Role of antibody-mediated tumor targeting and route of administration in nanoparticle tumor accumulation in vivo.
In this study, we have looked at enhancing tumor uptake and intracellular delivery of gold nanoparticles (AuNPs) while reducing the systemic exposure by systematic evaluation of the impact of targeting and route of administration on organ distribution. High-resolution microSPECT/CT imaging was used to track the in vivo fate of (111)In-labeled nontargeted and human epidermal growth factor receptor-2 (HER-2) targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl3 (for deactivation of macrophages) and nonspecific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to nontargeted AuNPs. I.T. injections with HER-2 targeted AuNPs resulted in high tumor retention with low systemic exposure and represents an attractive delivery strategy. Our results provide a strategy for optimizing tumor delivery and quantifying organ distribution of this widely studied class of nanomaterial.
Departments of †Pharmaceutical Sciences, ‡Medical Biophysics, §Medical Imaging and ∥Laboratory Medicine and Pathobiology, University of Toronto , Toronto, ON, Canada.
Niladri
N
Chattopadhyay
Humphrey
H
Fonge
Zhongli
Z
Cai
Deborah
D
Scollard
Eli
E
Lechtman
Susan J
SJ
Done
Jean-Philippe
JP
Pignol
Raymond M
RM
Reilly
D000818:Animals; D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005682:Gadolinium / Q000494:pharmacology; D006046:Gold / Q000378:metabolism*; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000069283:Rituximab; D000068878:Trastuzumab
D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D005682:Gadolinium; D006046:Gold; D018719:Erb-b2 Receptor Tyrosine Kinases; D000069283:Rituximab; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C038958:gadolinium chloride