癌细胞与材料表面的相互作用是生物界面化学研究中的前沿热点之一，对肿瘤诊断、抗癌药物筛选等研究具有重要意义。在国家自然科学基金委、科技部和中国科学院的大力支持下，中国科学院化学研究所有机固体重点实验室的科研人员，在生物界面上癌细胞的特异识别与粘附调控方面取得了重要进展。
受免疫细胞与肿瘤细胞的特异粘附界面启发，相关实验人员不再将细胞简化成理想的球体，而是还原其多尺度性，提出了结构匹配和分子识别的协同细胞粘附的研究思路，打破了传统上仅仅对分子水平识别的局限，设计制备了与癌细胞结构尺寸匹配的硅纳米线阵列表面，有效提高了靶向肿瘤细胞的捕获效率(Angew. Chem. Int. Ed. 2009， 48， 8970)，并将微流控技术和硅纳米线细胞粘附界面相结合，实现了高于97%的细胞捕获效率(Angew. Chem. Int. Ed. 2011， 50， 3084)。
在此基础上，研究人员将对血癌细胞特异性识别的核酸适配体修饰到硅纳米线阵列上，建立了一个酶响应的“高捕获易释放”的细胞检测平台(Adv. Mater. 2011， 23， 4376)。为了建立更普适响应界面，研究人员将生物相容性好的热响应性的聚（N-异丙基丙烯酰胺）引入到硅纳米线表面上，实现了温度响应的高效捕获与有效释放的癌细胞粘附可控界面(Adv. Mater. 2013，25， 922， 图1)。该表面设计的独特之处是利用牛血清蛋白易于吸附到疏水表面，而在亲水表面是去吸附的特点。以牛血清蛋白为桥，介导癌细胞特异性抗体在界面上的吸附与去吸附。而热响应聚合物在体温疏水，室温亲水。这样，通过牛血清蛋白与界面之间的疏水相互作用，就实现了抗体在表面的吸附和去吸附。相应的，在体温下就可以对癌细胞进行特异性识别粘附，在室温下可将捕获的癌细胞释放下来。另外，牛血清蛋白本身有抗非特异粘附的特点，从而降低了非靶向细胞的非特异粘附。该研究提供了一个无损的“高粘附易释放”的细胞检测平台，使捕获后释放细胞的存活率高达95.3 ± 1.2%。
图1 温度响应的“高粘附易释放”的癌细胞检测平台
进一步，研究人员通过表面引发的链转移聚合反应将苯硼酸基聚合物刷引入到硅纳米线表面，制备了对pH值和葡萄糖双重响应界面(J. Am. Chem. Soc. 2013， 135， 7603， 图2)。当pH 6.8时，苯硼酸聚合物与癌细胞表面的唾液酸残基的结合常数远大于苯硼酸聚合物与葡萄糖的结合常数，从而可以特异性癌细胞粘附。而当pH值升高到7.8时，苯硼酸聚合物与葡萄糖之间的结合常数大于其与唾液酸之间的结合常数，使粘附的癌细胞可以从表面释放下来。这样通过改变pH值和葡萄糖浓度，就实现了双响应的癌细胞特异粘附和去粘附的有效调控。同时，这个温和调控过程对细胞没有明显的损伤，细胞活性保持在95%以上。该研究为复杂生命体系中癌症检测与靶向药物传输提供了理论基础。
图2 利用不同pH值下苯硼酸聚合物对唾液酸和葡萄糖的结合常数的改变，设计制备了pH值和葡萄糖双重响应的癌细胞可控粘附纳米界面
相关研究成果发表后引起了广泛关注，被Wiley出版社选为Hot Topics，并被MaterialsViews、MaterialsViewsChina以及Global Medical Discovery作为新闻亮点进行了报道（生物谷Bioon.com）。
生物谷推荐的英文摘要
Advanced Materials doi: 10.1002/adma.201300888
Programmable fractal nanostructured interfaces for specific recognition and electrochemical release of cancer cells
Zhang P， Chen L， Xu T， Liu H， Liu X， Meng J， Yang G， Jiang L， Wang S.
Topographic recognition of cancer cells is triggered by fractal gold nanostructures (FAuNSs)， leading to dramatically enhanced recognition capability and efficient release of cancer cells with little damage. The unique characteristic of FAuNSs is the similar fractal dimension of their surface and that of a cancer cell. The design of fractal nanostructures will open up opportunities for functional design of bio-interfaces for highly efficient recognition and release of disease-related rare cells， which will improve detection in a clinical environment.
Journal of the American Chemical Society DOI: 10.1021/ja401000m
Dual-Responsive Surfaces Modified with Phenylboronic Acid-Containing Polymer Brush To Reversibly Capture and Release Cancer Cells
Hongliang Liu ， Yingying Li ， Kang Sun ， Junbing Fan ， Pengchao Zhang ， Jingxin Meng ， Shutao Wang *， and Lei Jiang
Artificial stimuli-responsive surfaces that can mimic the dynamic function of living systems have attracted much attention. However， there exist few artificial systems capable of responding to dual- or multistimulation as the natural system does. Herein， we synthesize a pH and glucose dual-responsive surface by grafting poly(acrylamidophenylboronic acid) (polyAAPBA) brush from aligned silicon nanowire (SiNW) array. The as-prepared surface can reversibly capture and release targeted cancer cells by precisely controlling pH and glucose concentration， exhibiting dual-responsive AND logic. In the presence of 70 mM glucose， the surface is pH responsive， which can vary from a cell-adhesive state to a cell-repulsive state by changing the pH from 6.8 to 7.8. While keeping the pH at 7.8， the surface becomes glucose responsive—capturing cells in the absence of glucose and releasing cells by adding 70 mM glucose. Through simultaneously changing the pH and glucose concentration from pH 6.8/0 mM glucose to pH 7.8/70 mM glucose， the surface is dual responsive with the capability to switch between cell capture and release for at least 5 cycles. The cell capture and release process on this dual-responsive surface is noninvasive with cell viability higher than 95%. Moreover， topographical interaction between the aligned SiNW array and cell protrusions greatly amplifies the responsiveness and accelerates the response rate of the dual-responsive surface between cell capture and release. The responsive mechanism of the dual-responsive surface is systematically studied using a quartz crystal microbalance， which shows that the competitive binding between polyAAPBA/sialic acid and polyAAPBA/glucose contributes to the dual response. Such dual-responsive surface can significantly impact biomedical and biological applications including cell-based diagnostics， in vivo drug delivery， etc.
