Delivery of ursolic acid (UA) in polymeric nanoparticles effectively promotes the apoptosis of gastric cancer cells through enhanced inhibition of cyclooxygenase 2 (COX-2)

• Published in: International journal of pharmaceutics 2013-01, Vol.441 (1-2), p.261-268
• Main Authors: Zhang, Hao, Li, Xiaolin, Ding, Jing, Xu, Huae, Dai, Xinzheng, Hou, Zhibo, Zhang, Kai, Sun, Kun, Sun, Weihao
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacology; apoptosis; Apoptosis - drug effects; Caspase 3 - metabolism; caspase-3; Cell Line, Tumor; Cell Membrane - metabolism; cell membranes; composite polymers; COX-2; Cyclooxygenase 2 - drug effects; Cyclooxygenase 2 Inhibitors - administration & dosage; Cyclooxygenase 2 Inhibitors - pharmacology; cytotoxicity; Dose-Response Relationship, Drug; drug carriers; Drug Carriers - chemistry; Drug Delivery Systems; drugs; ethylene glycol; Gastric cancer; Humans; Hydrophobic and Hydrophilic Interactions; hydrophobicity; mPEG–PCL; Nanoparticle; Nanoparticles; Polyesters - chemistry; Polyethylene Glycols - chemistry; prostaglandin synthase; stomach neoplasms; Stomach Neoplasms - drug therapy; Stomach Neoplasms - enzymology; Stomach Neoplasms - pathology; Time Factors; Triterpenes - administration & dosage; Triterpenes - pharmacology; Ursolic Acid
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2012.11.034

UA-loaded nanoparticles (UA-NPs) efficiently elicit more accumulation of intracellular drug by endocytosis, leading to more efficient inhibition of COX-2 and activation of caspase-3 and inducing more cell apoptosis, which demonstrates that UA-NPs statistically surpass free UA through COX-2 pathways. It has been demonstrated that ursolic acid (UA) could effectively induces apoptosis of cancer cells by inhibiting the expression of cyclooxygenase 2 (COX-2), which constitutively expresses in gastric cancer. However, the hydrophobicity of UA increases the difficulty in its potential clinical application, which raises the possibility for its application as a novel model drug in nanoparticle-based delivery system. UA-loaded nanoparticles (UA-NPs) were prepared by a nano-precipitation method using amphilic methoxy poly(ethylene glycol)–polycaprolactone (mPEG–PCL) block copolymers as drug carriers. UA was effectively transported into SGC7901 cells by nanoparticles and localized around the nuclei in the cytoplasms. The in vitro cytotoxicity and apoptosis test indicated that UA-NPs significantly elicited more cell death at almost equivalent dose and corresponding incubation time. Moreover, UA-NPs led to more cell apoptosis through stronger inhibition of COX-2 and activation of caspase 3. The most powerful evidence from this report is that the significant differences between the cytotoxicity of free UA and UA-NPs are closely related to the expression levels of COX-2 and caspase-3, which demonstrates the superiority of UA-NPs over free UA through penetrating cell membrane. Therefore, the study offer an effective way to improve the anticancer efficiency of UA through nano-drug delivery system.