Department of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy.
Institute of Molecular Bioimaging and Physiology of CNR, Segrate, 20090, Italy.
Int J Nanomedicine. 2021 Mar 8;16:1943-1960. doi: 10.2147/IJN.S276033. eCollection 2021.
The overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) is usually associated with aggressive and infiltrating breast cancer (BC) phenotype, and metastases. Functionalized silica-based nanocarriers (SiNPs) can be labeled for in vivo imaging applications and loaded with chemotherapy drugs, making possible the simultaneous noninvasive diagnosis and treatment (theranostic) for HER2-positive BC.
Firstly, FITC-filled SiNPs, were engineered with two different amounts of Hc-TZ (trastuzumab half-chain) per single nanoparticle (1:2 and 1:8, SiNPs to Hc-TZ ratio), which was Tc-radiolabeled at histidine residues for ex vivo and in vivo biodistribution evaluations. Secondly, nanoparticles were loaded with DOX and their in vitro and ex vivo/in vivo delivery was assessed, in comparison with liposomal Doxorubicin (Caelyx). Finally, the treatment efficacy of DOX-SiNPs-TZ (1:8 Hc-TZ) was evaluated in vivo by PET and supported by MS-based proteomics profiling of tumors.
SiNPs-TZ (1:8 Hc-TZ) tumor uptake was significantly greater than that of SiNPs-TZ (1:2 Hc-TZ) at 6 hours post-injection (p.i.) in ex vivo biodistribution experiment. At 24 h p.i., radioactivity values remained steady. Fluorescence microscopy, confirmed the presence of radiolabeled SiNPs-TZ (1:8 Hc-TZ) within tumor even at later times. SiNPs-TZ (1:8 Hc-TZ) nanoparticles loaded with Doxorubicin (DOX-SiNPs-TZ) showed a similar DOX delivery capability than Caelyx (at 6 h p.i.), in in vitro and ex vivo assays. Nevertheless, at the end of treatment, tumor volume was significantly reduced by DOX-SiNPs-TZ (1:8 Hc-TZ), compared to Caelyx and DOX-SiNPs treatment. Proteomics study identified 88 high stringent differentially expressed proteins comparing the three treatment groups with controls.
These findings demonstrated a promising detection specificity and treatment efficacy for our system (SiNPs-TZ, 1:8 Hc-TZ), encouraging its potential use as a new theranostic agent for HER2-positive BC lesions. In addition, proteomic profile confirmed that a set of proteins, related to tumor aggressiveness, were positively affected by targeted nanoparticles.
人表皮生长因子受体 2 (HER2) 的过表达通常与侵袭性和浸润性乳腺癌 (BC) 表型和转移有关。功能化的硅基纳米载体 (SiNPs) 可用于体内成像应用，并可装载化疗药物，从而实现 HER2 阳性 BC 的同时非侵入性诊断和治疗 (治疗)。
首先，用两种不同数量的 Hc-TZ（曲妥珠单抗半链）对 FITC 填充的 SiNPs 进行工程化，每个纳米颗粒 1:2 和 1:8（SiNPs 与 Hc-TZ 的比例），并用组氨酸残基放射性标记 Tc 进行离体和体内生物分布评估。其次，将纳米颗粒装载 DOX，并评估其体外和离体/体内递药情况，并与脂质体多柔比星 (Caelyx) 进行比较。最后，通过 PET 评估 DOX-SiNPs-TZ（1:8 Hc-TZ）的体内治疗效果，并通过肿瘤的 MS 基蛋白质组学分析提供支持。
SiNPs-TZ（1:8 Hc-TZ）在注射后 6 小时（p.i.）的离体生物分布实验中，肿瘤摄取量明显大于 SiNPs-TZ（1:2 Hc-TZ）。在 24 h p.i.，放射性值保持稳定。荧光显微镜证实，即使在稍后时间，放射性标记的 SiNPs-TZ（1:8 Hc-TZ）也存在于肿瘤中。载有阿霉素（DOX-SiNPs-TZ）的 SiNPs-TZ（1:8 Hc-TZ）纳米颗粒在体外和离体实验中表现出与 Caelyx 相似的 DOX 递送能力。然而，在治疗结束时，与 Caelyx 和 DOX-SiNPs 治疗相比，DOX-SiNPs-TZ（1:8 Hc-TZ）显著减小了肿瘤体积。蛋白质组学研究鉴定了 88 种高严格差异表达蛋白，将三组治疗组与对照组进行比较。
这些发现证明了我们的系统（SiNPs-TZ，1:8 Hc-TZ）具有有前途的检测特异性和治疗效果，鼓励其作为 HER2 阳性 BC 病变的新型治疗药物的潜在用途。此外，蛋白质组学分析证实了一组与肿瘤侵袭性相关的蛋白质受到靶向纳米颗粒的积极影响。
