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According to the prevalent concept of enhanced permeability and retention (EPR) effect proposed by Matsumura and Maeda in 1986 [1], nanoparticles can passively accumulate at the tumor site via gaps between endothelial cells (interendothelial gaps) in tumor-associated blood vessels that have abnormal structural integrity with pores ranging in size from submicron to micron. According to the paper published very recently by Sindhwani et al. [2], however, this classic concept needs to be modified or replaced by a new concept on the entry of nanoparticles into solid tumors. In their paper, Sindhwani and his team focused on how nanoparticles – represented by gold nanoparticles – enter tumors, by carrying out detailed visualization and data quantification on specific areas such as blood vessel gaps in tumors, accumulation and localization of nanoparticles in tumors, and also the comparison of transendothelially transported rate of nanoparticles to the rate of diffusion across blood vessel gaps. They analyzed 313 blood vessels across several tumor models, such as U87-MG glioma, 4T1 breast cancer, MMTV-PyMT breast cancer, PDX breast cancer and so on, and found only 26 gaps, which implied that gaps occurred at a very low frequency in all the aforementioned tumor types, which is consistent with the knowledge that gaps are also rare in tumor vessels from cancer patients. Furthermore, they demonstrated that only seven out of 26 openings were intercellular gaps (26.9%), while the rest were transendothelial pores. Through this study, they claimed that the main mechanism of nanoparticle tumor entry is through transendothelial openings. In fact, in 1997, researchers at Harvard University had proposed that the endothelial cell gaps that were induced by vasoactive mediators were mostly transcellular pores [3]. Feng et al. defined a novel endothelial cell organelle in the endothelial cells of both humans and animals, termed the vesiculovacuolar organelle (VVO) [3]. It participates in the regulation of intracellular transportation pathways during the transendothelial transport of soluble macromolecules. In this regard, there is a structural basis for nanoparticles to enter tumors through transendothelial pathways. According to this article, the extravasation of nanoparticles shows no significant relevance with tight junctions, fenestra, vesicles or endothelial gaps in blood vessels, which infers that nanoparticles primarily enter tumors by active transportation. Based on the aforementioned fact, there are two possible ends when nanoparticles enter the circulation. The first one is that nanoparticles are also capable of entering other organs by crossing the endothelial cells. Feng and coworkers showed that colloidal carbon could traverse endothelial cells via the development of pores; this mechanism does not require communication with the intercellular gap junction, nor do they need to disrupt intercellular junctions by gap formation in these vessels [4]. If this hypothesis of “nanoparticles entering normal vessels” proved to be true, this may explain why the efficiency of nanoparticle delivery to tumors is mostly lower than 1% in clinical experiments [5]. Hida et al. reported that endothelial cells in tumors exhibit different characteristics from normal vascular endothelial cells in terms of cell proliferation, migration ability, gene expression and response to growth factors and drugs [6]. Akino et al. showed that in human clear cell renal cell carcinoma (CCRCC), 22–58% (median, 33%) of tumor-associated endothelial cells were aneuploid, while normal endothelial cells were diploid [7]. Furthermore, tumor 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yatsen University, Guangzhou 510120, China

Understanding of the Entry Mechanism of Nanoparticles into Tumors Determines the Future Direction of Nanomedicine Development