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International Journal of Nanomedicine Volume 12, 2017 - Issue
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Original Research

Bioresponsive cancer-targeted polysaccharide nanosystem to inhibit angiogenesis

Fang YangDepartment of Chemistry, Jinan University, Guangzhou, ChinaCorrespondence[email protected] [email protected]
,
Xueyang FangDepartment of Chemistry, Jinan University, Guangzhou, China
,
Wenting JiangDepartment of Chemistry, Jinan University, Guangzhou, China
&
Tianfeng ChenDepartment of Chemistry, Jinan University, Guangzhou, ChinaCorrespondence[email protected] [email protected]
Pages 7419-7431 | Published online: 10 Oct 2017

Figures & data

Figure 1 (A, B) Design, delivery, and action mechanisms of bioresponsive cancer-targeted polysaccharide nanosystem to inhibit angiogenesis. (C) TEM images of mUPR@ Ru(POP). (D) Size distribution of mUPR@Ru(POP). (E) Changes in the particle size of mUPR@Ru(POP) following incubation with DMEM or 10% FBS; (F) FTIR spectra of (a) Ru(POP), (b) UP, (c) mUPR, and (d) mUPR@Ru(POP).

Abbreviations: FBS, fetal bovine serum; FTIR, Fourier transform infrared; HUVEC, human umbilical vein endothelial cell; mPEG, methoxy polyethylene glycol; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; TEM, transmission electron microscopy; Ru(POP), [Ru(phen)2p-MOPIP] (PF6)2·2H2O; UL, Ulva lactuca; UP, UL polysaccharide-NIPAM.

Figure 1 (A, B) Design, delivery, and action mechanisms of bioresponsive cancer-targeted polysaccharide nanosystem to inhibit angiogenesis. (C) TEM images of mUPR@ Ru(POP). (D) Size distribution of mUPR@Ru(POP). (E) Changes in the particle size of mUPR@Ru(POP) following incubation with DMEM or 10% FBS; (F) FTIR spectra of (a) Ru(POP), (b) UP, (c) mUPR, and (d) mUPR@Ru(POP).Abbreviations: FBS, fetal bovine serum; FTIR, Fourier transform infrared; HUVEC, human umbilical vein endothelial cell; mPEG, methoxy polyethylene glycol; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; TEM, transmission electron microscopy; Ru(POP), [Ru(phen)2p-MOPIP] (PF6)2·2H2O; UL, Ulva lactuca; UP, UL polysaccharide-NIPAM.

Figure 2 (A) Zeta potential of mUPR@Ru(POP) at different pH values. (B) TEM images of mUPR@Ru(POP) at pH 7.4 and 5.3. (C) Quantitative cellular uptake of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) in HUVECs (2×105 cells/mL). HUVECs were treated with Ru(POP) (10 μg/mL), mUP@Ru(POP) (10 μg/mL), and mUPR@Ru(POP) (10 μg/mL) for different periods of time. The concentrations of Ru(POP) were determined by ICP-MS. (D) Change in the particle size of mUPR@Ru(POP) with pH value. (E) In vitro drug release of Ru(POP) from mUPR@Ru(POP) in different solution. (F) The cell viability of HUVECs treated with different concentrations of Ru(POP), mUP@ Ru(POP), and mUPR@Ru(POP) for 72 h. Each value represents mean ± SD (n=3).

Abbreviations: HUVEC, human umbilical vein endothelial cell; ICP-MS, inductively coupled plasma mass spectrometry; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; TEM, transmission electron microscopy; UL, Ulva lactuca.

Figure 2 (A) Zeta potential of mUPR@Ru(POP) at different pH values. (B) TEM images of mUPR@Ru(POP) at pH 7.4 and 5.3. (C) Quantitative cellular uptake of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) in HUVECs (2×105 cells/mL). HUVECs were treated with Ru(POP) (10 μg/mL), mUP@Ru(POP) (10 μg/mL), and mUPR@Ru(POP) (10 μg/mL) for different periods of time. The concentrations of Ru(POP) were determined by ICP-MS. (D) Change in the particle size of mUPR@Ru(POP) with pH value. (E) In vitro drug release of Ru(POP) from mUPR@Ru(POP) in different solution. (F) The cell viability of HUVECs treated with different concentrations of Ru(POP), mUP@ Ru(POP), and mUPR@Ru(POP) for 72 h. Each value represents mean ± SD (n=3).Abbreviations: HUVEC, human umbilical vein endothelial cell; ICP-MS, inductively coupled plasma mass spectrometry; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; TEM, transmission electron microscopy; UL, Ulva lactuca.

Figure 3 Colocalization of mUPR@Ru(POP) (green fluorescence), Lyso-Tracker (red fluorescence), and DAPI (blue fluorescence) in HUVECs with an observation period of 8 h.

Abbreviations: DAPI, 4′,6-diamidino-2-phenylindole; HUVECs, human umbilical vein endothelial cells; mPEG, methoxy polyethylene glycol; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca.

Figure 3 Colocalization of mUPR@Ru(POP) (green fluorescence), Lyso-Tracker (red fluorescence), and DAPI (blue fluorescence) in HUVECs with an observation period of 8 h.Abbreviations: DAPI, 4′,6-diamidino-2-phenylindole; HUVECs, human umbilical vein endothelial cells; mPEG, methoxy polyethylene glycol; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca.

Figure 4 (A) Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) (1 μM) inhibited VEGF-induced HUVEC (2×105 cells/mL) migration. (B) mUPR@Ru(POP) (1 μM) inhibited VEGF-induced HUVEC (5×104 cells/mL) invasion. (C) Antiangiogenesis assay mUPR@Ru(POP) (1 μM) on HUVECs (5×104 cells/mL). (D) Representative images of angiogenesis inhibition of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) (30 μM) in CAM assay with VEGF.

Abbreviations: CAM, chorioallantoic membrane; HUVEC, human umbilical vein endothelial cell; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; UL, Ulva lactuca; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; VEGF, vascular endothelial growth factor.

Figure 4 (A) Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) (1 μM) inhibited VEGF-induced HUVEC (2×105 cells/mL) migration. (B) mUPR@Ru(POP) (1 μM) inhibited VEGF-induced HUVEC (5×104 cells/mL) invasion. (C) Antiangiogenesis assay mUPR@Ru(POP) (1 μM) on HUVECs (5×104 cells/mL). (D) Representative images of angiogenesis inhibition of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) (30 μM) in CAM assay with VEGF.Abbreviations: CAM, chorioallantoic membrane; HUVEC, human umbilical vein endothelial cell; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; UL, Ulva lactuca; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; VEGF, vascular endothelial growth factor.

Figure 5 Effects of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) on HUVEC cycle distribution for 72 h.

Abbreviations: HUVEC, human umbilical vein endothelial cell; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; UL, Ulva lactuca; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O.

Figure 5 Effects of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) on HUVEC cycle distribution for 72 h.Abbreviations: HUVEC, human umbilical vein endothelial cell; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; UL, Ulva lactuca; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O.

Scheme 1 Scheme of synthesis of mUPR@Ru(POP).

Abbreviations: APS, ammonium persulfate; EDC, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; MBA, 2-mercapto benzoic acid; mPEG, methoxy polyethylene glycol; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NHS, N-hydroxysuccinimide; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; RT, room temperature; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca; UP, UL polysaccharide-NIPAM.

Scheme 1 Scheme of synthesis of mUPR@Ru(POP).Abbreviations: APS, ammonium persulfate; EDC, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; MBA, 2-mercapto benzoic acid; mPEG, methoxy polyethylene glycol; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NHS, N-hydroxysuccinimide; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; RT, room temperature; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca; UP, UL polysaccharide-NIPAM.

Figure S1 The particle size of mUPR@Ru(POP) in 40 days.

Abbreviations: mPEG, methoxy polyethylene glycol; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca.

Figure S1 The particle size of mUPR@Ru(POP) in 40 days.Abbreviations: mPEG, methoxy polyethylene glycol; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca.

Figure S2 (A) Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) (1 μM) inhibited VEGF-induced HUVEC (5×104 cells/mL) invasion. (B) Antiangiogenesis assay of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) (1 μM) on HUVECs (5×104 cells/mL).

Note: Magnification is 100×.

Abbreviations: HUVEC, human umbilical vein endothelial cell; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca; VEGF, vascular endothelial growth factor.

Figure S2 (A) Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) (1 μM) inhibited VEGF-induced HUVEC (5×104 cells/mL) invasion. (B) Antiangiogenesis assay of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) (1 μM) on HUVECs (5×104 cells/mL).Note: Magnification is 100×.Abbreviations: HUVEC, human umbilical vein endothelial cell; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca; VEGF, vascular endothelial growth factor.

Figure S3 The relative reduction in the migrated cell numbers, invaded cell numbers, and capillary tube length suggested remarkable anti-metastasis effect of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP).

Note: The quantitative data were analyzed by manual counting (% of control).

Abbreviations: mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca; VEGF, vascular endothelial growth factor.

Figure S3 The relative reduction in the migrated cell numbers, invaded cell numbers, and capillary tube length suggested remarkable anti-metastasis effect of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP).Note: The quantitative data were analyzed by manual counting (% of control).Abbreviations: mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca; VEGF, vascular endothelial growth factor.

Figure S4 (A) Representative images of angiogenesis inhibition of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) (30 μM) in CAM assay without VEGF. (B) The relative quantitation of vascular density based on the CAM images.

Abbreviations: CAM, chorioallantoic membrane; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca; VEGF, vascular endothelial growth factor.

Figure S4 (A) Representative images of angiogenesis inhibition of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) (30 μM) in CAM assay without VEGF. (B) The relative quantitation of vascular density based on the CAM images.Abbreviations: CAM, chorioallantoic membrane; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca; VEGF, vascular endothelial growth factor.

Figure S5 Analysis of sub-G1 value obtained from flow cytometry.

Notes: (A) Effects of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) on HUVEC cycle distribution for 72 h. (B) Effects of different concentrations of mUPR@Ru(POP) on HUVEC cycle distribution for 72 h.

Abbreviations: HUVEC, human umbilical vein endothelial cell; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca.

Figure S5 Analysis of sub-G1 value obtained from flow cytometry.Notes: (A) Effects of Ru(POP), mUP@Ru(POP), and mUPR@Ru(POP) on HUVEC cycle distribution for 72 h. (B) Effects of different concentrations of mUPR@Ru(POP) on HUVEC cycle distribution for 72 h.Abbreviations: HUVEC, human umbilical vein endothelial cell; mPEG, methoxy polyethylene glycol; mUP, mPEG-UL polysaccharide-NIPAM; mUPR, mPEG-UL polysaccharide-NIPAM-RGD; NIPAM, N-isopropyl acrylamide; RGD, Arg–Gly–Asp; Ru(POP), [Ru(phen)2p-MOPIP](PF6)2·2H2O; UL, Ulva lactuca.

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