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. 2017 Jun 20;8(25):40906-40921.
doi: 10.18632/oncotarget.16641.

C-type natriuretic peptide-modified lipid vesicles: fabrication and use for the treatment of brain glioma

Jia-Shuan Wu  1 , Li-Min Mu  1 , Ying-Zi Bu  1 , Lei Liu  1 , Yan Yan  1 , Ying-Jie Hu  1 , Jing Bai  1 , Jing-Ying Zhang  1 , Weiyue Lu  1 , Wan-Liang Lu  1
Affiliations

C-type natriuretic peptide-modified lipid vesicles: fabrication and use for the treatment of brain glioma

Jia-Shuan Wu et al. Oncotarget. .

Abstract

Chemotherapy of brain glioma faces a major obstacle owing to the inability of drug transport across the blood-brain barrier (BBB). Besides, neovasculatures in brain glioma site result in a rapid infiltration, making complete surgical removal virtually impossible. Herein, we reported a novel kind of C-type natriuretic peptide (CNP) modified vinorelbine lipid vesicles for transferring drug across the BBB, and for treating brain glioma along with disrupting neovasculatures. The studies were performed on brain glioma U87-MG cells in vitro and on glioma-bearing nude mice in vivo. The results showed that the CNP-modified vinorelbine lipid vesicles could transport vinorelbine across the BBB, kill the brain glioma, and destroy neovasculatures effectively. The above mechanisms could be associated with the following aspects, namely, long circulation in the blood; drug transport across the BBB via natriuretic peptide receptor B (NPRB)-mediated transcytosis; elimination of brain glioma cells and disruption of neovasculatures by targeting uptake and cytotoxic injury. Besides, CNP-modified vinorelbine lipid vesicles could induce apoptosis of the glioma cells. The mechanisms could be related to the activations of caspase 8, caspase 3, p53, and reactive oxygen species (ROS), and inhibition of survivin. Hence, CNP-modified lipid vesicles could be used as a carrier material for treating brain glioma and disabling glioma neovasculatures.

Keywords: BBB; C-type natriuretic peptide; brain glioma; lipid vesicles; neovasculatures.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1. Synthesis of a CNP-TPGS1000 conjugate and characterization of CNP-modified lipid vesicles
Notes: (A) synthetic route of CNP-TPGS1000. (B1) MALDI-TOF-MS spectrum of COOH-TPGS1000; (B2) MALDI-TOF-MS spectrum of CNP-TPGS1000. (C1) TEM image of vinorelbine lipid vesicles (Bar = 100 nm); (C2) TEM image of CNP-modified vinorelbine lipid vesicles (Bar = 100 nm). (D) release rates of vinorelbine. Data are the mean ± standard deviation (n=3).
Figure 2
Figure 2. Transport across the co-cultured BBB
Notes: (A) in vitro co-culture BBB model. (B) NPRB expression in BMVECs is identified by confocal laser scanning microscopy; (B1) isotope control; (B2) anti-NPRB antibody. (C) NPRB expression in BMVECs is identified by flow cytometry; (C1) isotope control; (C2) anti-NPRB antibody. (D) transport across the BBB followed by killing of glioma cells; 1, free vinorelbine; 2, vinorelbine lipid vesicles; 3, CNP-modified vinorelbine lipid vesicles pretreated with Rp-8-CPT-cGMPS; 4, CNP-modified vinorelbine lipid vesicles. p < 0.05, a, vs. 1; b, vs. 2; c, vs. 3. Data are the mean ± standard deviation (n = 3). (E) CNP-modified vinorelbine lipid vesicles transporting across the BBB (schematic); E1, normal view; E2, enlarged view.
Figure 3
Figure 3. Targeting uptake by brain glioma cells and cytotoxicity
Notes: (A) NPRB expression in U87-MG cells identified by confocal laser scanning microscopy; (A1) isotope control; (A2) anti-NPRB antibody. (B) NPRB expression in U87-MG cells identified by flow cytometry; (B1) isotope control; (B2) anti-NPRB antibody. (C) cellular uptake in U87-MG cells; 1, blank control; 2, free coumarin; 3, coumarin lipid vesicles; 4, CNP-modified coumarin lipid vesicles. p < 0.05, a, vs. 1; b, vs. 2; c, vs. 3. Data are the mean ± standard deviation (n = 3). (D) toxicity to U87-MG cells. p < 0.05, d, vs. blank control; e, vs. free vinorelbine; f, vs. vinorelbine lipid vesicles. Data are the mean ± standard deviation (n = 6).
Figure 4
Figure 4. Apoptosis of brain glioma cells and mechanism of action
Notes: (A) induction of apoptotic effects on U87-MG cells. (B) ROS activity of U87-MG cells. (C1) activity of caspase 8; (C2) activity of caspase 3; (C3) activity of p53; (C4) activity of survivin. (D) mechanism of apoptosis in U87-MG cells (schematic). 1, blank control; 2, free vinorelbine; 3, vinorelbine lipid vesicles; 4, CNP-modified vinorelbine lipid vesicles. p < 0.05, a, vs. 1; b, vs. 2; c, vs. 3. Data are the mean ± standard deviation (n = 4).
Figure 5
Figure 5. Targeting and disruption of glioma neovasculatures in vitro
Notes: (A) NPRB expression in HUVECs identified by confocal laser scanning microscopy; (A1) isotope control; (A2) anti-NPRB antibody. (B) NPRB expression in HUVECs identified by flow cytometry; (B1) isotope control; (B2) anti-NPRB antibody. (C) cellular uptake in HUVECs; 1, blank control; 2, free coumarin; 3, coumarin lipid vesicles; 4, CNP-modified coumarin lipid vesicles. p < 0.05, a, vs. 1; b, vs. 2; c, vs. 3. Data are the mean ± standard deviation (n = 3). (D) inhibitory effects on HUVECs. p < 0.05, d, vs. blank control; e, vs. free vinorelbine; f, vs. vinorelbine lipid vesicles. Data are the mean ± standard deviation (n = 6). (E) destruction of neovasculatures in vitro after treatment with various formulations; (E1) blank control; (E2) free vinorelbine; (E3) vinorelbine lipid vesicles; (E4) CNP-modified vinorelbine lipid vesicles.
Figure 6
Figure 6. Real-time imaging and overall anticancer efficacy in glioma-bearing mice in vivo
Notes: (A) in vivo real-time images and ex vivo images of glioma-bearing brains and organs at 48 h; a, physiologic saline; b, free DiR; c, DiR lipid vesicles; d, CNP-modified DiR lipid vesicles. (B) disruptive effects on brain glioma neovasculatures in glioma-bearing mice. Glioma neovasculatures are indicated as green fluorescence stained by anti-CD31 antibody. White lines indicate the boundary between the brain-glioma region and normal brain tissue. (C) Kaplan–Meier survival curves of glioma-bearing mice treated with various formulations (n = 8). 1, physiologic saline; 2, free vinorelbine; 3, vinorelbine lipid vesicles; 4, CNP-modified vinorelbine lipid vesicles.
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