Paclitaxel/tetrandrine coloaded nanoparticles effectively promote the apoptosis of gastric cancer cells based on "oxidation therapy".

Abstract

Paclitaxel (Ptx) has demonstrated encouraging activity in the treatment of gastric cancer. Development of drug-containing biodegradable polymeric nanoparticles (np) becomes one of the solutions to relieve side effects of Ptx. However, Ptx-loaded nanoparticles prepared by the nanoprecipitation method are unstable in the aqueous phase. Here we report that tetrandrine (Tet) effectively increases the stability of Ptx-loaded nanoparticles when Tet is coencapsulated with Ptx into mPEG-PCL nanoparticles. The current study demonstrates the synergistic antitumor effect of Tet and Ptx against gastric cancer cells, which provides the basis of coadministration of Tet and Ptx by nanoparticles. It is reported that the cellular chemoresistance to Ptx correlates with intracellular antioxidant capacity and the depletion of cellular antioxidant capacity could enhance the cytotoxicity of Ptx. Tet effectively induces intracellular ROS production. Therefore, the present study provides a promising novel therapeutic strategy basing on "oxidation therapy" that it could amplify the antitumor effect of paclitaxel by employing Tet as a pro-oxidant. More intracellular Tet accumulation by endocytosis of Ptx/Tet-np than equivalent doses of free drug leads to more intracellular ROS induction, which could efficiently enhance the cytotoxicity of Ptx by sequential inhibition of ROS-dependent Akt pathway and activation of apoptotic pathways, all of which would mediate the superior cytotoxicity of Ptx/Tet-np over free drug. The present results suggest that the codelivery of Ptx and Tet by nanoparticles provides a novel therapeutic strategy basing on "oxidation therapy" against gastric cancer.

• Authors: Xiaolin Li, Xiaowei Lu, Huae Xu, Zhenshu Zhu, Haitao Yin, Xiaoping Qian, Rutian Li, Xiqun Jiang, Baorui Liu
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 9 Issue 2 Pg. 222-9 (Feb 06 2012) ISSN: 1543-8392 [Electronic] United States
• PMID: 22171565 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Benzylisoquinolines
• Drug Carriers
• Polyesters
• Reactive Oxygen Species
• bcl-2-Associated X Protein
• methoxy poly(ethylene glycol-co-epsilon-caprolactone)
• Vitamin E
• tetrandrine
• Polyethylene Glycols
• Proto-Oncogene Proteins c-akt
• Caspase 3
• Paclitaxel

Topics

• Antineoplastic Agents, Phytogenic (administration & dosage)
• Apoptosis (drug effects)
• Benzylisoquinolines (administration & dosage)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Survival
• Drug Carriers (chemistry)
• Drug Synergism
• Genes, bcl-2
• Humans
• Nanoparticles (chemistry)
• Paclitaxel (administration & dosage)
• Particle Size
• Polyesters (chemistry)
• Polyethylene Glycols (chemistry)
• Proto-Oncogene Proteins c-akt (drug effects)
• Reactive Oxygen Species (metabolism)
• Stomach Neoplasms (drug therapy)
• Vitamin E (pharmacology)
• bcl-2-Associated X Protein (metabolism)