Dendrimer antibody conjugate to target and image HER-2 overexpressing cancer cells

Abstract

Although many breast and lung cancers overexpress human epidermal growth factor receptor-2 (HER-2), no methods currently exist for effective and early detection of HER-2-positive cancers. To address this issue, we designed and synthesized dendrimer-based novel nano-imaging agents that contain gold nanoparticles (AuNPs) and gadolinium (Gd), conjugated with the humanized anti-HER-2 antibody (Herceptin). Generation 5 (G5) polyamidoamine (PAMAM) dendrimers were selected as the backbone for the nano-imaging agents due to their unique size, high ratio of surface functional groups and bio-functionality. We modified G5 PAMAM dendrimer surface with PEG and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to encapsulate AuNPs and complex Gd. These dendrimer entrapped AuNPs were further conjugated with Herceptin through copper-catalyzed azide- alkyne click reaction to construct the nano-imaging agent Au-G5-Gd-Herceptin. The targeted nano-imaging agent bound selectively to HER-2 overexpressing cell lines, with subsequent internalization into the cells. More importantly, non-targeted nano-imaging agent neither bound nor internalized into cells overexpressing HER-2. These results suggest that our approach could provide a platform to develop nano-diagnostic agents or nano-therapeutic agents for early detection and treatment of HER-2-positive cancers.

Immunoreactivity changes of human serum albumin and alpha-1-microglobulin induced by their interaction with dendrimers

“…Interaction between dendrimers and antibodies, as well as the impact of dendrimers on immunoreactivity of proteins and antibodies, have been intensively explored ( [36][37][38][39] and see below). It can be divided in 2 main directions, the first being where dendrimers are used to improve the action of antibodies [36,37] or multivalent antibody-antigen interactions [40,41], to present new kinds of adjuvants [42][43][44], to improve visualization of proteins [45,46], to construct dendrimerconjugated peptide vaccines [47,48] and dendrimer-antibody complex systems for siRNA or drug delivery [49][50][51]. In second direction, immunoreactivity of proteins as well as the interaction of dendrimers with antibodies are examined as a side effect of possible application of dendrimers [52][53][54][55][56].…”

Focused ultrasound induced hyperthermia accelerates and increases the uptake of anti-HER-2 antibodies in a xenograft model

“…Nanotheranostics coupled to antibodies may have the potential to lead to a new era in treating tumours with a real time monitoring of the therapy. Targeted nanoparticles can provide an important tool for diagnosis and drug therapy and/or radiotherapy [50,51].…”

Dendrimer nanoparticles for colorectal cancer applications

“…For instance, dendrimer nanoparticles find useful functionalization in the following areas: i) increase biocompatibility (by PEGylating [53] or acetylation [54]); ii) enhance transfection efficiency (usually by aminoacid [55] or lipid functionalization [18]); iii) induce site specific delivery (e.g. aptamer [56], antibody [57], vitamin [58], peptides [59,60]); or iv) to render stimuli responsive dendrimer nanoparticles (e.g. pH [61], thermo [62], photo [63], redox-responsive [64]).…”