Here, we have exploited the heightened extracellular concentration of matrix metalloproteinase-9 (MMP-9) to induce surface-conversional properties of nanogels with the aim of tumor-specific enhanced cellular uptake. A modular polymeric nanogel platform was designed and synthesized for facile formulation and validation of MMP-9-mediated dePEGylation and generation of polyamine-type surface characteristics through peptide N-termini. Nanogels containing MMP-9-cleavable motifs and different poly(ethylene glycol) corona lengths (350 and 750 g/mol) were prepared, and enzymatic surface conversional properties were validated by MALDI characterization of cleaved byproducts, fluorescamine assay amine quantification, and zeta potential. The nanogel with a shorter PEG length, mPEG350-NG, exhibited superior surface conversion in response to extracellular concentrations of MMP-9 compared to that of the longer PEG length, mPEG750-NG. Confocal microscopy images of HeLa cells incubated with both fluorescein-labeled nanogels and DiI-encapsulated nanogels demonstrated greater uptake following MMP-9 “activation” for mPEG350-NG compared to its nontreated “passive” mPEG350-NG parent, demonstrating the versatility of such systems to achieve stimuli-responsive uptake in response to cancer-relevant proteases.

中文翻译：

---

基质金属蛋白酶9响应纳米凝胶的近端表面转化和激活的细胞摄取。

在这里，我们已经利用增加的细胞外基质金属蛋白酶9（MMP-9）的浓度来诱导纳米凝胶的表面转化特性，目的是增强肿瘤特异性的细胞摄取。设计并合成了模块化聚合物纳米凝胶平台，以方便配制和验证MMP-9介导的去聚乙二醇化，并通过肽N-末端生成多胺型表面特征。制备了包含MMP-9可裂解基序和不同聚（乙二醇）电晕长度（350和750 g / mol）的纳米凝胶，并通过裂解副产物的MALDI表征，荧光胺分析法，胺定量分析和zeta电位验证了酶的表面转化性能。 。PEG长度较短的纳米凝胶，mPEG350-NG，与更长的PEG长度mPEG750-NG相比，它对细胞外MMP-9浓度具有更好的表面转化能力。与未经处理的“被动” mPEG350-NG亲本相比，与荧光素标记的纳米凝胶和DiI封装的纳米凝胶一起孵育的HeLa细胞的共聚焦显微镜图像显示，在MMP-9“激活”后，mPEG350-NG的摄取量更大。实现对癌症相关蛋白酶的刺激反应摄取。