Tumor Retention of Enzyme-Responsive Pt(II) Drug-Loaded Nanoparticles Imaged by Nanoscale Secondary Ion Mass Spectrometry and Fluorescence Microscopy,ACS Central Science

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Tumor Retention of Enzyme-Responsive Pt(II) Drug-Loaded Nanoparticles Imaged by Nanoscale Secondary Ion Mass Spectrometry and Fluorescence Microscopy
ACS Central Science ( IF 12.7 ) Pub Date : 2018-10-23 00:00:00 , DOI: 10.1021/acscentsci.8b00444
Maria T Proetto _{1,

2} , Cassandra E Callmann _{1,

2} , John Cliff ₃ , Craig J Szymanski ₃ , Dehong Hu ₃ , Stephen B Howell ₁ , James E Evans ₃ , Galya Orr ₃ , Nathan C Gianneschi _{1,

2}

Affiliation

In nanomedicine, determining the spatial distribution of particles and drugs, together and apart, at high resolution within tissues, remains a major challenge because each must have a different label or detectable feature that can be observed with high sensitivity and resolution. We prepared nanoparticles capable of enzyme-directed assembly of particle therapeutics (EDAPT), containing an analogue of the Pt(II)-containing drug oxaliplatin, an ¹⁵N-labeled monomer in the hydrophobic block of the backbone of the polymer, the near-infrared dye Cy5.5, and a peptide that is a substrate for tumor metalloproteinases in the hydrophilic block. When these particles reach an environment rich in tumor associated proteases, the hydrophilic peptide substrate is cleaved, causing the particles to accumulate through a morphology transition, locking them in the tumor extracellular matrix. To evaluate the distribution of drug and EDAPT carrier in vivo, the localization of the isotopically labeled polymer backbone was compared to that of Pt by nanoscale secondary ion mass spectrometry (NanoSIMS). The correlation of NanoSIMS with super-resolution fluorescence microscopy revealed the release of the drug from the nanocarrier and colocalization with cellular DNA within tumor tissue. The results confirmed the dependence of particle accumulation and Pt(II) drug delivery on the presence of a Matrix Metalloproteinase (MMP) substrate and demonstrated antitumor activity. We conclude that these techniques are powerful for the elucidation of the localization of cargo and carrier, and enable a high-resolution assessment of their performance following in vivo delivery.

中文翻译：

通过纳米级二次离子质谱和荧光显微镜成像的酶响应 Pt(II) 载药纳米颗粒的肿瘤保留

在纳米医学中，以高分辨率确定组织内颗粒和药物的空间分布（无论是在一起还是分开）仍然是一个重大挑战，因为每种颗粒和药物都必须具有不同的标签或可检测特征，并且可以以高灵敏度和分辨率进行观察。我们制备了能够酶引导粒子治疗组装 (EDAPT) 的纳米颗粒，其中含有含 Pt(II) 药物奥沙利铂的类似物，是聚合物主链疏水嵌段中的 15 N 标记单体，^近红外染料 Cy5.5 和一种肽，该肽是亲水性块中肿瘤金属蛋白酶的底物。当这些颗粒到达富含肿瘤相关蛋白酶的环境时，亲水性肽底物被裂解，导致颗粒通过形态转变而积累，将它们锁定在肿瘤细胞外基质中。为了评估药物和 EDAPT 载体在体内的分布，通过纳米级二次离子质谱 (NanoSIMS) 将同位素标记的聚合物主链的定位与 Pt 的定位进行比较。NanoSIMS 与超分辨率荧光显微镜的相关性揭示了药物从纳米载体中的释放以及与肿瘤组织内细胞 DNA 的共定位。结果证实了颗粒积累和 Pt(II) 药物递送对基质金属蛋白酶 (MMP) 底物存在的依赖性，并证明了抗肿瘤活性。我们的结论是，这些技术对于阐明货物和载体的定位非常有用，并且能够对其体内递送后的性能进行高分辨率评估。

更新日期：2018-10-23

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