Mitochondrial targeting by use of lipid nanocapsules loaded with SV30, an analogue of the small-molecule Bcl-2 inhibitor HA14-1

• DOI: 10.1016/j.jconrel.2010.11.032
• Publication Date: 2010-12-06T10:50:13Z
• Authors: M. Weyland; F. Manero; A. Paillard; D. Grée; G. Viault; D. Jarnet; P. Menei; P. Juin; I. Chourpa; J.-P. Benoit; R. Grée; E. Garcion
• Keywords: 0301 basic medicine; MESH: Cell Line, Tumor; MESH: Rats; MESH: Mitochondria; Antineoplastic Agents; MESH: Glioma; 03 medical and health sciences; Nanocapsules; MESH: Nanocapsules; Cell Line, Tumor; MESH: Caspase 3; Nitriles; Animals; MESH: Animals; Benzopyrans; [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]; [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]; Caspase 3; Glioma; MESH: Lipids; Lipids; MESH: Nitriles; Mitochondria; Rats; MESH: Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcl-2; MESH: Benzopyrans; MESH: Antineoplastic Agents

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.