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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3090-3101 |
| Number of pages | 12 |
| Journal | Pharmaceutical Research |
| Volume | 29 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2012 |
| Externally published | Yes |
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Keywords
- lung cancer
- mitochondria targeting
- non-steroidal anti-inflammatory drugs
- phospho-sulindac
- solid lipid nanoparticles
ASJC Scopus subject areas
- Biotechnology
- Molecular Medicine
- Pharmacology
- Pharmaceutical Science
- Organic Chemistry
- Pharmacology (medical)
Cite this
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. / Zhu, Rongrong; Cheng, Ka Wing; Mackenzie, Gerardo; Huang, Liqun; Sun, Yu; Xie, Gang; Vrankova, Kveta; Constantinides, Panayiotis P.; Rigas, Basil.
In: Pharmaceutical Research, Vol. 29, No. 11, 01.11.2012, p. 3090-3101.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phospho-sulindac (OXT-328) inhibits the growth of human lung cancer xenografts in mice
T2 - Enhanced efficacy and mitochondria targeting by its formulation in solid lipid nanoparticles
AU - Zhu, Rongrong
AU - Cheng, Ka Wing
AU - Mackenzie, Gerardo
AU - Huang, Liqun
AU - Sun, Yu
AU - Xie, Gang
AU - Vrankova, Kveta
AU - Constantinides, Panayiotis P.
AU - Rigas, Basil
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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.
AB - 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.
KW - lung cancer
KW - mitochondria targeting
KW - non-steroidal anti-inflammatory drugs
KW - phospho-sulindac
KW - solid lipid nanoparticles
UR - http://www.scopus.com/inward/record.url?scp=84867851229&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867851229&partnerID=8YFLogxK
U2 - 10.1007/s11095-012-0801-x
DO - 10.1007/s11095-012-0801-x
M3 - Article
C2 - 22723123
AN - SCOPUS:84867851229
VL - 29
SP - 3090
EP - 3101
JO - Pharmaceutical Research
JF - Pharmaceutical Research
SN - 0724-8741
IS - 11
ER -