HER2 Expression in Breast Cancer Cells Is Downregulated Upon Active Targeting by Antibody-Engineered Multifunctional Nanoparticles in Mice

Corsi, Fabio; Fiandra, Luisa; Palma, Clara De; Colombo, Miriam; Mazzucchelli, Serena; Verderio, Paolo; Allevi, Raffaele; Tosoni, Antonella; Nebuloni, Manuela; Clementi, Emilio; Prosperi, Davide

doi:10.1021/nn201570n

Cited by 65 publications

(47 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…39 However, previous evidence suggested that major impact of TZ on HER2 expression upon endocytosis should be expected as mediated by NP delivery. 40,41 Hence, TZ nanoencapsulation might benefit the antitumor activity harnessing extracellular release of TMA and intracellular accumulation favored by NP-assisted endocytosis.…”

Section: Nanoformulation Of Tz Enhances Her2 Degradationmentioning

confidence: 99%

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Colzani¹,

Pandolfi²,

Hoti³

et al. 2018

IJN

Self Cite

View full text Add to dashboard Cite

Background We report the development of an efficient antibody delivery system for the incorporation of trastuzumab (TZ) into poly(lactic- co -glycolic) acid nanoparticles (PLGA NPs). The aim of the work was to overcome the current limitations in the clinical use of therapeutic antibodies, including immunogenicity, poor pharmacokinetics, low tumor penetration and safety issues. Materials and methods Trastuzumab-loaded PLGA NPs (PLGA-TZ) were synthesized according to a double emulsion method. The same protocol was used to produce control batches of nonspecific IgG-loaded NPs and empty PLGA NPs. After release of TZ from PLGA NPs, the effects on the main biological activities of the antibody were evaluated on SKBR3 (human epidermal growth factor receptor 2 [HER2]-positive breast cancer cell line), including specific binding to HER2, phosphorylation of HER2 (Y1248), degradation of HER2 protein and antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. In addition, an MTT assay was performed for treating SKBR3 cells with PLGA NPs loaded with TZ and doxorubicin to evaluate the cytotoxic activity of the combined treatment. Results and discussion TZ was gradually released in a prolonged way over 30 days. The physical characterization performed with circular dichroism, Fourier transform infrared and fluorescence spectroscopy of TZ after release demonstrated that no structural alterations occurred compared to the native antibody. In vitro experiments using SKBR3 cells showed that TZ released from PLGA NPs maintained the same biological activity of native TZ. PLGA NPs allowed a good co-encapsulation efficiency of TZ and doxorubicin resulting in improved therapy. Conclusion With the TZ case study, we demonstrate that the distinctive features of therapeutic monoclonal antibodies, including molecular targeting efficiency, capability to inhibit or properly affect the regulatory signaling pathways of cancer cells and stimulation of the ADCC, are fully preserved after loading into and release from PLGA NPs. In addition, PLGA NPs are shown to allow for the simultaneous incorporation of TZ and conventional chemotherapeutics, resulting in a potent antitumor nanodrug well suited for in situ combination and neoadjuvant therapy.

show abstract

Section: Nanoformulation Of Tz Enhances Her2 Degradationmentioning

confidence: 99%

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Colzani¹,

Pandolfi²,

Hoti³

et al. 2018

IJN

Self Cite

View full text Add to dashboard Cite

show abstract

“…The drop of SiNP-NTA-TZ uptake value at late time points may represent a further potential confirmation of an active targeting mechanism, involving receptormediated endocytosis, which leads to lysosomal (pH≈4-5) degradation of radiolabeled nanocomplex with time, as previously described with different colloidal NPs. 46 The labeling of NTA ligand (SiNP surface) with the 99m Tc-tricarbonyl precursor, preserves its high stability in a physiological solution (pH≈7), while low pH condition may impair the property of this complex. In this condition, the destabilization of complex could promote the washout of radioactivity, due to 99m Tctricarbonyl clearance instead to a real elimination of NPs core (FITC/Treatment).…”

Section: Discussionmentioning

confidence: 99%

Development of<sup> 99m</sup>Tc-radiolabeled nanosilica for targeted detection of HER2-positive breast cancer

Rainone¹,

Riva²,

Belloli³

et al. 2017

IJN

Self Cite

View full text Add to dashboard Cite

The human epidermal growth factor receptor 2 (HER2) is normally associated with a highly aggressive and infiltrating phenotype in breast cancer lesions with propensity to spread into metastases. In clinic, the detection of HER2 in primary tumors and in their metastases is currently based on invasive methods. Recently, nuclear molecular imaging techniques, including positron emission tomography and single photon emission computed tomography (SPECT), allowed the detection of HER2 lesions in vivo. We have developed a 99m Tc-radiolabeled nanosilica system, functionalized with a trastuzumab half-chain, able to act as drug carrier and SPECT radiotracer for the identification of HER2-positive breast cancer cells. To this aim, nanoparticles functionalized or not with trastuzumab half-chain, were radiolabeled using the 99m Tc-tricarbonyl approach and evaluated in HER2 positive and negative breast cancer models. Cell uptake experiments, combined with flow cytometry and fluorescence imaging, suggested that active targeting provides higher efficiency and selectivity in tumor detection compared to passive diffusion, indicating that our radiolabeling strategy did not affect the nanoconjugate binding efficiency. Ex vivo biodistribution of 99m Tc-nanosilica in a SK-BR-3 (HER2 + ) tumor xenograft at 4 h postinjection was higher in targeted compared to nontargeted nanosilica, confirming the in vitro data. In addition, viability and toxicity tests provided evidence on nanoparticle safety in cell cultures. Our results encourage further assessment of silica 99m Tc-nanoconjugates to validate a safe and versatile nanoreporter system for both diagnosis and treatment of aggressive breast cancer.

show abstract

“…DOXloaded MSN had a higher DOX-loading content (15.7 ± 0.013%) than that of DOX-loaded MSN-CD44 (8.9 ± 0.24%), suggesting that CD44 McAb housed within pores of MSNs decreased the drug loading of DOX. Antibody-conjugated nanoparticles are often prepared by the higher loading ratio of antibody (e.g., antibody to Her-2, MW ∼ 185 kDa; antibody/nanoparticles, 0.3/1, w/w) and few drug molecules attached [38,39]. In our study, CD44 McAb was modified on the MSNs through strong carboxylic acid-amine interactions which was not easy to be broken to release CD44 McAb from MSN-CD44.…”

Section: Drug Loading and Releasementioning

confidence: 92%

CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

Wang

Liu

Wang

et al. 2015

Applied Surface Science

View full text Add to dashboard Cite

HER2 Expression in Breast Cancer Cells Is Downregulated Upon Active Targeting by Antibody-Engineered Multifunctional Nanoparticles in Mice

Cited by 65 publications

References 37 publications

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Development of<sup> 99m</sup>Tc-radiolabeled nanosilica for targeted detection of HER2-positive breast cancer

CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

Contact Info

Product

Resources

About