International Journal of Pharmaceutics, Oct 1, 2022
Ovarian cancer is one of the deadliest epithelial malignancies in women, owing to the multidrug r... more Ovarian cancer is one of the deadliest epithelial malignancies in women, owing to the multidrug resistance that restricts the success of conventional chemotherapy, carboplatin and paclitaxel. High grade serous ovarian carcinoma can be classified into two subtypes, the chemosensitive High OXPHOS and the Low OXPHOS tumour, less sensitive to chemotherapy. This difference of treatment efficacy could be explained by the redox status of these tumours, High OXPHOS exhibiting a chronic oxidative stress and an accumulation of reactive oxygen species. Ferrocifens, bio-organometallic compounds, are believed to be ROS producers with a good cytotoxicity on ovarian cancer cell lines. The aim of this study was to evaluate the in vivo efficacy of ferrocifen stealth lipid nanocapsules on High and Low OXPHOS ovarian Patient-Derived Xenograft models, alone or in combination to standard chemotherapy. Accordingly, two ferrocifens, P53 and P722, were encapsulated in stealth LNCs. The treatment by stealth P722-LNCs in combination with standard chemotherapy induced, with a concentration eight time lower than in stealth P53-LNCs, similar tumour reduction on a Low OXPHOS model, allowing us to conclude that P722 could be a leading ferrocifen to treat ovarian cancer. This combination of treatments may represent a promising synergistic approach to treat resistant ovarian adenocarcinoma.
HAL (Le Centre pour la Communication Scientifique Directe), 2018
Considering that lung carcinoma is the major cause of cancer-related death worldwide, the main ob... more Considering that lung carcinoma is the major cause of cancer-related death worldwide, the main objective is to find new treatments through a nebulization therapy. In this project, a new class of molecules developed by the start-up called Feroscan has been studied: ferrocifens. They have powerful in vitro anticancer properties but are highly insoluble in water, requiring a formulation stage before being in vivo administered [1]. The objective of this project is to combine three strategies to vectorize ferrocifens: a combination of cell-penetrating peptides (CPP), prodrug and self-assembly. The coupling of a hydrophilic CPP (Argn, n=6-9) with a hydrophobic drug should facilitate the release mainly in the targeted cancer cells [2]. Concretely, CPP were prepared by solid-phase peptide synthesis using a standard 9-fluorenylmethoxycarbonyl (Fmoc) chemistry and a ferrocifen containing a carboxylic function (p54) was linked to the N-terminal extremity of the peptide. After the cleavage, Argn-ferrocifen conjugates were purified by preparative reverse-phase high-performance chromatography and nanoassemblies were formulated by a solvent displacement technique using a microfluidic device. A comparison of their biological activities was performed in vitro on human lung cancer cells (A549 cell line). Argn-p54 were synthesized with a yield between 30 % and 70 % and a purity of 90 %. Subsequently, nanoassemblies were obtained with an apparent diameter of 150 nm, a polydispersity index of 0.15 and a drug loading of 30 %. Preliminary in vitro studies showed that Arg7-p54 is more active than the other conjugates. The complete characterization of nanoassemblies formed, via the determination of the supramolecular organization, will be investigated by cryo-TEM analysis and synchrotron radiation small-angle X-ray scattering. REFERENCES [1] G. Jaouen, A. Vessieres and S. Top. Royal Society of chemistry, 2015, 8802-88017. [2] F. Wang, Y. Wang, X. Zhang, W. Zhang, S. Guo, F. Jin. Journal of Controled Release, 2014, 126–136.
HAL (Le Centre pour la Communication Scientifique Directe), 2018
Le cancer du poumon etant la cause la plus frequente de deces par cancer chez les hommes, le prin... more Le cancer du poumon etant la cause la plus frequente de deces par cancer chez les hommes, le principal objectif de ce projet est de developper un nouveau traitement qui sera administre par nebulisation. Dans ce projet, des molecules anticancereuses developpees par l’entreprise Feroscan sont etudiees : les ferrocifenes. Ces composes innovants possedent des proprietes anticancereuses tres interessantes mais un fort caractere hydrophobe, necessitant une strategie de vectorisation adequate [1]. L’objectif est ainsi de combiner trois strategies : (i) l’utilisation d’un peptide penetrant, via (ii) la formation d’une prodrogue qui (iii) s’auto-assemble en nanoparticule. Les peptides penetrants, polyarginines (Argn) contenant entre 7 et 9 unites, ont ete synthetises sur support solide via une strategie Fmoc (9-fluorenylmethoxycarbonyl) et le ferrocifene (p54), possedant une fonction acide carboxylique, est couple au niveau de l’extremite N-terminale du peptide. Apres clivage, des auto-assemblages ont ete obtenu par le procede de nanoprecipitation en utilisant un procede microfluidique. La comparaison de l’activite biologique est realisee in vitro sur une lignee humaine de cellules du cancer du poumon (lignee A549). Les conjugues ont ete synthetises avec un rendement compris entre 30 % et 70 % et une purete superieure a 90 %. Des auto-assemblages ont ete obtenus avec un diametre apparent de 150 nm, un indice de polydispersite de 0,15 et une charge en ferrocifene theorique de 30 %. Les resultats preliminaires de l’activite biologique ont montre que le conjugue Arg7-p54 est plus actif que les autres composes. La caracterisation complete des auto-assemblages sera effectuee par des analyses en Cryo-MET ainsi que par de la diffusion des rayons X aux petits angles, au synchrotron SOLEIL. [1] G. Jaouen, A. Vessieres and S. Top. Royal Society of chemistry, 2015, 8802-88017.
HAL (Le Centre pour la Communication Scientifique Directe), 2018
Titre Self-assemblies formed by cell-penetrating peptide and ferrocifen for lung cancer treatment... more Titre Self-assemblies formed by cell-penetrating peptide and ferrocifen for lung cancer treatment Type de publication Communication Type Communication par affiche dans un congrès Année 2018 Langue Anglais Date du colloque 29/05/2018 Titre du colloque Journée scientifique de la SFR ICAT4208
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
European Journal of Inorganic Chemistry, Feb 2, 2022
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
As previously reported, the ferrocenyl derivative HO(CH2)3C(Fc)=C(C6H4OH)2 (2) shows an excellent... more As previously reported, the ferrocenyl derivative HO(CH2)3C(Fc)=C(C6H4OH)2 (2) shows an excellent cytotoxic effect against MDA-MB-231 (TNBC) cancer cell lines. Building on an analysis of this molecular framework, a series of novel hydroxypropyl-ferrociphenol derivatives with modified terminal hydroxyl groups were synthesized, and their antiproliferative activities against MDA-MB-231 cell lines were evaluated. Biological results showed that compound 8, whose terminal hydroxyl was protected by acetylation, exhibited the greatest cytotoxic effect among this series of hydroxypropyl derivatives. Furthermore, the impact of acetyl as a protecting group on the cytotoxicity of hydroxypropyl-ferrociphenol compounds by incorporating it to alkyl or phenyl hydroxyl positions of the core structure has been studied. Several of compounds presented in this study revealed lipophilicity more suitable for formulation in lipid nanocapsules (LNCs) for subsequent in vivo studies. They also inhibit the cancer cell growth of MDA-MB-231 at a submicromolar IC50 value, providing an interesting potential for further development as innovative anticancer agents.
We report here the synthesis and cell-proliferation properties of derivatives of the breast cance... more We report here the synthesis and cell-proliferation properties of derivatives of the breast cancer drug tamoxifen, in which the-O(CH 2) 2 N(CH 3) 2 side chain, responsible for the drug's antiestrogenic properties, has been modified by a ferrocenyl moiety. We recently reported the diphenol compound 5, in which this amino chain had been replaced with an acyl-ferrocenyl (-O(CH 2) 2 C(O)[(η 5-C 5 H 4)FeCp]) group, and which showed antiproliferative effects against both the hormone-dependent MCF-7 and-independent MDA-MB-231 breast cancer cell lines. We now report the results of a structure-activity relationship (SAR) study, in which the lateral chain length has been varied, the ketone group has been omitted, and the number of phenol groups has been varied. Compounds 1-4, with a side chain lacking the carbonyl function (-O(CH 2) n [(η 5-C 5 H 4)FeCp], n=1-4) and which show a decreasing affinity for ERα (ER=estrogen receptor) with increasing chain length, act as estrogens on MCF-7 cells, and mild cytotoxics on PC-3 prostate cancer cells, with IC 50 values around 10 μM. The two monophenolic derivatives of 2, 2 a and 2 b, which show a reduced affinity for ERα compared to 2, are also estrogenic, but are only slightly cytotoxic. Finally, we have reexamined compound 5 and discovered that its antiproliferative effect against the MCF-7 cell line does not arise from antiestrogenicity as we had originally suspected, but by means of a cytotoxic pathway. This compound is also sensitive to the number of phenol groups as cell death is diminished when one of the hydroxyl groups is omitted (5 a and 5 b). Molecular modeling studies of the ligand-ERα binding stability are broadly consistent with the experimental binding affinity results for compounds 2, 2 a, 2 b, 5, 5 a, and 5 b. Electrochemical experiments show that 1-4, 2 a, and 2 b are stable to oxidation on the electrochemical timescale, unlike 5, 5 a, and 5 b, and that cytotoxicity is related to less positive phenol oxidation potentials. The SAR study shows that the presence of a ketone group and two phenol groups is necessary for strong receptor binding and cytotoxic effects, and that all compounds are estrogenic, despite the presence of a bulky side chain.
A series of organometallic antiestrogens based on the OH-tamoxifen (OH-Tam) skeleton and bearing ... more A series of organometallic antiestrogens based on the OH-tamoxifen (OH-Tam) skeleton and bearing the (η 5-C 5 H 4)Re I (CO) 3 unit has been prepared by using McMurry coupling for the purpose of studying their biological behaviour. The cyclopentadienylrhenium tricarbonyl moiety is indeed stable in biological media, compact, lipophilic and easy to handle. Furthermore, this study allowed us to select the best candidates for subsequent use as radiopharmaceuticals either for imaging or therapy by using appropriate radionucleides, namely 99m Tc and 188 Re. In these molecules the βphenyl group of OH-Tam has been replaced by the (η 5-C 5 H 4)Re(CO) 3 moiety, and the length of the dimethylamino side chain-O(CH 2) n N(CH 3) 2 was varied (n=2, 3, 4, 5 and 8). The compounds 7 a-7 e were obtained as mixtures of their Z and E isomers, which could be separated by semipreparative HPLC. Unlike their ferrocene homologues, the compounds do not isomerise in solution. Structural identification was carried out with NMR spectroscopy by using the HMBC and NOE techniques and was confirmed by the X-ray structural determination of (E)-7 a (n=2). These molecules were more lipophilic than OH-Tam (log P o/w =4.5-6.3) and they were all reasonably well recognized by the two forms of the estrogen receptor (ERα and ERβ). For example, (Z)-7 b (n=3) has high relative binding affinity (RBA) values of 31 % for ERα and 16.8 % for ERβ. The antiproliferative effects of two pairs of isomers, (Z)-and (E)-7 b (n=3) and (Z)-and (E)-7 d (n=5), were studied at a molarity of 1 μM on two breast-cancer cell lines, MCF7 (ERα positive) and MDA-MB231 (ERα negative). These molecules had an antiproliferative effect on MCF7 cells slightly higher than that of OH-Tam and no effect on MDA-MB231 cells. Thus, the antiproliferative effect observed on the MCF7 cells seemed essentially to be linked to an antiestrogenic effect. Molecular modelling studies have allowed us to rationalise these effects and select the best compounds for future development of a radioactive series.
International Journal of Pharmaceutics, Oct 1, 2022
Ovarian cancer is one of the deadliest epithelial malignancies in women, owing to the multidrug r... more Ovarian cancer is one of the deadliest epithelial malignancies in women, owing to the multidrug resistance that restricts the success of conventional chemotherapy, carboplatin and paclitaxel. High grade serous ovarian carcinoma can be classified into two subtypes, the chemosensitive High OXPHOS and the Low OXPHOS tumour, less sensitive to chemotherapy. This difference of treatment efficacy could be explained by the redox status of these tumours, High OXPHOS exhibiting a chronic oxidative stress and an accumulation of reactive oxygen species. Ferrocifens, bio-organometallic compounds, are believed to be ROS producers with a good cytotoxicity on ovarian cancer cell lines. The aim of this study was to evaluate the in vivo efficacy of ferrocifen stealth lipid nanocapsules on High and Low OXPHOS ovarian Patient-Derived Xenograft models, alone or in combination to standard chemotherapy. Accordingly, two ferrocifens, P53 and P722, were encapsulated in stealth LNCs. The treatment by stealth P722-LNCs in combination with standard chemotherapy induced, with a concentration eight time lower than in stealth P53-LNCs, similar tumour reduction on a Low OXPHOS model, allowing us to conclude that P722 could be a leading ferrocifen to treat ovarian cancer. This combination of treatments may represent a promising synergistic approach to treat resistant ovarian adenocarcinoma.
HAL (Le Centre pour la Communication Scientifique Directe), 2018
Considering that lung carcinoma is the major cause of cancer-related death worldwide, the main ob... more Considering that lung carcinoma is the major cause of cancer-related death worldwide, the main objective is to find new treatments through a nebulization therapy. In this project, a new class of molecules developed by the start-up called Feroscan has been studied: ferrocifens. They have powerful in vitro anticancer properties but are highly insoluble in water, requiring a formulation stage before being in vivo administered [1]. The objective of this project is to combine three strategies to vectorize ferrocifens: a combination of cell-penetrating peptides (CPP), prodrug and self-assembly. The coupling of a hydrophilic CPP (Argn, n=6-9) with a hydrophobic drug should facilitate the release mainly in the targeted cancer cells [2]. Concretely, CPP were prepared by solid-phase peptide synthesis using a standard 9-fluorenylmethoxycarbonyl (Fmoc) chemistry and a ferrocifen containing a carboxylic function (p54) was linked to the N-terminal extremity of the peptide. After the cleavage, Argn-ferrocifen conjugates were purified by preparative reverse-phase high-performance chromatography and nanoassemblies were formulated by a solvent displacement technique using a microfluidic device. A comparison of their biological activities was performed in vitro on human lung cancer cells (A549 cell line). Argn-p54 were synthesized with a yield between 30 % and 70 % and a purity of 90 %. Subsequently, nanoassemblies were obtained with an apparent diameter of 150 nm, a polydispersity index of 0.15 and a drug loading of 30 %. Preliminary in vitro studies showed that Arg7-p54 is more active than the other conjugates. The complete characterization of nanoassemblies formed, via the determination of the supramolecular organization, will be investigated by cryo-TEM analysis and synchrotron radiation small-angle X-ray scattering. REFERENCES [1] G. Jaouen, A. Vessieres and S. Top. Royal Society of chemistry, 2015, 8802-88017. [2] F. Wang, Y. Wang, X. Zhang, W. Zhang, S. Guo, F. Jin. Journal of Controled Release, 2014, 126–136.
HAL (Le Centre pour la Communication Scientifique Directe), 2018
Le cancer du poumon etant la cause la plus frequente de deces par cancer chez les hommes, le prin... more Le cancer du poumon etant la cause la plus frequente de deces par cancer chez les hommes, le principal objectif de ce projet est de developper un nouveau traitement qui sera administre par nebulisation. Dans ce projet, des molecules anticancereuses developpees par l’entreprise Feroscan sont etudiees : les ferrocifenes. Ces composes innovants possedent des proprietes anticancereuses tres interessantes mais un fort caractere hydrophobe, necessitant une strategie de vectorisation adequate [1]. L’objectif est ainsi de combiner trois strategies : (i) l’utilisation d’un peptide penetrant, via (ii) la formation d’une prodrogue qui (iii) s’auto-assemble en nanoparticule. Les peptides penetrants, polyarginines (Argn) contenant entre 7 et 9 unites, ont ete synthetises sur support solide via une strategie Fmoc (9-fluorenylmethoxycarbonyl) et le ferrocifene (p54), possedant une fonction acide carboxylique, est couple au niveau de l’extremite N-terminale du peptide. Apres clivage, des auto-assemblages ont ete obtenu par le procede de nanoprecipitation en utilisant un procede microfluidique. La comparaison de l’activite biologique est realisee in vitro sur une lignee humaine de cellules du cancer du poumon (lignee A549). Les conjugues ont ete synthetises avec un rendement compris entre 30 % et 70 % et une purete superieure a 90 %. Des auto-assemblages ont ete obtenus avec un diametre apparent de 150 nm, un indice de polydispersite de 0,15 et une charge en ferrocifene theorique de 30 %. Les resultats preliminaires de l’activite biologique ont montre que le conjugue Arg7-p54 est plus actif que les autres composes. La caracterisation complete des auto-assemblages sera effectuee par des analyses en Cryo-MET ainsi que par de la diffusion des rayons X aux petits angles, au synchrotron SOLEIL. [1] G. Jaouen, A. Vessieres and S. Top. Royal Society of chemistry, 2015, 8802-88017.
HAL (Le Centre pour la Communication Scientifique Directe), 2018
Titre Self-assemblies formed by cell-penetrating peptide and ferrocifen for lung cancer treatment... more Titre Self-assemblies formed by cell-penetrating peptide and ferrocifen for lung cancer treatment Type de publication Communication Type Communication par affiche dans un congrès Année 2018 Langue Anglais Date du colloque 29/05/2018 Titre du colloque Journée scientifique de la SFR ICAT4208
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
European Journal of Inorganic Chemistry, Feb 2, 2022
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
As previously reported, the ferrocenyl derivative HO(CH2)3C(Fc)=C(C6H4OH)2 (2) shows an excellent... more As previously reported, the ferrocenyl derivative HO(CH2)3C(Fc)=C(C6H4OH)2 (2) shows an excellent cytotoxic effect against MDA-MB-231 (TNBC) cancer cell lines. Building on an analysis of this molecular framework, a series of novel hydroxypropyl-ferrociphenol derivatives with modified terminal hydroxyl groups were synthesized, and their antiproliferative activities against MDA-MB-231 cell lines were evaluated. Biological results showed that compound 8, whose terminal hydroxyl was protected by acetylation, exhibited the greatest cytotoxic effect among this series of hydroxypropyl derivatives. Furthermore, the impact of acetyl as a protecting group on the cytotoxicity of hydroxypropyl-ferrociphenol compounds by incorporating it to alkyl or phenyl hydroxyl positions of the core structure has been studied. Several of compounds presented in this study revealed lipophilicity more suitable for formulation in lipid nanocapsules (LNCs) for subsequent in vivo studies. They also inhibit the cancer cell growth of MDA-MB-231 at a submicromolar IC50 value, providing an interesting potential for further development as innovative anticancer agents.
We report here the synthesis and cell-proliferation properties of derivatives of the breast cance... more We report here the synthesis and cell-proliferation properties of derivatives of the breast cancer drug tamoxifen, in which the-O(CH 2) 2 N(CH 3) 2 side chain, responsible for the drug's antiestrogenic properties, has been modified by a ferrocenyl moiety. We recently reported the diphenol compound 5, in which this amino chain had been replaced with an acyl-ferrocenyl (-O(CH 2) 2 C(O)[(η 5-C 5 H 4)FeCp]) group, and which showed antiproliferative effects against both the hormone-dependent MCF-7 and-independent MDA-MB-231 breast cancer cell lines. We now report the results of a structure-activity relationship (SAR) study, in which the lateral chain length has been varied, the ketone group has been omitted, and the number of phenol groups has been varied. Compounds 1-4, with a side chain lacking the carbonyl function (-O(CH 2) n [(η 5-C 5 H 4)FeCp], n=1-4) and which show a decreasing affinity for ERα (ER=estrogen receptor) with increasing chain length, act as estrogens on MCF-7 cells, and mild cytotoxics on PC-3 prostate cancer cells, with IC 50 values around 10 μM. The two monophenolic derivatives of 2, 2 a and 2 b, which show a reduced affinity for ERα compared to 2, are also estrogenic, but are only slightly cytotoxic. Finally, we have reexamined compound 5 and discovered that its antiproliferative effect against the MCF-7 cell line does not arise from antiestrogenicity as we had originally suspected, but by means of a cytotoxic pathway. This compound is also sensitive to the number of phenol groups as cell death is diminished when one of the hydroxyl groups is omitted (5 a and 5 b). Molecular modeling studies of the ligand-ERα binding stability are broadly consistent with the experimental binding affinity results for compounds 2, 2 a, 2 b, 5, 5 a, and 5 b. Electrochemical experiments show that 1-4, 2 a, and 2 b are stable to oxidation on the electrochemical timescale, unlike 5, 5 a, and 5 b, and that cytotoxicity is related to less positive phenol oxidation potentials. The SAR study shows that the presence of a ketone group and two phenol groups is necessary for strong receptor binding and cytotoxic effects, and that all compounds are estrogenic, despite the presence of a bulky side chain.
A series of organometallic antiestrogens based on the OH-tamoxifen (OH-Tam) skeleton and bearing ... more A series of organometallic antiestrogens based on the OH-tamoxifen (OH-Tam) skeleton and bearing the (η 5-C 5 H 4)Re I (CO) 3 unit has been prepared by using McMurry coupling for the purpose of studying their biological behaviour. The cyclopentadienylrhenium tricarbonyl moiety is indeed stable in biological media, compact, lipophilic and easy to handle. Furthermore, this study allowed us to select the best candidates for subsequent use as radiopharmaceuticals either for imaging or therapy by using appropriate radionucleides, namely 99m Tc and 188 Re. In these molecules the βphenyl group of OH-Tam has been replaced by the (η 5-C 5 H 4)Re(CO) 3 moiety, and the length of the dimethylamino side chain-O(CH 2) n N(CH 3) 2 was varied (n=2, 3, 4, 5 and 8). The compounds 7 a-7 e were obtained as mixtures of their Z and E isomers, which could be separated by semipreparative HPLC. Unlike their ferrocene homologues, the compounds do not isomerise in solution. Structural identification was carried out with NMR spectroscopy by using the HMBC and NOE techniques and was confirmed by the X-ray structural determination of (E)-7 a (n=2). These molecules were more lipophilic than OH-Tam (log P o/w =4.5-6.3) and they were all reasonably well recognized by the two forms of the estrogen receptor (ERα and ERβ). For example, (Z)-7 b (n=3) has high relative binding affinity (RBA) values of 31 % for ERα and 16.8 % for ERβ. The antiproliferative effects of two pairs of isomers, (Z)-and (E)-7 b (n=3) and (Z)-and (E)-7 d (n=5), were studied at a molarity of 1 μM on two breast-cancer cell lines, MCF7 (ERα positive) and MDA-MB231 (ERα negative). These molecules had an antiproliferative effect on MCF7 cells slightly higher than that of OH-Tam and no effect on MDA-MB231 cells. Thus, the antiproliferative effect observed on the MCF7 cells seemed essentially to be linked to an antiestrogenic effect. Molecular modelling studies have allowed us to rationalise these effects and select the best compounds for future development of a radioactive series.
Uploads
Papers by Pascal Pigeon