Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth
Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth
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DOI：
10.1073/pnas.0908401107
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发表时间：
2010-03-02
影响因子：
11.1
通讯作者：
Kostarelos, Kostas
中科院分区：
文献类型：
--
作者：
Al-Jamal, Khuloud T.;Al-Jamal, Wafa' T.;Kostarelos, Kostas
这项研究描述了以前未报道的多L赖氨酸(PLL)第六代(G(6))树枝状分子的内在能力，显示出全身性抗血管生成活性，可能导致实体瘤生长停滞。PLL-Dendrimer抑制SVEC4-10小鼠内皮细胞的小管形成和鸡胚绒毛尿囊膜(CAM)实验中的新生血管形成。将PLL-树状分子静脉注射到C57BL/6小鼠体内，可抑制皮下植入的Matrigel栓子的血管形成。通过对生长在背侧皮褶窗腔内的肿瘤进行活体显微镜观察，进一步证实了抗血管生成活性。尾静脉给药后，移植于SCID小鼠背侧窗腔的P22大鼠肉瘤的血管生成减少。PLL树枝状大分子。此外，在所研究的剂量范围内，PLL-树枝状大分子的体内毒理学特征被证明是安全的。进一步证明，PLL树枝状分子的抗血管生成活性与显著抑制B16F10实体瘤体积和延缓肿瘤生长有关。与鱼精蛋白治疗相比，仅PLL树枝状大分子治疗的动物肿瘤内的凋亡/坏死增加，CD31阳性细胞的数量减少。这项研究表明，PLL-树枝状大分子可以表现出全身性的抗血管生成活性，可以用于实体肿瘤的治疗，结合它们携带其他治疗或诊断药物的能力，可能会为治疗系统的设计提供潜在的能力。
This study describes the previously unreported intrinsic capacity of poly-L-lysine (PLL) sixth generation (G(6)) dendrimer molecules to exhibit systemic antiangiogenic activity that could lead to solid tumor growth arrest. The PLL-dendrimer-inhibited tubule formation of SVEC4-10 murine endothelial cells and neovascularization in the chick embryo chick chorioallantoic membrane (CAM) assay. Intravenous administration of the PLL-dendrimer molecules into C57BL/6 mice inhibited vascularisation in Matrigel plugs implanted subcutaneously. Antiangiogenic activity was further evidenced using intravital microscopy of tumors grown within dorsal skinfold window chambers. Reduced vascularization of P22 rat sarcoma implanted in the dorsal window chamber of SCID mice was observed following tail vein administration (i.v.) of the PLL dendrimers. Also, the in vivo toxicological profile of the PLL-dendrimer molecules was shown to be safe at the dose regime studied. The antiangiogenic activity of the PLL dendrimer was further shown to be associated with significant suppression of B16F10 solid tumor volume and delayed tumor growth. Enhanced apoptosis/necrosis within tumors of PLL-dendrimer-treated animals only and reduction in the number of CD31 positive cells were observed in comparison to protamine treatment. This study suggests that PLL-dendrimer molecules can exhibit a systemic antiangiogenic activity that may be used for therapy of solid tumors, and in combination with their capacity to carry other therapeutic or diagnostic agents may potentially offer capabilities for the design of theranostic systems.