Recognized as the EPR effect overturned, one day bursts of three \”Nature Materials\”: challenges and opportunities for cancer treatment

1, challenged nano drug delivery mechanism

Since the tumor growth rate significantly higher than normal tissues, the presence of defects between tumor vascular endothelial cells, are not arranged closely, permeable, and less internal tumor lymphatic drainage, blood lower flow rates, the nanoparticles once inside, will be retained at the tumor site, a phenomenon known as EPR (enhanced permeability and retention) effect . EPR effect since the late 1980s reported the last century, is recognized as a major factor of nanoparticles in the tumor site enrichment. But recently, the University of Toronto Warren C. W. Chan team discussed the tumor infiltration phenomenon nanoparticles, and questioned the mechanism of nano-particles into solid tumors. Sufficient evidence that the transcytosis may be the main mechanism of nanoparticles in the tumor site enriched . In the paper \”The entry of nanoparticles into solid tumours\” was published in the Nature Materials on. Since the conclusion overturn cognition, this paper will be a widespread concern by researchers, Nature Materials in one day published an editorial on the article, news and views, review articles three articles, called for further exploration of the challenges and the future of cancer treatment. ​公认的EPR效应翻车了,一天内连发三篇《Nature Materials》:肿瘤治疗的挑战和机遇 gap between endothelial cells considered one of the leading factors EPR effect, but the study authors observed that the frequency of occurrence of endothelial cell gap is not high. In all tumor models, 313 of the blood vessel was observed, only to discover at the gap 26, the gap coverage rate is only 0.048% of the total surface area of ​​the vessel, the number of endothelial gap 60 less than the number of nanoparticles accumulated experimental times. While this provides evidence for the EPR effect, but can not fully explain the enrichment of nanoparticles at the tumor site.

​公认的EPR效应翻车了,一天内连发三篇《Nature Materials》:肿瘤治疗的挑战和机遇
FIG. 1 tumor vasculature largely continuous occurrence of low frequency gap

is then investigated the influence transcytosis nanoparticles enrichment at the tumor site. Endocytosis is a need for endothelial cell metabolism activity rearranged cytoskeleton and the cell membrane, comprising forming vesicles may absorbent nanoparticles, known as diaphragm forming the wall of the hole or by a cytoplasmic transport. After preparation of the three sizes ((15 nm, 50 nm and 100 nm) gold nanoparticles AuNPs, in the TEM photograph clearly observed AuNPs vesicle transport, and AuNPs and tumor vascular endothelial cells and a significant interaction by absorption, it provided direct evidence for the transcytosis.

​公认的EPR效应翻车了,一天内连发三篇《Nature Materials》:肿瘤治疗的挑战和机遇
FIG nanoparticles into the tumor may be by way transendothelial

considering the coexistence of two mechanisms, of which further species mechanisms play a leading role verified by established mouse model, to the loss of other cells while preserving activity of the vascular structure, the passive and active elements endothelial space of transcytosis separated. it was found that when the barrier after breaking transcytosis pathway, AuNPs enrichment in the tumor site is significantly reduced. further analysis of the data, via the leakage gap into the tumor endothelial cells AuNPs only 3-25% of the total number (depending on the particle size of AuNPs). these early results subvert the understanding of the EPR effect, it is highly likely to affect drug design ideas late nanometers.

​公认的EPR效应翻车了,一天内连发三篇《Nature Materials》:肿瘤治疗的挑战和机遇
FIG. 3 Zombie mouse model in vivo angiogenesis model maintains the structure of the animal

2, a new awareness of the bottlenecks in the development of nano-drug

the editorial examines the nano-drug bottlenecks encountered in clinical application, the EPR effect admitted that the traditional mechanism has been challenged. Harvard University David Mooney and Irene de Lázaro summarize the text, emphasized that these disruptive discovery, and calls for a re-examination long-established pattern in nanoparticle delivery mechanism. ​公认的EPR效应翻车了,一天内连发三篇《Nature Materials》:肿瘤治疗的挑战和机遇 ​公认的EPR效应翻车了,一天内连发三篇《Nature Materials》:肿瘤治疗的挑战和机遇 this is not the first time the EPR effect controversial in recent years, the vascular system and cross-species heterogeneity of tumor types, as well as the tumor microenvironment variability of other parameters, so that people on the EPR effectIt should be suspicious. Over the past 30 years, the development of nano-cancer therapy drugs emerging, more complex designs. But so far, 10 kinds of nanometers only drugs with FDA approval , only 14% of the drug showed clinical efficacy. Studies have shown that, after systemic administration, only 0.7% of the drug reaching the nanometer solid tumors. There is no doubt, nano drug is beneficial in the treatment of cancer. Chemotherapeutic agents as a carrier, which by limiting systemic toxicity, greatly enhances patient tolerance. However, , unfortunately, led to a high turnover rate the effectiveness of nanomedicine had some doubts. The main difference between the nano-drug efficacy because of insufficient accumulation of nanoparticles in the tumor and poor pharmacokinetics. The results the authors draw attention to the limited understanding of this area of ​​the tumor spillover mechanism, as well as concerns about the EPR effect could confuse the design of nano-medicine. Other nanoparticles parameters, including material composition, geometry, surface chemistry, charge, and mechanical properties, which will affect interaction with the biological barrier, and may affect the relative importance of specific mechanisms and their extravasation action.

3, transcytosis to new opportunities for cancer nanomedicine

Although the authors results indicate that transcytosis is indeed the dominant mechanism can be used as nano-particles into solid tumors, but they only studied three sizes AuNPs, an EPR effect on 15 nm, 50 nm, 100 nm is more complex in tumor AuNPs enriched contributions were 12%, 3% and 25%, generally inconsistent with this trend cognitive, therefore, there may be way affect the EPR effect 50 nm particles, pending further study. ​公认的EPR效应翻车了,一天内连发三篇《Nature Materials》:肿瘤治疗的挑战和机遇 Currently, the details regarding the mechanism of endocytosis, and to trigger cellular uptake of nanoparticles in the vascular endothelium, transport and release of the structural elements, little is known. Studies have shown that the receptor – binding glycoprotein, charge reversal process may trigger transcytosis. Antibodies, nucleic acids, carbohydrates, polypeptides and other macromolecules can even be attached selectively targeting and transport of the nanoparticle surface. University of Illinois Nie Shuming and colleagues , these findings should motivate researchers to develop the use of initiativeTranscytosis improve delivery efficiency of the art , including the use of tumor penetratin, the cationic polymer conjugate designed to allow active sorption mediated endocytosis and the like. Transcytosis addition, the use of nanotechnology to enhance the immune response offers a new approach to cancer therapy. Compared with the design to overcome the barrier of the endothelial cells nanoparticles using more effective immune cells destroy the tumor. First, you need to activate only a small fraction of immune cells can give rise to anti-tumor immune response, and so need to transport a large number of traditional chemotherapy agents to the tumor, causing serious side effects. Second, immunotherapy will produce an immunological memory, prevent tumor recurrence, while effectively inhibit tumor metastasis distally. Nanoparticles can be achieved while various immunological medicament delivery, the immune response induced by a variety of mechanisms, therefore, the use of the nanocarrier to a tumor-specific immune medicine delivery will be a promising direction. In addition, the unique optical properties of nanoparticles may be combined with the treatment phase, the development of multi-mode pharmaceutical carrier for use in cancer immunotherapy.

4, experts recommend

Perhaps it was for people to overestimate the EPR effect of the drug caused a bottleneck in the development of nano. In order to understand the basic principles of human interaction with nanoparticles, Harvard University David Mooney and Irene de Lázaro called on the scientific community should be more attention to basic research. The field should also cooperate more closely with life scientists and oncologists, because they have a better understanding of tumor biology and patient-specific. Finally, in order to make progress in cancer nano-medicine, also we need more research to really bold challenge existing models. Original link:

https://doi.org/10.1038/s41563-019-0566-2

References:

https://doi.org/10.1038/s41563-020-0676-xhttps: //doi.org/10.1038/s41563-020-0669-9https://doi.org/10.1038/s41563-020-0672-1

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