Development and application of a novel model system to study "active" and "passive" tumor targeting

Amarnath Mukherjee, Binod Kumar, Koji Hatano, Luisa M. Russell, Bruce J. Trock, Peter C. Searson, Alan K. Meeker, Martin G. Pomper, Shawn E. Lupold

Research output: Contribution to journalArticle

5 Scopus citations

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 halflife 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 PSMAnegative 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.

Original languageEnglish (US)
Pages (from-to)2541-2550
Number of pages10
JournalMolecular cancer therapeutics
Volume15
Issue number10
DOIs
StatePublished - Oct 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Mukherjee, A., Kumar, B., Hatano, K., Russell, L. M., Trock, B. J., Searson, P. C., Meeker, A. K., Pomper, M. G., & Lupold, S. E. (2016). Development and application of a novel model system to study "active" and "passive" tumor targeting. Molecular cancer therapeutics, 15(10), 2541-2550. https://doi.org/10.1158/1535-7163.MCT-16-0051