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Docetaxel loaded oleic acid-coated hydroxyapatite nanoparticles enhance the docetaxel-induced apoptosis through activation of caspase-2 in androgen independent prostate cancer cells.
- Source :
-
Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2010 Oct 15; Vol. 147 (2), pp. 278-88. Date of Electronic Publication: 2010 Jul 23. - Publication Year :
- 2010
-
Abstract
- Docetaxel (Dtxl) remains the preferred choice of improving the survival of patients with hormone refractory prostate cancer (HRPC), but many patients suffer from modest drug response and significant toxicity. In the present study, we investigated the efficiency of novel Dtxl loaded-[1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-carboxy(polyethylene glycol)]2000 (DSPE-PEG-COOH) stabilized-oleic acid (OA) coated hydroxyapatite (HA) nanoparticles (Dtxl-NPs) and gained insights into the molecular mechanism of the apoptosis induced by these novel Dtxl-loaded nanoparticles. The drug encapsulation efficiency of Dtxl was 83.6% and the sustained drug release was observed over 30days. The Dtxl-NPs exhibited significantly more cytotoxicity in both prostate cancer cell lines (PC3 and DU145) compared with Dtxl in vitro and increased the Dtxl-induced apoptosis in the PC3 cells. Cell cycle analysis showed that the PC3 cells treated with Dtxl-NPs exhibited significant arrest in the G2-M phase but a higher sub-G(0)/G(1) population when compared with Dtxl. The enhanced apoptosis induced by Dtxl-NPs in the PC3 cells was associated with the changes in mitochondrial membrane potential (MMP) and seemed to involve the activation of caspase-2. The kinetic studies of caspases demonstrated an early activation of caspase-2 in Dtxl-NPs-induced apoptosis in PC3 cells, which differs from Dtxl-induced apoptosis. The inhibition of caspase-2 activation by small interfering RNA (siRNA) knockdown resulted in the significant inhibition of Dtxl-NPs-induced disruption of MMP and Dtxl-NPs-induced apoptosis, indicating that the activation of caspase-2 was the critical event before the mitochondrial depolarization in the PC3 cells. Our findings showed that nanoparticles, more than simple drug carriers, may play an active role in mediating the biological effects.<br /> (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Subjects :
- Androgens metabolism
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents pharmacology
Blotting, Western
Caspase 2 genetics
Cell Cycle drug effects
Cell Line, Tumor
Cell Survival drug effects
Cysteine Endopeptidases genetics
Docetaxel
Drug Compounding
Enzyme Activation
Flow Cytometry
Humans
Male
Membrane Potential, Mitochondrial drug effects
Particle Size
Prostatic Neoplasms drug therapy
Prostatic Neoplasms metabolism
Prostatic Neoplasms pathology
RNA, Small Interfering pharmacology
Taxoids pharmacokinetics
Taxoids pharmacology
Antineoplastic Agents administration & dosage
Apoptosis drug effects
Caspase 2 metabolism
Cysteine Endopeptidases metabolism
Drug Carriers chemistry
Durapatite chemistry
Nanoparticles chemistry
Oleic Acid chemistry
Taxoids administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4995
- Volume :
- 147
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of controlled release : official journal of the Controlled Release Society
- Publication Type :
- Academic Journal
- Accession number :
- 20655966
- Full Text :
- https://doi.org/10.1016/j.jconrel.2010.07.108