Abstract
Oridonin (ORI) has been shown to inhibit tumor cell growth and proliferation in vitro, while its optimum anti-tumor activity in vivo is limited due to the poor aqueous solubility and bioavailability. In this study, to improve the bioavailability, we developed a nanoparticle-based drug delivery system to facilitate delivery of ORI to breast tumor. ORI was encapsulated in biodegradable nanoparticles (NPs) based on poly-lactic-co-glycolic acid (PLGA) and polyethylene glycol (PEG) to form ORI NPs (ORI-NPs). The resulting ORI-NPs exhibited a mean particle diameter of 100 nm and displayed an efficient cellular uptake by human breast cancer MCF-7 cells. Compared to free ORI that showed no effects on tumor cell proliferation, the ORI-NPs showed significant cytotoxicity and delayed endothelial cell migration, tube formation and angiogenesis. Pharmacokinetics studies showed that ORI-NPs significantly increased the half-life of ORI in the blood circulation. In the nude mouse xenograft model, ORI-NPs markedly inhibited tumor growth and angiogenesis, while ORI did not show any inhibitory effects on the growth of tumor xenografts. The mechanism experiments showed that the antitumor activity of ORI-NPs against breast cancer might be through ROS related Nrf2/HO-1 signaling pathway. Together, these results demonstrated that ORI-loaded PEG-PLGA NPs enhanced bioactivity and bioavailability in vivo over ORI, indicating that ORI-NPs may represent a promisingly effective candidate against breast cancer.
Highlights
Breast cancer is one of the most common cancers diagnosed among women in the world and the second leading cause of cancer death among women after lung cancer (DeSantis et al, 2014)
ORI was encapsulated in poly-lactic-coglycolic acid (PLGA)-polyethylene glycol (PEG) polymer to form nanoparticles (ORI-NPs) with double emulsion method
The incorporation efficiency of drug in ORI NPs (ORI-NPs) was determined with high pressure liquid chromatography (HPLC) assay which showed that the incorporation efficiency of ORI in NPs is about 60%
Summary
Breast cancer is one of the most common cancers diagnosed among women in the world and the second leading cause of cancer death among women after lung cancer (DeSantis et al, 2014). Most deaths related to breast cancer are caused by metastases in vital organs. The tumor microenvironment is critical for cancer progression, such as growth, dissemination and metastasis (Bonapace et al, 2014). Oridonin Nanoparticles Inhibit Breast Tumor by interaction with tumor cells or formation of blood vessel. The newly formed blood vessels carry oxygen and nutrients to growing tumors, facilitating progression and metastasis. The role of tumor angiogenesis has been demonstrated in many preclinical models and clinical trials, including breast cancer (Batlle et al, 2019; Faulkner et al, 2019; Lang et al, 2019). Anti-angiogenic agent is another kind of promising drug in addition to commonly used cytotoxic anticancer agents for the treatment of breast cancer
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