Ability of co-administered peptide liposome nanoparticles to exploit tumour acidity for drug delivery
Ability of co-administered peptide liposome nanoparticles to exploit tumour acidity for drug delivery
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共同施用的肽脂质体纳米颗粒利用肿瘤酸度进行药物输送的能力
DOI：
10.1039/c3ra44746d
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Offerman S
中科院分区：
文献类型：
--
作者：
Offerman S
使用先前表征的实体瘤模型，我们证明了pH敏感肽和脂质体纳米颗粒（PLN）的混合物可用于响应于肿瘤酸度的微小变化而诱导有效载荷释放。在两个不同的位置修饰经典的pH敏感性GALA肽，以帮助与预先形成的脂质体连接，并响应于pH从生理值下降小于1.0单位而引起钙黄绿素标记物的释放。肽的圆二色性光谱表明，与GALA序列不同，其螺旋结构不寻常地独立于pH，这表明钙黄绿素释放的不同作用机制。静脉内施用PLN在小鼠的肿瘤组织中积累，并且将切除的肿瘤组织切片置于低pH缓冲液中证实这些纳米颗粒保持pH响应性。植入小鼠背部皮肤的肿瘤的定量体内成像允许纳米颗粒积累的真实的时间测量，通过脂质体膜的DiI标记监测，以及肿瘤内pH依赖性释放，通过钙黄绿素释放监测，随后进行。用MIBG葡萄糖处理以诱导肿瘤酸化至约pH 6.5，进一步增强了活肿瘤中在其天然酸度pH 6.8下钙黄绿素的释放。与施用缺乏肽的脂质体的对照肿瘤或未用MIBG处理的肿瘤相比，在施用PLN并使用MIBG处理进行pH降低的肿瘤中观察到累积后显著更大和更快的钙黄绿素释放。这项工作突出表明，虽然PLN对内在肿瘤pH相对无反应，但它们确实有能力对接近病理生理范围的外部诱导的pH微小变化迅速作出反应。
Using a previously-characterised solid tumour model we demonstrate that a mixture of pH sensitive peptide and liposome nanoparticles (PLNs) can be used to induce payload release in response to small changes in tumour acidity. The classical pH sensitive GALA peptide was modified at two different positions to help tether with preformed liposomes and cause release of calcein marker in response to a less than 1.0 unit drop in pH from the physiological value. The circular dichroic spectra of the peptide showed that, unlike the GALA sequence, its helical structure was unusually independent of pH suggesting a different mechanism of action for calcein release. Intravenously-administered PLNs accumulated in tumour tissue in mice, and subjecting the excised tumour tissue slices to low pH buffer confirmed that these nanoparticles remained pH responsive. Quantitative in vivo imaging of tumours implanted in mouse dorsal skin allowed real time measurements of nanoparticle accumulation, monitored through DiI labelling of the liposome membrane, and intra-tumour pH dependent release, monitored by calcein release, to be followed. The release of calcein in the live tumours at their natural acidity of pH 6.8 was further enhanced with MIBG glucose treatment to induce tumour acidification to approximately pH 6.5. Following accumulation a substantially greater and more rapid calcein release was observed in tumours administered with PLNs and subjected to pH-lowering using MIBG treatment, compared to control tumours administered with liposomes lacking the peptide or tumours not treated with MIBG. This work highlights that while PLNs were relatively unresponsive to intrinsic tumour pH, they did have the ability to respond rapidly to extrinsically-induced small changes in pH near the patho-physiological range.
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