Meikle S T, Piñeiro Y, Bañobre López M, Rivas J, Santin M
Brighton Studies in Tissue-mimicry and Aided Regeneration, Brighton Centre for Regenerative Medicine, University of Brighton, Brighton BN2 4GJ, UK.
Department of Applied Physics, University of Santiago de Compostela University, Santiago de Compostela E15782, Spain.
Acta Biomater. 2016 Aug;40:235-242. doi: 10.1016/j.actbio.2016.04.043. Epub 2016 Apr 28.
UNLABELLED: Vascular endothelial growth factor (VEGF) is the growth factor responsible for the triggering of angiogenesis, the process of blood vessel formation supporting the long-term viability of any repaired or regenerated tissue. As the growth factor is effective only when concentration gradients are generated, new shuttles need to be developed that ensure both the control of gradients at the site of tissue repair and the release of VEGF at physiological levels. Magnetic hyperthermia is the production of heat induced by magnetic materials through their exposure to an external oscillating magnetic field. In this paper, magnetic nanoparticles capable of generating controllable hyperthermia were functionalised with hyperbranched poly(epsilon-lysine) peptides integrating in their core parallel thermoresponsive elastin-like peptide sequences and presenting an uppermost branching generation tethered by the zwitterionic amino acid carboxybetaine. The results show that these functionalised magnetic nanoparticles avidly bind VEGF and release it only upon generation of mild-hyperthermic pulses generated by oscillating magnetic filed. The VEGF release occurred in a temperature range at which the elastin-like peptides collapse. It is proposed that, through the application of an external magnetic field, these magnetic carriers could generated gradients of VEGF in vivo and allow its tuned delivery in a number of clinical applications. STATEMENT OF SIGNIFICANCE: The present paper for the first time reveals the possibility to control the delivery of VEGF through mild hyperthermia stimuli generated by a oscillating magnetic field. To this purpose, magnetic nanoparticles of high size homogeneity and coated with a thin coating of poly(acrylic acid) were functionalised with a novel class of poly(epsilon lysine) dendrimers integrating in their structure a thermoresponsive amino acid sequence mimicking elastin and exposing at high density a zwitterionic modified amino acid, the carboxybetaine, known to be able to bind macromolecules. Physicochemical and biochemical characterisation elegantly show the link between the thermal properties of the nanoparticles and of the dendrimer change of conformation and how this enable the release of VEGF at temperature values compatible with the growth factor stability.
未标注:血管内皮生长因子(VEGF)是负责触发血管生成的生长因子,血管生成是支持任何修复或再生组织长期存活的血管形成过程。由于该生长因子仅在产生浓度梯度时才有效,因此需要开发新的载体,以确保在组织修复部位控制梯度并以生理水平释放VEGF。磁热疗是磁性材料通过暴露于外部振荡磁场而产生热量。在本文中,能够产生可控热疗的磁性纳米颗粒用超支化聚(ε-赖氨酸)肽进行功能化,该肽在其核心整合了平行的热响应弹性蛋白样肽序列,并呈现由两性离子氨基酸羧基甜菜碱连接的最上层支化代。结果表明,这些功能化的磁性纳米颗粒能 avidly 结合VEGF,并且仅在振荡磁场产生的温和热脉冲时才释放它。VEGF释放发生在弹性蛋白样肽塌陷的温度范围内。有人提出,通过施加外部磁场,这些磁性载体可以在体内产生VEGF梯度,并允许其在许多临床应用中进行调节递送。 意义声明:本文首次揭示了通过振荡磁场产生的温和热刺激来控制VEGF递送的可能性。为此,具有高尺寸均匀性并涂有聚丙烯酸薄涂层的磁性纳米颗粒用一类新型的聚(ε-赖氨酸)树枝状大分子进行功能化,该树枝状大分子在其结构中整合了模拟弹性蛋白的热响应氨基酸序列,并以高密度暴露两性离子修饰的氨基酸羧基甜菜碱,已知其能够结合大分子。物理化学和生物化学表征优雅地显示了纳米颗粒的热性质与树枝状大分子构象变化之间的联系,以及这如何使VEGF在与生长因子稳定性相容的温度值下释放。
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