Journal
MOLECULAR CANCER THERAPEUTICS
Volume 15, Issue 10, Pages 2541-2550Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-16-0051
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Funding
- National Cancer Institute CCNE [U54CA151838, CA134675]
- Prostate Cancer Foundation
- Safeway Foundation
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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. (C) 2016 AACR.
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