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Published on: September 3, 2013
Folate receptor-targeted pH-sensitive liposomes loaded with TGX-221 against prostate cancer by inhibiting PI3K/110β
Weibo Xu1,2, Xiaohan Li3, Fujin He3
1Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 China guopeng661@mail.xjtu.edu.cn.
Abstract:
Prostate cancer (PCa) is the most common cancer in men and the leading cause of cancer death worldwide. Overactivation of PI3K signaling has been reported to be associated with PCa. TGX221 is an effective specific inhibitor of PI3K, but its clinical application is greatly limited due to its poor solubility. Herein, by using folic acid-PEG-cholesterol semi-succinate (FA-PEG-CHEMS) as the targeting component, we developed a folate receptor-targeted pH-sensitive liposomal delivery system loaded with TGX221 (FA-Lip-TGX221) that could realize effective delivery and controlled release of drugs in the tumor. The prepared liposomes exhibited a uniform particle size and high stability. In addition, FA-Lip-TGX221 could be effectively internalized by PC-3 cells due to its ability to target folate receptors, thereby accumulating in tumor tissues. Meanwhile, in vitro and in vivo experiments suggested that FA-Lip-TGX221 could activate the PERK-ATF4-CHOP signaling pathway by inhibiting PI3K/110β signaling in PCa, thus significantly promoting endoplasmic reticulum (ER) stress-mediated cancer cell death. In conclusion, FA-Lip-TGX221 is a promising nano-delivery vehicle for the treatment of PCa, and also provide valuable references for all tumors overexpressing folate receptors.
Insights
This study introduces FA-Lip-TGX221, a novel liposomal delivery system targeting prostate cancer (PCa). This system enhances drug delivery and promotes cancer cell death by activating endoplasmic reticulum stress.
Area of Science:
- Oncology
- Nanotechnology
- Biochemistry
Background:
- Prostate cancer (PCa) is a leading cause of cancer death globally.
- Overactivation of PI3K signaling is implicated in PCa development.
- TGX221, a PI3K inhibitor, has limited clinical use due to poor solubility.
Purpose of the Study:
- To develop a targeted drug delivery system for PCa treatment.
- To overcome the solubility limitations of TGX221.
- To investigate the efficacy of a novel liposomal formulation.
Main Methods:
- Development of folate receptor-targeted, pH-sensitive liposomes (FA-Lip-TGX221) encapsulating TGX221.
- Characterization of liposome particle size and stability.
- In vitro and in vivo evaluation of cellular uptake, drug release, and therapeutic effects in PCa models.
Main Results:
- FA-Lip-TGX221 exhibited uniform particle size and high stability.
- The formulation was effectively internalized by PC-3 cells via folate receptor targeting, leading to tumor accumulation.
- FA-Lip-TGX221 inhibited PI3K/110β signaling, activating the PERK-ATF4-CHOP pathway and inducing endoplasmic reticulum stress-mediated cancer cell death.
Conclusions:
- FA-Lip-TGX221 is a promising nano-delivery vehicle for PCa treatment.
- This approach offers a potential therapeutic strategy for tumors overexpressing folate receptors.
- The study provides valuable insights into targeted cancer therapy.
