Bioresponsive cancer-targeted polysaccharide nanosystem to inhibit angiogenesis

Abstract

With many desirable features, such as being more effective and having multiple effects, antiangiogenesis has become one of the promising cancer treatments. The aim of this study was to design and synthesize a new targeted bioresponsive nanosystem with antiangiogenesis properties. The mUPR@Ru(POP) nanosystem was constructed by the polymerization of Ulva lactuca polysaccharide and N-isopropyl acrylamide, decorated with methoxy polyethylene glycol and Arg–Gly–Asp peptide, and encapsulated with anticancer complex [Ru(phen)2p-MOPIP](PF₆)₂·2H₂O. The nanosystem was both pH responsive and targeted. Therefore, the cellular uptake of the drug was greatly improved. Moreover, the mUPR@Ru(POP) had strong suppressive effects against vascular endothelial growth factor (VEGF)-induced angiogenesis through apoptosis. The mUPR@Ru(POP) significantly inhibited VEGF-induced human umbilical vein endothelial cell migration, invasion, and tube formation. These findings have presented new insights into the development of antiangiogenesis drugs.

Keywords:

• polysaccharide nanosystem
• antiangiogenesis
• cancer-targeted
• bioresponsive

Acknowledgments

This work was supported by the Natural Science Foundation of China (21401076, 21271002), National High Technology Research and Development Program of China (863 Program, SS2014AA020538), Science Foundation for Distinguished Young Scholars (S2013050014667) of Guangdong Province, Foundation for High-level Talents in Higher Education of Guangdong, YangFan Innovative & Entrepreneurial Research Team Project (201312H05), Guangdong Special Support Program, and Guangdong Frontier and Key Technological Innovation Special Funds.

Disclosure

The authors report no conflicts of interest in this work.

Supplementary materials

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 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 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.