Quantifying the Targeting Efficiency of Ligand-Coated Intact Nanoparticles to Cancer Cells in Solid Tumours

Dai, Qin 1 ;  Wilhelm, Stefan 1 ;  Ding, Ding 1, 2 ;  Sindhwani, Shrey 1 ;  Syed, Abdullah Muhammad 1 ;  Chan, Warren C.W. 1, 3, 4

1. Institute of Biomaterials and Biomedical Engineering, University of Toronto; 2. Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha, 410082, China; 3. Donnelly Center for Cellular and Biomolecular Research, University of Toronto; 4. Departments of Chemistry, Materials Science and Engineering, and Chemical Engineering, University of Toronto

“Active targeting” is a prominent concept for enhancing the specific delivery of nanoparticles to malignant cells in the body. Here, we surprisingly show that less than 14 out of one million intravenously administered Herceptin-coated nanoparticles interact with ErbB2(+) cancer cells and that less than 2% of cancer cells within solid tumours have access to nanoparticles. The majority of nanoparticles that accumulate in solid tumours fail to reach cancer cells. Nanoparticles are either trapped in tumour associated macrophages, other cells, or acellular regions. Using an in vitro tumour cellular transport model, we show that the acellular region limits the diffusion of 17 different nanomaterials with various compositions (e.g., inorganic, polymeric, and liposomes), sizes, and surface chemistries (e.g., transferrin, folic acid, and protein corona). Our results reveal that intratumoural barriers impede efficient transport of nanoparticles to cancer cells, and suggest that the meaning of “active targeting” needs to be re-defined.