Triptolide-nanoliposome-APRPG, a novel sustained-release drug delivery system targeting vascular endothelial cells, enhances the inhibitory effects of triptolide on laser-induced choroidal neovascularization

• Published in: Biomedicine & pharmacotherapy Vol. 131; p. 110737
• Main Authors: Lai, Kunbei, Li, Yingqin, Gong, Yajun, Li, Longhui, Huang, Chuangxin, Xu, Fabao, Zhong, Xiaojing, Jin, Chenjin
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-11-2020; Elsevier
• Subjects: Animals; APRPG; Cell Movement - drug effects; Choroidal neovascularization; Choroidal Neovascularization - etiology; Choroidal Neovascularization - prevention & control; Delayed-Action Preparations; Diterpenes - administration & dosage; Diterpenes - chemistry; Diterpenes - pharmacokinetics; Drug Liberation; Endothelial Cells - drug effects; Epoxy Compounds - administration & dosage; Epoxy Compounds - chemistry; Epoxy Compounds - pharmacokinetics; Inflammation; Liposomes - chemistry; Macrophage; Macrophages - drug effects; Macrophages - physiology; Male; Mice; Mice, Inbred C57BL; Nanoliposome; Nanoparticles - chemistry; Oligopeptides - chemistry; Phenanthrenes - administration & dosage; Phenanthrenes - chemistry; Phenanthrenes - pharmacokinetics; Retina - drug effects; Triptolide; Vascular Endothelial Growth Factor A - analysis; Inflammation; APRPG; Choroidal neovascularization; Nanoliposome; Triptolide; Macrophage
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.110737

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•Intravitreal injections of triptolide inhibit choroidal neovascularization.•TP-nanolip-APRPG enhances the effects of triptolide on choroidal neovascularization.•TP-nanolip-APRPG significantly inhibits the expression of VEGF, ICAM-1, and MCP-1.•TP-nanolip-APRPG has therapeutic potential for treating choroidal neovascularization.
To investigate whether triptolide-nanoliposome-APRPG (TP-nanolip-APRPG), a novel sustained-release nano-drug delivery system that targets vascular endothelial cells, could enhance the inhibition of triptolide (TP) on laser-induced choroidal neovascularization (CNV).
TP was encapsulated with or without APRPG (Ala-Pro-Arg-Pro-Gly) peptide-modified nanoliposomes. CNV was induced by laser photocoagulation in C57BL/6J mice. One microliter of 10 μg free TP monomer, TP-nanolip containing 10 μg TP, TP-nanolip-APRPG containing 10 μg TP, or an identical volume of PBS was intravitreally injected in mice immediately after laser photocoagulation. Seven days after laser photocoagulation, CNV volumes were calculated in each group. Infiltration of M2 macrophages as well as protein levels of vascular endothelial growth factor (VEGF) and inflammatory factors including ICAM-1 and MCP-1 in the RPE-choroid complex were determined. In vitro assays for cell proliferation, migration, and tube formation were also performed.
TP-nanolip-APRPG was successfully synthesized and exhibited good TP delivery and enhanced the cellular uptake of TP in vitro. In vitro studies showed that TP-nanolip-APRPG was a better inhibitor of cell proliferation (31.34 ± 3.89 % vs 41.25 ± 4.67 % vs 53.55 ± 5.76 %), migration (62.60 ± 8.88 vs 104.60 ± 13.32 vs 147.00 ± 13.15), and tube formation (681.26 ± 108.15 vs 926.75 ± 54.01 vs 1189.84 ± 157.14) than TP-nanolip or free TP (all P < 0.05). Intravitreal injections of free TP (77588.10±7719.28 μm3), TP-nanolip (64628.23 ± 5857.96 μm3), and TP-nanolip-APRPG (50880.34 ± 6606.56 μm3) inhibited the development of CNV compared with the PBS control group (120338.07 ± 17428.90 μm3) (P < 0.01, n=6). TP-nanolip-APRPG and TP-nanolip significantly down-regulated the protein levels of VEGF (152.76±19.55 vs 182.24±19.98 vs 208.55±21.93 pg/mg total protein) and inflammatory factors including ICAM-1 (61.69±3.49 vs 72.04±3.49 vs 81.92±4.09 ng/mg total protein) and MCP-1 (40.14±3.50 vs 50.75±4.18 vs 60.27±5.23 pg/mg total protein) compared with the free TP monomer group (all P < 0.05, n=8), which paralleled the decreased infiltration of M2 macrophages in the CNV lesions. Moreover, no influence on retinal morphology and function was observed before or after treatment in each group (P > 0.05, n=6).
TP-nanolip-APRPG, a novel sustained-release drug delivery system targeting endothelial cells of CNV lesions, could enhance TP inhibition of the development of CNV without toxicity in the retina, suggesting therapeutic potential for CNV-related diseases in future clinical practice.