title: Development and Application of a Novel Model System to Study "Active" and "Passive" Tumor Targeting.
abstract: Macromolecular reagents can be targeted to tumors through active and passive mechanisms. "Active" targeting involves moieties, such as receptor ligands, to direct tumor cell binding, whereas "passive" targeting relies on long reagent circulating half-life, abnormal tumor vasculature, and poor lymphatic drainage for tumor entrapment. Here, we sought to study the impact of reagent circulating half-life on "active" and "passive" tumor uptake. The humanized prostate-specific membrane antigen (PSMA)-targeting antibody HuJ591 was used as the "active" targeting agent. HuJ591 was labeled with a Near Infrared (NIR) dye and its circulating half-life was modified by conjugation to high-molecular-weight Polyethylene Glycol (PEG). PEGylation did not negatively impact PSMA-binding specificity. "Active" and "passive" tumor targeting of intravenously injected antibody conjugates were then quantified by NIR fluorescent imaging of immunocompromised mice bearing bilateral isogenic PSMA-positive and PSMA-negative human tumor xenografts. Two isogenic tumor pairs were applied, PC3 ± PSMA (PC3-PIP/PC3-Flu) or LMD-MDA-MB-231 ± PSMA (LMD-PSMA/LMD). This study provided a unique model system to simultaneously observe "active" and "passive" tumor targeting within a single animal. "Passive" targeting was observed in all PSMA-negative tumors, and was not enhanced by increased HuJ591 size or extended circulating half-life. Interestingly, "active" targeting was only successful in some situations. Both PSMA-positive tumor models could be actively targeted with J591-IR800 and J591-PEG10K. However, the larger J591-PEG30K enhanced "active" targeting in the PC-3 tumor models, but inhibited "active" targeting the LMD-MDA-MB-231 tumor model. Successful "active" targeting was associated with higher PSMA expression. These results support the potential for "active" targeting to enhance overall macromolecular reagent uptake within tumors. Mol Cancer Ther; 15(10); 2541-50. ©2016 AACR.
authors.affiliation: Department of Urology and The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Amarnath
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Department of Urology and The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Binod
authors.initials: B
authors.lastname: Kumar
authors.affiliation: Department of Urology and The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Koji
authors.initials: K
authors.lastname: Hatano
authors.affiliation: Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Russell
authors.affiliation: Department of Urology and The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Trock
authors.affiliation: Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, Maryland. Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland. Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Searson
authors.affiliation: Department of Urology and The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Meeker
authors.affiliation: Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, Maryland. Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Russel H. Morgan Department of Radiology and Radiologic Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: Department of Urology and The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, Maryland. Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. slupold@jhmi.edu.
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Lupold
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D000918:Antibody Specificity / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D004195:Disease Models, Animal; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods; D058990:Molecular Targeted Therapy; D061848:Optical Imaging / Q000379:methods; D011092:Polyethylene Glycols / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018796:Immunoconjugates; D011092:Polyethylene Glycols