant des microparticules magnétiques en vue du traitement de tumeurs par induction magnétique d'une hyperthermie locale modérée. Nous exposons tout d'abord le contexte physique, biologique et clinique de l'hyperthermie comme traitement anticancéreux, particulièrement des modalités électromagnétiques. Les performances in vitro et in vivo des matériaux et formulations ...
In this chapter we review both preformulation and formulation efforts relevant to magnetically-in... more In this chapter we review both preformulation and formulation efforts relevant to magnetically-induced hyperthermia as a new and attractive modality for the treatment of cancer lesions eligible for a thermotherapy. Also addressed are the efforts to apply this method to de novo indications in specific clinical situations. Following a pharmaceutical approach, we first introduce the general biological rationale for the use of hyperthermia, considering the techniques available to generate hyperthermia. We then detail several different magnetically-induced heating modalities and review the literature on formulations in an attempt to compare their specificities, advantages and shortcomings. First, we consider the formulation of glass ceramics and cement biomaterials for magnetically mediated hyperthermia with respect to the biological specificities in the treatment of solid bone tumors. Secondly, formulations intended for magnetically mediated hyperthermia are considered for soft tissue solid tumors, emphasizing the potential for pharmacological modulation. In the final section, we consider magnetic liposome formulations that can be equally administrated in various types of tumors. We do not detail magnetic fluid hyperthermia that uses suspensions of magnetic nanoparticles stabilized by various coatings. Biological and immunological considerations revealed by liposomes are outlined. This chapter focuses on the importance of the formulation and on