Endocytosis of PEGylated agents enhances cancer imaging and anticancer efficacy

Kuo Hsiang Chuang, Hsin Ell Wang, Fang Ming Chen, Shey Cherng Tzou, Chiu Min Cheng, Ya Chen Chang, Wei Lung Tseng, Jentaie Shiea, Shiu Ru Lin, Jaw Yuan Wang, Bing Mae Chen, Steve R. Roffler, Tian Lu Cheng

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27 Citations (Scopus)

Abstract

PEGylated nanoparticles and macromolecules are increasingly used in cancer imaging and anticancer treatment. The role of receptor-mediated endocytosis in the efficacy of these agents, however, has not been clearly defined. Here, we developed a matched pair of endocytic and nonendocytic receptors to directly and unambiguously assess this issue. The ligand-binding domains of the low-density lipoprotein receptor (LDLR) or a truncated LDLR lacking the NPXY endocytosis motif (ΔLDLR) were replaced with an anti-polyethylene glycol antibody (αPEG) to form endocytic αPEG-LDLR and nonendocytic αPEG-ΔLDLR receptors. The receptors were stably expressed at similar levels on the surface of HCC36 cells. HCC36/αPEG-LDLR cells, but not HCC36/αPEG-ΔLDLR cells, rapidly endocytosed PEG-quantum dots and PEG-liposomal doxorubicin (Lipo-Dox) in vitro and in vivo. Lipo-Dox was significantly more cytotoxic to HCC36/αPEG-LDLR cells than to HCC36/αPEG-ΔLDLR cells. HCC36/αPEG-LDLR tumors also accumulated significantly more PEGylated near-IR probes (PEG-NIR797) and PEG-liposomal-111In than HCC36/αPEG-ΔLDLR tumors in vivo. Furthermore, Lipo-Dox more significantly suppressed the growth of established HCC36/αPEG-LDLR tumors as compared with HCC36/αPEG-ΔLDLR tumors. Our data show that endocytosis of PEGylated probes and drugs enhances both cancer imaging and anticancer efficacy, indicating that endocytic receptors are superior targets for the design of cancer imaging probes and immunoliposomal drugs.

Original languageEnglish
Pages (from-to)1903-1912
Number of pages10
JournalMolecular Cancer Therapeutics
Volume9
Issue number6
DOIs
Publication statusPublished - Jun 2010
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Chuang, K. H., Wang, H. E., Chen, F. M., Tzou, S. C., Cheng, C. M., Chang, Y. C., Tseng, W. L., Shiea, J., Lin, S. R., Wang, J. Y., Chen, B. M., Roffler, S. R., & Cheng, T. L. (2010). Endocytosis of PEGylated agents enhances cancer imaging and anticancer efficacy. Molecular Cancer Therapeutics, 9(6), 1903-1912. https://doi.org/10.1158/1535-7163.MCT-09-0899