Endocytosis of PEGylated Agents Enhances Cancer Imaging and Anticancer Efficacy

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 (LipoDox) 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 In 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. Mol Cancer Ther; 9(6); 1903-12.

High expression of integrin αvβ3 enables uptake of targeted fluorescent probes into ovarian cancer cells and tumors

“…32–33 This is important as probe accumulation inside the cancer cells is expected to give a higher and more sustained imaging signal. 34 To ensure that the fluorescent signal was only due to probe molecules inside the cell, the imaging protocol included several wash steps to remove any probe from the external surface. 35 Additionally, automated focusing on the nucleus was used to view the intracellular region, and deconvolution image processing removed fluorescence signal from outside this region.…”

Critical evaluation of biodegradable polymers used in nanodrugs

“…For example, PEGylated nanoparticles with endocytic and nonendocytic receptors show the important role of receptor-mediated endocytosis in the efficacy of nanoparticles used in the imaging and treatment of cancer. 35 Thus, doxorubicin-loaded nanoparticles with endocytic receptors showed better cellular uptake and anticancer efficiency than those with nonendocytic receptors.…”

“…For instance, PLGA provides a hydrophobic core that is able to retain oily material, 34 while PEG reduces the interaction with untargeted tissues, increasing specificity. 35 This review begins by describing the mechanisms of synthesis and degradation of a variety of biodegradable polymers. It also discusses encapsulation techniques used to prepare nanoparticles from these polymers, their biomedical applications, cellular uptake, and factors that affect bioavailability and internalization of nanoparticles.…”

“…35 Further studies suggest that the increase in cytotoxicity of the compound delivered by liposomes is probably due to a different distribution of liposomes inside the cell compartments, which improves the efficiency of activity. 35,138 Toxicity of nanoparticles is also related to their size.…”

“…35 Further studies suggest that the increase in cytotoxicity of the compound delivered by liposomes is probably due to a different distribution of liposomes inside the cell compartments, which improves the efficiency of activity. 35,138 Toxicity of nanoparticles is also related to their size. Some studies show that the PEG-coated gold nanoparticles with a diameters of 5-10 nm accumulate in the liver; 30 nm particles accumulate preferentially in the spleen, and particles with diameters of 10-60 nm have low toxicity in the liver and kidneys.…”