99mTc-Radiolabeled Silica Nanocarriers for Targeted Detection and Treatment of HER2-Positive Breast Cancer

Int J Nanomedicine. 2021 Mar 8:16:1943-1960. doi: 10.2147/IJN.S276033. eCollection 2021.


Introduction: 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.

Methods: 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 99mTc-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.

Results: 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.

Conclusion: 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.

Keywords: 99mTc-radiolabeling; HER2-positive BC; SPECT imaging; TZ-half chain conjugation; doxorubicin-loaded nanoparticles; targeted silica nanoparticles.

MeSH terms

  • Animals
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / diagnostic imaging
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Doxorubicin / analogs & derivatives
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacology
  • Doxorubicin / therapeutic use
  • Drug Carriers / chemistry*
  • Endocytosis
  • Female
  • Fluorescein-5-isothiocyanate / chemistry
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nanoparticles / chemistry*
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / pharmacology
  • Polyethylene Glycols / therapeutic use
  • Proteome / metabolism
  • Proteomics
  • Radiopharmaceuticals / chemistry*
  • Radiopharmaceuticals / pharmacokinetics
  • Receptor, ErbB-2 / metabolism*
  • Silicon Dioxide / chemistry*
  • Technetium / chemistry*
  • Technetium / pharmacokinetics
  • Tissue Distribution / drug effects
  • Tomography, Emission-Computed, Single-Photon
  • Treatment Outcome


  • Drug Carriers
  • Proteome
  • Radiopharmaceuticals
  • liposomal doxorubicin
  • Polyethylene Glycols
  • Technetium
  • Silicon Dioxide
  • Doxorubicin
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Fluorescein-5-isothiocyanate