Mitochondrial targeting by use of lipid nanocapsules loaded with SV30, an analogue of the small-molecule Bcl-2 inhibitor HA14-1.
Taking advantage from the development of SV30, a new analogue of the pro-apoptotic molecule HA14-1, the aim of this study was to functionally evaluate SV30 and to develop safe nanocarriers for its administration. By using an inversion phase process, 57nm organic solvent-free lipid nanocapsules loaded with SV30 (SV30-LNCs) were formulated. Biological performance of SV30 and SV30-LNCs were evaluated on F98 cells that express Bax and Bcl-2, through survival assays, HPLC, flow cytometry, confocal microscopy and spectral imaging. We observed that SV30 alone or in combination with paclitaxel, etoposide or beam radiation could trigger cell death in a similar fashion to HA14-1. Although partially blocked by Z-VAD-fmk, this effect was coincident to caspase-3 activation. Hence, we established that SV30-LNCs improved SV30 biological activity together with a potentiation of the mitochondrial membrane potential decrease. Interestingly, flow cytometry and confocal analysis indicated that SV30 itself conferred to LNCs improved mitochondrial targeting skills that may present a great interest toward the development of mitochondria targeted nanomedicines.
Inserm, UMR-S 646, Angers, France.
M
M
Weyland
F
F
Manero
A
A
Paillard
D
D
Grée
G
G
Viault
D
D
Jarnet
P
P
Menei
P
P
Juin
I
I
Chourpa
J-P
JP
Benoit
R
R
Grée
E
E
Garcion
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D005910:Glioma / Q000188:drug therapy*; D008055:Lipids / Q000737:chemistry*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D053769:Nanocapsules / Q000737:chemistry*; D009570:Nitriles / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D051381:Rats
D000970:Antineoplastic Agents; D001578:Benzopyrans; D008055:Lipids; D053769:Nanocapsules; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D053148:Caspase 3