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- Title
Phospho-Sulindac (OXT-328) Inhibits the Growth of Human Lung Cancer Xenografts in Mice: Enhanced Efficacy and Mitochondria Targeting by its Formulation in Solid Lipid Nanoparticles.
- Authors
Zhu, Rongrong; Cheng, Ka-Wing; Mackenzie, Gerardo; Huang, Liqun; Sun, Yu; Xie, Gang; Vrankova, Kveta; Constantinides, Panayiotis; Rigas, Basil
- Abstract
Purpose: To evaluate the antitumor efficacy of solid lipid nanoparticle-encapsulated phospho-sulindac (SLN-PS) in human lung cancer. Methods: PS was incorporated into SLNs using the emulsion evaporation technique. We determined the antitumor activity of SLN-PS in cultured lung cancer cells. The performance of SLN-PS was further evaluated by pharmacokinetic studies in mice and in a model of human lung cancer xenografts in nude mice. Results: SLN-PS was >4-fold more potent than PS in inhibiting the growth of A549 and H510 cells in vitro. SLN-PS enhanced cellular uptake and facilitated PS accumulation in mitochondria, leading to oxidative stress and apoptosis via the mitochondrial-apoptosis pathway. SLN-PS was highly effective in suppressing the growth of A549 xenografts (78% inhibition compared to control, p < 0.01); while PS had no significant effect. Formulation of PS in SLNs resulted in improved pharmacokinetics in mice and an enhanced (∼14-fold) accumulation of PS and its metabolites in A549 xenografts. Finally, SLN-PS enhanced urinary F2-isoprostane uniquely in mice bearing A549 xenografts compared to untreated controls, suggesting that SLN-PS specifically induced oxidative stress in tumors. Conclusions: Our results show that SLN-PS is efficacious in suppressing the growth of lung cancer and merits further evaluation.
- Subjects
ANTINEOPLASTIC agents; DRUG efficacy; NANOMEDICINE; MITOCHONDRIA; PHARMACOKINETICS; LUNG cancer; XENOGRAFTS; TARGETED drug delivery; LABORATORY mice
- Publication
Pharmaceutical Research, 2012, Vol 29, Issue 11, p3090
- ISSN
0724-8741
- Publication type
Article
- DOI
10.1007/s11095-012-0801-x