Highly Specific HER2-mediated Cellular Uptake of Antibody-modified Nanoparticles in Tumour Cells

Abstract

Nanoparticles represent useful drug delivery systems for the specific transport of drugs to tumour cells. In the present study biodegradable nanoparticles based on gelatin and human serum albumin (HSA) were developed. The surface of the nanoparticles was modified by covalent attachment of the biotin-binding protein NeutrAvidin enabling the binding of biotinylated drug targeting ligands by avidin-biotin-complex formation. Using the HER2 receptor specific antibody trastuzumab (Herceptin) conjugated to the surface of these nanoparticles, a specific targeting to HER2-overexpressing cells could be shown. Attachment of the antibody-conjugated nanoparticles to the surface of HER2-overexpressing cells was time and dose dependent. Confocal laser scanning microscopy demonstrated an effective internalisation of the nanoparticles by HER2-overexpressing cells via receptor-mediated endocytosis. The results indicate that nanoparticles conjugated with an antibody against a specific tumour antigen holds promise, as selective drug delivery systems for the treatment of tumours expressing a specific tumour antigen. To our knowledge, this is the first study that demonstrates the effective and specific targeting of protein-based nanoparticles as drug delivery systems.

Trastuzumab therapy vs tetracycline controlled ERBB2 downregulation: influence on tumour development in an ERBB2-dependent mouse tumour model

“…Trastuzumab is a humanised monoclonal antibody that binds to the membrane adjacent cysteine rich part of the extracellular domain of ERBB2 (Cho et al, 2003). Several distinct mechanisms are responsible for its antitumour activity: (i) internalisation of ERBB2 from the cell surface (Wartlick et al, 2004), (ii) blockade of metalloprotease-induced cleavage of ERBB2 generating a soluble extracellular domain and a kinase active intracellular fragment (Molina et al, 2001) and (iii) antibodydependent cytotoxicity mediated by the Fc portion of trastuzumab (Clynes et al, 2000).…”

Adenovirus 5 vector genetically re-targeted by an Affibody molecule with specificity for tumor antigen HER2/neu

“…For successful targeting, endocytosis is required for delivery of the agent into the interior of the cell. Selfefficient internalization of antibodies against Her2/neu has been described both for trastuzumab (Herceptin) [48][49][50] and F5. 51 Other receptors that are known to induce internalization are the EGF 52 and transferrin receptors.…”

Recent Advances in the Generation of Antibody–Nanomaterial Conjugates

“…Based on model calculations, NeutrAvidinbiotin conjugation resulted in the attachment of >300 antibodies per nanoparticle surface enabling an effective and promising targeting strategy. [53] Michaelis et al performed a similar study using Apo lipoprotein-modified albumin nanoparticles for loperamide drug delivery to the brain. [104] Further studies have demonstrated effective binding of avidin-biotin complexes for the targeted delivery of nanomaterials.…”