超pH敏感荧光纳米探针的pH转变点对其肿瘤成像效果的影响

The effect of pH transition points of ultra-pH sensitive fluorescent nanoprobes on tumor imaging efficiency

在荧光引导的肿瘤手术治疗中,基于肿瘤偏酸性微环境而设计的超pH敏感(ultra-pH sensitive,UPS)荧光纳米探针具有实时、超高灵敏度和适用于多种肿瘤等多重优势,而受到广泛关注。超pH敏感探针在高pH环境下处于“OFF”状态,在低pH环境下转变成“ON”状态,发出强烈荧光,并可通过结构设计精确控制其pH转变点(transi‐tion pH point,pH_(t))。目前已报道的UPS纳米探针具有良好成像效果,然而由于肿瘤微酸环境的复杂性,尚不清楚UPS纳米探针的pH_(t)对其肿瘤成像效果的影响。在本研究中,通过调节UPS聚合物中疏水性嵌段的结构,分别合成pH_(t)为4.5、6.2、6.6和7.8的UPS纳米探针。动态光散射检测显示,合成的UPS纳米探针在“OFF”状态下具有良好的稳定性。透射电子显微镜检测表明,该纳米探针粒径均一且形态完整。体外的成像效果检测显示,其都能够较为灵敏地响应pH的变化,在环境pH<pH_(t)时被激活,发出强烈荧光。体内小动物活体成像结果表明,pH_(t)为6.2和6.6的两种超pH敏感纳米探针具有较好肿瘤成像效果。所有动物实验均经过北京大学医学部动物伦理委员会批准,严格遵循北京大学医学部实验动物福利规定。本研究筛选出具有良好成像效果的UPS纳米探针,并为其他肿瘤微环境响应型纳米探针的设计和筛选提供新的思路。

During fluorescence-guided cancer surgery,ultra-pH sensitive(UPS)fluorescent nanoprobes has multiple advantages such as real-time imaging procedures,ultra-high imaging sensitivity as well as broad tumor detection specificity.UPS nanoprobes stay at"OFF"state at higher pH and turn into"ON"state at lower pH with emission of strong fluorescence.Moreover,the transition pH points(transition pH point,pH_(t))can be precisely controlled by structural-based strategy.One of the previously-reported UPS nanoprobes showed good imaging effect.However,it is still not clear about the effect of pH_(t) on cancer imaging efficiency of UPS nanoprobes and to further identify the optimal UPS.In this study,we synthesized a series of UPS nanoprobes with pH_(t) at 4.5,6.2,6.6,7.8 by adjusting the hydrophobic blocks of UPS polymers.Each nanoprobe showed excellent stability in"OFF"state by dynamic light scattering and uniform morphology observed by transmission electron microscopy.In vitro imaging characterized the ultra-pH sensitive fluorescence transition of each probe.In vivo imaging results identified two UPS nanoprobes(NP-6.2 and NP-6.6)with superior tumor imaging effect.All animal experiments in this study were approved by the Animal Ethics Committee of Peking University Health Science Center and were strictly followed by the welfare regulations of laboratory animals of Peking University Health Science Center.Therefore,this study has explored the effect of pH_(t) on the cancer imaging efficiency of UPS nanoprobes and provides a new idea for design of the other cancer microenvironment-responsive polymers.