Abstract
Glioblastoma multiforme (GBM) is the most common lethal primary brain malignancy without reliable therapeutic drugs. IL-13Rα2 is frequently expressed in GBMs as a molecular marker. Resveratrol (Res) effectively inhibits GBM cell growth but has not been applied in vivo because of its low brain bioavailability when administered systemically. A sustained-release and GBM-targeting resveratrol form may overcome this therapeutic dilemma. To achieve this goal, encapsulated Res 30 ± 4.8 nm IL-13Rα2-targeting nanoparticles (Pep-PP@Res) were constructed. Ultraviolet spectrophotometry revealed prolonged Res release (about 25%) from Pep-PP@Res in 48 h and fluorescent confocal microscopy showed the prolonged intracellular Res retention time of Pep-PP@Res (>24 h) in comparison with that of free Res (<4 h) and PP@Res (<4 h). MTT and EdU cell proliferation assays showed stronger suppressive effects of Pep-PP@Res on rat C6 GBM cells than that of PP@Res (p = 0.024) and Res (p = 0.009) when used twice for 4 h/day. Pep-PP@Res had little toxic effect on normal rat brain cells. The in vivo anti-glioblastoma effects of Res can be distinctly improved in the form of Pep-PP@Res nanoparticles via activating JNK signaling, upregulating proapoptosis gene expression and, finally, resulting in extensive apoptosis. Pep-PP@Res with sustained release and GBM-targeting properties would be suitable for in vivo management of GBMs.
Highlights
Glioblastoma multiforme (GBM) is the most common primary brain malignancy with extremely poor prognosis [1,2]
IL-13Rα2-positive labeling was observed in the cytoplasm and on the membranes of both rat C6 GBM cells but not in the astrocytes (Figure 1A)
Distinct IL-13Rα2 immunohistochemical labeling was observed in human GBM cells in the similar staining pattern of C6 cells (Figure 1D)
Summary
Glioblastoma multiforme (GBM) is the most common primary brain malignancy with extremely poor prognosis [1,2]. Surgical resection combined with radiotherapy and/or chemotherapy is the preferred treatment for GBMs [3]. The current median survival time of GBM patients is only 12–16 months, and the five-year survival rate is less than 10% [4,5]. Combination of tumor treatment fields (TTField) with temozolomide (TMZ) increases twoyear relative survival (RS) rates of GBM patients [7], while persistent administration of TMZ may cause secondary drug resistance, resulting in tumor recurrence and patient death [8].
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