Abstract
BackgroundGlioblastoma (GBM) is the most common and fatal primary tumor in the central nervous system (CNS). Due to the existence of blood–brain barrier (BBB), most therapeutics cannot efficiently reach tumors in the brain, and as a result, they are unable to be used for effective GBM treatment. Accumulating evidence shows that delivery of therapeutics in form of nanoparticles (NPs) may allow crossing the BBB for effective GBM treatment.MethodsBetulinic acid NPs (BA NPs) were synthesized by the standard emulsion approach and characterized by electron microscopy and dynamic light scattering analysis. The resulting NPs were characterized for their anti-tumor effects by cell viability assay, EdU-DNA synthesis assay, cell cycle assay, mitochondrial membrane potential, and PI-FITC apoptosis assay. Further mechanistic studies were carried out through Western Blot and immunostaining analyses. Finally, we evaluated BA NPs in vivo for their pharmacokinetics and antitumor effects in intracranial xenograft GBM mouse models.ResultsBA NPs were successfully prepared and formed into rod shape. BA NPs could significantly suppress glioma cell proliferation, induce apoptosis, and arrest the cell cycle in the G0/G1 phase in vitro. Furthermore, BA NPs downregulated the Akt/NFκB-p65 signaling pathway in a concentration dependent manner. We found that the observed anti-tumor effect of BA NPs was dependent on the function of CB1/CB2 receptors. Moreover, in the intracranial GBM xenograft mouse models, BA NPs could effectively cross the BBB and greatly prolong the survival time of the mice.ConclusionsWe successfully synthesized BA NPs, which could cross the BBB and demonstrated a strong anti-tumor effect. Therefore, BA NPs may potentially be used for effective treatment of GBM.Graphical
Highlights
Glioblastoma (GBM) is the most common, malignant, and fatal primary tumor in the central nervous system (CNS), accounting for approximately 50% of all gliomas [1]
Using high performance liquid chromatography (HPLC), we found that 85% of Betulinic acid NPs (BA NPs) remain in the form of nanoparticles after being stored at room temperature for seven days (Additional file 1: Fig. S2)
We found that the signal in tumors increased significantly, which indicated that Betulinic acid (BA) NP could reach the brain tumor tissue through blood-brain barrier (BBB) compared with PLGA-IR780 NPs and free IR780 (Fig. 5F; Additional file 1: Fig. S11)
Summary
Glioblastoma (GBM) is the most common, malignant, and fatal primary tumor in the central nervous system (CNS), accounting for approximately 50% of all gliomas [1]. Increasing the dose of glioma-treating drugs has been shown to result in increased systemic toxicity and is not an option for GBM treatment [6]. Identifying a drug that can efficiently pass through the systemic circulation, cross the BBB, and enter into the tumor parenchyma is urgently needed for improved GBM treatment. Glioblastoma (GBM) is the most common and fatal primary tumor in the central nervous system (CNS). Due to the existence of blood–brain barrier (BBB), most therapeutics cannot efficiently reach tumors in the brain, and as a result, they are unable to be used for effective GBM treatment. Accumulating evidence shows that delivery of therapeutics in form of nanoparticles (NPs) may allow crossing the BBB for effective GBM treatment
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