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

Rongrong Zhu, Ka Wing Cheng, Gerardo Mackenzie, Liqun Huang, Yu Sun, Gang Xie, Kveta Vrankova, Panayiotis P. Constantinides, Basil Rigas

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)3090-3101
Number of pages12
JournalPharmaceutical Research
Volume29
Issue number11
DOIs
StatePublished - Nov 1 2012
Externally publishedYes

Fingerprint

Sulindac
Mitochondria
Heterografts
Nanoparticles
Lung Neoplasms
Lipids
Growth
Oxidative stress
Pharmacokinetics
Oxidative Stress
Bearings (structural)
F2-Isoprostanes
Apoptosis
OXT-328
Metabolites
Emulsions
Nude Mice
Tumors
Evaporation
Cells

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 journalArticle

Zhu, Rongrong ; Cheng, Ka Wing ; Mackenzie, Gerardo ; Huang, Liqun ; Sun, Yu ; Xie, Gang ; Vrankova, Kveta ; Constantinides, Panayiotis P. ; Rigas, Basil. / 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. In: Pharmaceutical Research. 2012 ; Vol. 29, No. 11. pp. 3090-3101.
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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.",
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AU - Mackenzie, Gerardo

AU - Huang, Liqun

AU - Sun, Yu

AU - Xie, Gang

AU - Vrankova, Kveta

AU - Constantinides, Panayiotis P.

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