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Article ; Online: Current perspectives for external control arms in oncology clinical trials: Analysis of EMA approvals 2016-2021.

Wang, Xiaomeng / Dormont, Flavio / Lorenzato, Christelle / Latouche, Aurélien / Hernandez, Ramon / Rouzier, Roman

Journal of cancer policy

2023 Volume 35, Page(s) 100403

Abstract: Leveraging external control data, especially real-world data (RWD), has drawn particular attention in recent years for facilitating oncology clinical development and regulatory decision-making. Medical regulators have published guidance on accelerating ... ...

Abstract	Leveraging external control data, especially real-world data (RWD), has drawn particular attention in recent years for facilitating oncology clinical development and regulatory decision-making. Medical regulators have published guidance on accelerating the use of RWD and external controls. However, few systematic discussions have been conducted on external controls in cancer drug submissions and regulatory feedback. This study aimed to identify European oncology drug approvals using external control data to demonstrate clinical efficacy. We included 18 eligible submissions employing 24 external controls and then discussed the use of external control, data sources, analysis methods, and regulators' feedback. The external controls have been actively submitted to the European Medical Agency (EMA) recently. We found that 17 % of the EMA-approved cancer drugs in 2016-2021 used external controls, among which 37 % of the cases leveraged RWD. However, nearly one-third of the external controls were not considered supportive evidence by EMA due to limitations regarding heterogeneous patient populations, missing outcome assessment in RWD, and inappropriate statistical analysis. This study highlighted that proper use of external controls requires a careful assessment of clinical settings, data availability, and statistical methodology. For better use of external controls in oncology clinical trials, we recommend: prospective study designs to avoid selection bias, sufficient baseline data to ensure the comparability of study populations, consistent endpoint measurements to enable outcome comparison, robust statistical methodology for comparative analysis, and collaborative efforts of sponsors and regulators to establish regulatory frameworks.
MeSH term(s)	Humans ; Prospective Studies ; Neoplasms/drug therapy ; Antineoplastic Agents/therapeutic use ; Medical Oncology ; Drug Approval/methods
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2023-01-14
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ISSN	2213-5383
ISSN (online)	2213-5383
DOI	10.1016/j.jcpo.2023.100403
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Assessment of Squalene-Adenosine Nanoparticles in Two Rodent Models of Cardiac Ischemia-Reperfusion.

Brusini, Romain / Tran, Natalie Lan Linh / Cailleau, Catherine / Domergue, Valérie / Nicolas, Valérie / Dormont, Flavio / Calet, Serge / Cajot, Caroline / Jouran, Albin / Lepetre-Mouelhi, Sinda / Laloy, Julie / Couvreur, Patrick / Varna, Mariana

Pharmaceutics

2023 Volume 15, Issue 7

Abstract: Reperfusion injuries after a period of cardiac ischemia are known to lead to pathological modifications or even death. Among the different therapeutic options proposed, adenosine, a small molecule with platelet anti-aggregate and anti-inflammatory ... ...

Abstract	Reperfusion injuries after a period of cardiac ischemia are known to lead to pathological modifications or even death. Among the different therapeutic options proposed, adenosine, a small molecule with platelet anti-aggregate and anti-inflammatory properties, has shown encouraging results in clinical trials. However, its clinical use is severely limited because of its very short half-life in the bloodstream. To overcome this limitation, we have proposed a strategy to encapsulate adenosine in squalene-based nanoparticles (NPs), a biocompatible and biodegradable lipid. Thus, the aim of this study was to assess, whether squalene-based nanoparticles loaded with adenosine (SQAd NPs) were cardioprotective in a preclinical cardiac ischemia/reperfusion model. Obtained SQAd NPs were characterized in depth and further evaluated in vitro. The NPs were formulated with a size of about 90 nm and remained stable up to 14 days at both 4 °C and room temperature. Moreover, these NPs did not show any signs of toxicity, neither on HL-1, H9c2 cardiac cell lines, nor on human PBMC and, further retained their inhibitory platelet aggregation properties. In a mouse model with experimental cardiac ischemia-reperfusion, treatment with SQAd NPs showed a reduction of the area at risk, as well as of the infarct area, although not statistically significant. However, we noted a significant reduction of apoptotic cells on cardiac tissue from animals treated with the NPs. Further studies would be interesting to understand how and through which mechanisms these nanoparticles act on cardiac cells.
Language	English
Publishing date	2023-06-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15071790
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Squalene-based nanoparticles for the targeting of atherosclerotic lesions.

Brusini, Romain / Dormont, Flavio / Cailleau, Catherine / Nicolas, Valerie / Peramo, Arnaud / Varna, Mariana / Couvreur, Patrick

International journal of pharmaceutics

2020 Volume 581, Page(s) 119282

Abstract: Native low-density lipoproteins (LDL) naturally accumulate at atherosclerotic lesions and are thought to be among the main drivers of atherosclerosis progression. Numerous nanoparticular systems making use of recombinant lipoproteins have been developed ... ...

Abstract	Native low-density lipoproteins (LDL) naturally accumulate at atherosclerotic lesions and are thought to be among the main drivers of atherosclerosis progression. Numerous nanoparticular systems making use of recombinant lipoproteins have been developed for targeting atherosclerotic plaque. These innovative formulations often require complicated purification and synthesis procedures which limit their eventual translation to the clinics. Recently, squalenoylation has appeared as a simple and efficient technique for targeting agents to endogenous lipoproteins through a bioconjugation approach. In this study, we have developed a fluorescent squalene bioconjugate to evaluate the biodistribution of squalene-based nanoparticles in an ApoE
MeSH term(s)	Animals ; Atherosclerosis/drug therapy ; Atherosclerosis/metabolism ; Atherosclerosis/pathology ; Drug Delivery Systems/methods ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nanoparticles/administration & dosage ; Nanoparticles/metabolism ; RAW 264.7 Cells ; Rhodamines/administration & dosage ; Rhodamines/metabolism ; Squalene/administration & dosage ; Squalene/metabolism
Chemical Substances	Rhodamines ; Squalene (7QWM220FJH) ; rhodamine B (K7G5SCF8IL)
Language	English
Publishing date	2020-04-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2020.119282
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Article ; Online: Squalene-based multidrug nanoparticles for improved mitigation of uncontrolled inflammation in rodents.

Dormont, Flavio / Brusini, Romain / Cailleau, Catherine / Reynaud, Franceline / Peramo, Arnaud / Gendron, Amandine / Mougin, Julie / Gaudin, Françoise / Varna, Mariana / Couvreur, Patrick

Science advances

2020 Volume 6, Issue 23, Page(s) eaaz5466

Abstract: Uncontrolled inflammatory processes are at the root of numerous pathologies. Most recently, studies on confirmed COVID-19 cases have suggested that mortality might be due to virally induced hyperinflammation. Uncontrolled pro-inflammatory states are ... ...

Abstract	Uncontrolled inflammatory processes are at the root of numerous pathologies. Most recently, studies on confirmed COVID-19 cases have suggested that mortality might be due to virally induced hyperinflammation. Uncontrolled pro-inflammatory states are often driven by continuous positive feedback loops between pro-inflammatory signaling and oxidative stress, which cannot be resolved in a targeted manner. Here, we report on the development of multidrug nanoparticles for the mitigation of uncontrolled inflammation. The nanoparticles are made by conjugating squalene, a natural lipid, to adenosine, an endogenous immunomodulator, and then encapsulating α-tocopherol, as antioxidant. This resulted in high drug loading, biocompatible, multidrug nanoparticles. By exploiting the endothelial dysfunction at sites of acute inflammation, these multidrug nanoparticles delivered the therapeutic agents in a targeted manner, conferring survival advantage to treated animals in models of endotoxemia. Selectively delivering adenosine and antioxidants together could serve as a novel therapeutic approach for safe treatment of acute paradoxal inflammation.
MeSH term(s)	Adenosine/administration & dosage ; Adenosine/chemistry ; Animals ; Antioxidants/administration & dosage ; Antioxidants/chemistry ; Betacoronavirus ; COVID-19 ; Coronavirus Infections/drug therapy ; Coronavirus Infections/pathology ; Coronavirus Infections/virology ; Disease Models, Animal ; Drug Delivery Systems/methods ; Endotoxemia/chemically induced ; Endotoxemia/drug therapy ; Female ; Immunologic Factors/administration & dosage ; Immunologic Factors/chemistry ; Lipopolysaccharides/pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Nanoparticles/administration & dosage ; Nanoparticles/chemistry ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/pathology ; Pneumonia, Viral/virology ; SARS-CoV-2 ; Squalene/administration & dosage ; Squalene/chemistry ; Systemic Inflammatory Response Syndrome/chemically induced ; Systemic Inflammatory Response Syndrome/drug therapy ; Treatment Outcome ; alpha-Tocopherol/administration & dosage ; alpha-Tocopherol/chemistry
Chemical Substances	Antioxidants ; Immunologic Factors ; Lipopolysaccharides ; Squalene (7QWM220FJH) ; alpha-Tocopherol (H4N855PNZ1) ; Adenosine (K72T3FS567)
Keywords	covid19
Language	English
Publishing date	2020-06-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.aaz5466
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Translation of nanomedicines from lab to industrial scale synthesis: The case of squalene-adenosine nanoparticles

Dormont, Flavio / Rouquette, Marie / Mahatsekake, Clement / Gobeaux, Frédéric / Peramo, Arnaud / Brusini, Romain / Calet, Serge / Testard, Fabienne / Lepetre-Mouelhi, Sinda / Desmaële, Didier / Varna, Mariana / Couvreur, Patrick

Journal of controlled release. 2019 Aug. 10, v. 307

2019

Abstract: A large variety of nanoparticle-based delivery systems have become increasingly important for diagnostic and/or therapeutic applications. Yet, the numerous physical and chemical parameters that influence both the biological and colloidal properties of ... ...

Abstract	A large variety of nanoparticle-based delivery systems have become increasingly important for diagnostic and/or therapeutic applications. Yet, the numerous physical and chemical parameters that influence both the biological and colloidal properties of nanoparticles remain poorly understood. This complicates the ability to reliably produce and deliver well-defined nanocarriers which often leads to inconsistencies, conflicts in the published literature and, ultimately, poor translation to the clinics. A critical issue lies in the challenge of scaling-up nanomaterial synthesis and formulation from the lab to industrial scale while maintaining control over their diverse properties. Studying these phenomena early on in the development of a therapeutic agent often requires partnerships between the public and private sectors which are hard to establish.In this study, through the particular case of squalene-adenosine nanoparticles, we reported on the challenges encountered in the process of scaling-up nanomedicines synthesis. Here, squalene (the carrier) was functionalized and conjugated to adenosine (the active drug moiety) at an industrial scale in order to obtain large quantities of biocompatible and biodegradable nanoparticles. After assessing nanoparticle batch-to-batch consistency, we demonstrated that the presence of squalene analogs resulting from industrial scale-up may influence several features such as size, surface charge, protein adsorption, cytotoxicity and crystal structure. These analogs were isolated, characterized by multiple stage mass spectrometry, and their influence on nanoparticle properties further evaluated. We showed that slight variations in the chemical profile of the nanocarrier's constitutive material can have a tremendous impact on the reproducibility of nanoparticle properties. In a context where several generics of approved nanoformulated drugs are set to enter the market in the coming years, characterizing and solving these issues is an important step in the pharmaceutical development of nanomedicines.
Keywords	adenosine ; adsorption ; biodegradability ; colloidal properties ; crystal structure ; cytotoxicity ; drug development ; generic drugs ; markets ; mass spectrometry ; moieties ; nanocarriers ; nanomedicine ; nanoparticles ; squalene
Language	English
Dates of publication	2019-0810
Size	p. 302-314.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2019.06.040
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 2055: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article: Squalene-based multidrug nanoparticles for improved mitigation of uncontrolled inflammation in rodents

Dormont, Flavio / Brusini, Romain / Cailleau, Catherine / Reynaud, Franceline / Peramo, Arnaud / Gendron, Amandine / Mougin, Julie / Gaudin, Françoise / Varna, Mariana / Couvreur, Patrick

Sci Adv

Abstract	Uncontrolled inflammatory processes are at the root of numerous pathologies. Most recently, studies on confirmed COVID-19 cases have suggested that mortality might be due to virally induced hyperinflammation. Uncontrolled pro-inflammatory states are often driven by continuous positive feedback loops between pro-inflammatory signaling and oxidative stress, which cannot be resolved in a targeted manner. Here, we report on the development of multidrug nanoparticles for the mitigation of uncontrolled inflammation. The nanoparticles are made by conjugating squalene, a natural lipid, to adenosine, an endogenous immunomodulator, and then encapsulating α-tocopherol, as antioxidant. This resulted in high drug loading, biocompatible, multidrug nanoparticles. By exploiting the endothelial dysfunction at sites of acute inflammation, these multidrug nanoparticles delivered the therapeutic agents in a targeted manner, conferring survival advantage to treated animals in models of endotoxemia. Selectively delivering adenosine and antioxidants together could serve as a novel therapeutic approach for safe treatment of acute paradoxal inflammation.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #602279
Database	COVID19

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Article ; Online: Squalene-based multidrug nanoparticles for improved mitigation of uncontrolled inflammation in rodents

Dormont, Flavio / Brusini, Romain / Cailleau, Catherine / Reynaud, Franceline / Peramo, Arnaud / Gendron, Amandine / Mougin, Julie / Gaudin, Françoise / Varna, Mariana / Couvreur, Patrick

Science Advances

2020 Volume 6, Issue 23, Page(s) eaaz5466

Abstract	Uncontrolled inflammatory processes are at the root of numerous pathologies. Most recently, studies on confirmed COVID-19 cases have suggested that mortality might be due to virally induced hyperinflammation. Uncontrolled pro-inflammatory states are often driven by continuous positive feedback loops between pro-inflammatory signaling and oxidative stress, which cannot be resolved in a targeted manner. Here, we report on the development of multidrug nanoparticles for the mitigation of uncontrolled inflammation. The nanoparticles are made by conjugating squalene, a natural lipid, to adenosine, an endogenous immunomodulator, and then encapsulating α-tocopherol, as antioxidant. This resulted in high drug loading, biocompatible, multidrug nanoparticles. By exploiting the endothelial dysfunction at sites of acute inflammation, these multidrug nanoparticles delivered the therapeutic agents in a targeted manner, conferring survival advantage to treated animals in models of endotoxemia. Selectively delivering adenosine and antioxidants together could serve as a novel therapeutic approach for safe treatment of acute paradoxal inflammation.
Keywords	covid19
Language	English
Publisher	American Association for the Advancement of Science (AAAS)
Publishing country	us
Document type	Article ; Online
ZDB-ID	2810933-8
ISSN	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.aaz5466
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Translation of nanomedicines from lab to industrial scale synthesis: The case of squalene-adenosine nanoparticles.

Journal of controlled release : official journal of the Controlled Release Society

2019 Volume 307, Page(s) 302–314

Abstract	A large variety of nanoparticle-based delivery systems have become increasingly important for diagnostic and/or therapeutic applications. Yet, the numerous physical and chemical parameters that influence both the biological and colloidal properties of nanoparticles remain poorly understood. This complicates the ability to reliably produce and deliver well-defined nanocarriers which often leads to inconsistencies, conflicts in the published literature and, ultimately, poor translation to the clinics. A critical issue lies in the challenge of scaling-up nanomaterial synthesis and formulation from the lab to industrial scale while maintaining control over their diverse properties. Studying these phenomena early on in the development of a therapeutic agent often requires partnerships between the public and private sectors which are hard to establish. In this study, through the particular case of squalene-adenosine nanoparticles, we reported on the challenges encountered in the process of scaling-up nanomedicines synthesis. Here, squalene (the carrier) was functionalized and conjugated to adenosine (the active drug moiety) at an industrial scale in order to obtain large quantities of biocompatible and biodegradable nanoparticles. After assessing nanoparticle batch-to-batch consistency, we demonstrated that the presence of squalene analogs resulting from industrial scale-up may influence several features such as size, surface charge, protein adsorption, cytotoxicity and crystal structure. These analogs were isolated, characterized by multiple stage mass spectrometry, and their influence on nanoparticle properties further evaluated. We showed that slight variations in the chemical profile of the nanocarrier's constitutive material can have a tremendous impact on the reproducibility of nanoparticle properties. In a context where several generics of approved nanoformulated drugs are set to enter the market in the coming years, characterizing and solving these issues is an important step in the pharmaceutical development of nanomedicines.
MeSH term(s)	Adenosine/administration & dosage ; Adenosine/chemistry ; Adsorption ; Animals ; Blood Proteins/chemistry ; Cell Line ; Cell Survival/drug effects ; Male ; Mice ; Nanomedicine ; Nanoparticles/administration & dosage ; Nanoparticles/chemistry ; Rats, Sprague-Dawley ; Squalene/administration & dosage ; Squalene/chemistry
Chemical Substances	Blood Proteins ; Squalene (7QWM220FJH) ; Adenosine (K72T3FS567)
Language	English
Publishing date	2019-06-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2019.06.040
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics.

Bertrand, Nicolas / Grenier, Philippe / Mahmoudi, Morteza / Lima, Eliana M / Appel, Eric A / Dormont, Flavio / Lim, Jong-Min / Karnik, Rohit / Langer, Robert / Farokhzad, Omid C

Nature communications

2017 Volume 8, Issue 1, Page(s) 777

Abstract: In vitro incubation of nanomaterials with plasma offer insights on biological interactions, but cannot fully explain the in vivo fate of nanomaterials. Here, we use a library of polymer nanoparticles to show how physicochemical characteristics influence ... ...

Abstract	In vitro incubation of nanomaterials with plasma offer insights on biological interactions, but cannot fully explain the in vivo fate of nanomaterials. Here, we use a library of polymer nanoparticles to show how physicochemical characteristics influence blood circulation and early distribution. For particles with different diameters, surface hydrophilicity appears to mediate early clearance. Densities above a critical value of approximately 20 poly(ethylene glycol) chains (MW 5 kDa) per 100 nm
MeSH term(s)	Adsorption ; Animals ; Apolipoproteins/metabolism ; Complement Activation ; Complement C3/genetics ; Complement C3/metabolism ; Drug Delivery Systems ; Hydrophobic and Hydrophilic Interactions ; Male ; Mice ; Mice, Knockout ; Nanoparticles/administration & dosage ; Nanoparticles/chemistry ; Particle Size ; Polyethylene Glycols/administration & dosage ; Polyethylene Glycols/chemistry ; Protein Corona/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, LDL/metabolism ; Surface Properties
Chemical Substances	Apolipoproteins ; C3 protein, mouse ; Complement C3 ; Protein Corona ; Receptors, LDL ; Polyethylene Glycols (30IQX730WE)
Language	English
Publishing date	2017-10-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2041-1723
ISSN (online)	2041-1723
DOI	10.1038/s41467-017-00600-w
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics

Nicolas Bertrand / Philippe Grenier / Morteza Mahmoudi / Eliana M. Lima / Eric A. Appel / Flavio Dormont / Jong-Min Lim / Rohit Karnik / Robert Langer / Omid C. Farokhzad

Nature Communications, Vol 8, Iss 1, Pp 1-

2017 Volume 8

Abstract: Understanding the interaction between nanoparticles and biomolecules is crucial for improving current drug-delivery systems. Here, the authors shed light on the essential role of the surface and other physicochemical properties of a library of ... ...

Abstract	Understanding the interaction between nanoparticles and biomolecules is crucial for improving current drug-delivery systems. Here, the authors shed light on the essential role of the surface and other physicochemical properties of a library of nanoparticles on their in vivo pharmacokinetics.
Keywords	Science ; Q
Language	English
Publishing date	2017-10-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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