Overcoming Instability of Antibody-Nanomaterial Conjugates: Next Generation Targeted Nanomedicines Using Bispecific Antibodies.
Targeted nanomaterials promise improved therapeutic efficacy, however their application in nanomedicine is limited due to complexities associated with protein conjugations to synthetic nanocarriers. A facile method to generate actively targeted nanomaterials is developed and exemplified using polyethylene glycol (PEG)-functional nanostructures coupled to a bispecific antibody (BsAb) with dual specificity for methoxy PEG (mPEG) epitopes and cancer targets such as epidermal growth factor receptor (EGFR). The EGFR-mPEG BsAb binds with high affinity to recombinant EGFR (KD : 1 × 10(-9) m) and hyperbranched polymer (HBP) consisting of mPEG (KD : 10 × 10(-9) m) and demonstrates higher avidity for HBP compared to linear mPEG. The binding of BsAb-HBP bioconjugate to EGFR on MDA-MB-468 cancer cells is investigated in vitro using a fluorescently labeled polymer, and in in vivo xenograft models by small animal optical imaging. The antibody-targeted nanostructures show improved accumulation in tumor cells compared to non-targeted nanomaterials. This demonstrates a facile approach for tuning targeting ligand density on nanomaterials, by modulating surface functionality. Antibody fragments are tethered to the nanomaterial through simple mixing prior to administration to animals, overcoming the extensive procedures encountered for developing targeted nanomedicines.
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Christopher B
CB
Howard
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Nicholas
N
Fletcher
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Zachary H
ZH
Houston
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Adrian V
AV
Fuchs
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Nathan R B
NR
Boase
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Joshua D
JD
Simpson
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Lyndon J
LJ
Raftery
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Tim
T
Ruder
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Martina L
ML
Jones
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Christopher J
CJ
de Bakker
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Stephen M
SM
Mahler
Australian Institute for Bioengineering and Nanotechnology (AIBN), Centre for Advanced Imaging (CAI), School of Chemical Engineering, ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, 4072, Australia.
Kristofer J
KJ
Thurecht
D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry / Q000494:pharmacology; D000912:Antibodies, Neoplasm / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D049329:Nanostructures / Q000737:chemistry / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D000068936:Theranostic Nanomedicine / Q000379:methods; D023041:Xenograft Model Antitumor Assays
D018033:Antibodies, Bispecific; D000912:Antibodies, Neoplasm; D011092:Polyethylene Glycols; C000595213:polyethylene glycol 400; C512478:EGFR protein, human; D066246:ErbB Receptors
bispecific antibodies; epidermal growth factor receptor; poly(ethylene glycol); polymers; targeted nanomaterials