Efficient ferrocifen anticancer drug and Bcl-2 gene therapy using lipid nanocapsules on human melanoma xenograft in mouse.
Metastatic melanoma has been described as a highly aggressive cancer with low sensibility to chemotherapeutic agents. New types of drug, such as metal-based drugs (ferrocifens) have emerged and could represent an alternative for melanoma treatment since they show interesting anticancer potential. Furthermore, molecular analysis has evidenced the role of apoptosis in the low sensibility of melanomas and especially of the key regulator, Bcl-2. The objective of this study was to combine two strategies in the same lipid nanocapsules (LNCs): i) gene therapy to modulate anti-apoptotic proteins by the use of Bcl-2 siRNA, and ii) ferrocifens as a new type of anticancer agent. The efficient gene silencing with LNCs was verified by the specific extinction of Bcl-2 in melanoma cells. The cellular toxicity of ferrocifens (ferrociphenol (FcDiOH) or Ansa-FcDiOH) was demonstrated, showing higher efficacy than dacarbazine. Interestingly, the association of siBcl-2 LNCs with Ansa-FcDiOH demonstrated a significant effect on melanoma cell viability. Moreover, the co-encapsulation of siRNA and ferrocifens was successfully performed into LNCs for animal experiments. A reduction of tumor volume and mass was proved after siBcl-2 LNC treatment and Ansa-FcDiOH LNC treatment, individually (around 25%). Finally, the association of both components into the same LNCs increased the reduction of tumor volume to about 50% compared to the control group. In conclusion, LNCs appeared to provide a promising tool for the co-encapsulation of a metal-based drug and siRNA.
MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France. Electronic address: pauline.resnier@etud.univ-angers.fr.
Pauline
P
Resnier
SCAHU - Faculté de Médecine, Pavillon Ollivier, rue Haute de Reculée, F-49933 Angers, France. Electronic address: natacha.galopin@laposte.net.
Natacha
N
Galopin
INSERM U1078 - Equipe 'Transfert de gènes et thérapie génique', Faculté de Médecine, 22 avenue Camille Desmoulins, CS 93837, F-29238 Brest, Cedex 3, France; CHRU de Brest, Service de Génétique Moléculaire et d'histocompatibilité, 5 avenue Maréchal Foch, 29609 Brest, France. Electronic address: yann.sibiril@univ-brest.fr.
Yann
Y
Sibiril
MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France. Electronic address: anne.clavreul@univ-angers.fr.
Anne
A
Clavreul
MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France; PACeM (Plateforme d'Analyse Cellulaire et Moléculaire), SFR ICAT 4208, Université d'Angers, 4 rue Larrey, F-49933 Angers, France. Electronic address: jerome.cayon@univ-angers.fr.
Jérôme
J
Cayon
MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France. Electronic address: a.briganti@studenti.unina.it.
Alessandro
A
Briganti
SCAHU - Faculté de Médecine, Pavillon Ollivier, rue Haute de Reculée, F-49933 Angers, France. Electronic address: pierre.legras@univ-angers.fr.
Pierre
P
Legras
CNRS, UMR 8232, ENSCP, 11 rue P. et M. Curie, F-75231 Paris Cedex05, France. Electronic address: anne.vessieres@upmc.fr.
Anne
A
Vessières
INSERM U1078 - Equipe 'Transfert de gènes et thérapie génique', Faculté de Médecine, 22 avenue Camille Desmoulins, CS 93837, F-29238 Brest, Cedex 3, France; CHRU de Brest, Service de Génétique Moléculaire et d'histocompatibilité, 5 avenue Maréchal Foch, 29609 Brest, France. Electronic address: tristan.montier@univ-brest.fr.
Tristan
T
Montier
CNRS, UMR 8232, ENSCP, 11 rue P. et M. Curie, F-75231 Paris Cedex05, France. Electronic address: gerard.jaouen@upmc.fr.
Gérard
G
Jaouen
MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France. Electronic address: jean-pierre.benoit@univ-angers.fr.
Jean-Pierre
JP
Benoit
MINT, UNIV Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France. Electronic address: catherine.passirani@univ-angers.fr.
Catherine
C
Passirani
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005296:Ferrous Compounds / Q000494:pharmacology*; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D008055:Lipids; D053769:Nanocapsules; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C514120:ferrocifen; C533771:ferrociphenol
Gene therapy; Metal-based drug; Nanoparticles; Passive targeting; SK-Mel28