Angelw, Zheng Jie group, University of Texas, Dallas, USA: gold nanoparticles that can be removed by the kidney can solve the dilemma of anticancer nanodrugs!

Renal clearance and vascular permeability are the main reasons for the low targeting efficiency, poor therapeutic effect and toxic and side effects of anti-tumor drugs The drug delivery system based on nanoparticles can enhance the therapeutic effect and safety to a certain extent However, most of the nanodrugs currently used are large in size (~ 100 nm), so the ability to penetrate through blood vessels and into the deep part of the tumor is poor Because the blood clearance of nanoparticles is slow, the retention time of drugs in other normal tissues will be prolonged, resulting in side effects So, in order to achieve high tumor targeting efficiency, we must sacrifice rapid renal clearance? To achieve long-term blood circulation and strong EPR effect, we must sacrifice rapid tumor targeting? Is it necessary to sacrifice strong vascular permeability to reduce the nonspecific enrichment and side effects of nanodrugs in normal tissues? Recently, Zheng Jie's research group at the University of Texas at Dallas in a new research (angel Chem Int ed 2019, Doi: 10.1002/anie.201903256) successfully answered these questions This study shows that the properties mentioned in the above questions can be taken into account at the same time The gold nanoparticles that can be removed by the kidney can significantly enhance the enrichment of anticancer drugs in tumor sites by relying on strong tissue permeability and EPR effect At the same time, it can also reduce the accumulation of drugs in normal organs and tissues by using the characteristics of rapid renal clearance, so as to significantly reduce the toxic and side effects (image source: angelw Chem Int ed.) the author synthesized PEGylated gold nanoparticles (PEG AuNPs, ~ 4 nm), and then modified them with 4-o-mercaptobenzoic acid (MBA) by ligand exchange reaction, hoping to use the π - π stacking effect of MBA and doxorubicin (DOX) to adsorb DOX on the surface of peg AuNPs (Figure 1a) The results showed that each particle could adsorb 33 ± 7 DOX molecules (DOX @ AuNPs) (Figure 1b) without significant influence on particle dispersion, and the loading efficiency was 5 times of that of the particles without MBA modification Dox @ AuNPs hardly adsorbs human serum albumin because of peg-aunps' anti protein adhesion 24 hours after intravenous injection, 56.0% of AuNPs were excreted in urine, 22% of DOX was also excreted in urine, while only 6% of DOX was excreted (Figure 1D, e) These results show that DOX and AuNPs can be separated slowly and released faster under acidic conditions, which will be beneficial to drug release at tumor site (Figure 1F) At the same time, loading DOX on AuNPs did not affect the cytotoxicity of DOX (Figure 1g) Based on the above properties and previous studies, the authors used MCF-7 and 4T1 breast cancer models to carry out tumor treatment experiments It can be seen from the tumor growth curve that compared with DOX, DOX @ AuNPs significantly enhanced the inhibition effect of DOX on tumor growth (77.6% vs 40.7%) (Figure 2a, c); also significantly prolonged the survival period of mice (Figure 2B, d) It significantly reduced the number of tumor nodules (15.7 times less than DOX group) and the size of tumor nodules (0.83mM vs 1.64mm) (Figure 2E, f) (image source: angel Chem Int ed.) next, the author explored the reason why DOX @ AuNPs has better anticancer effect than DOX Through the quantitative analysis of the drug content in the tumor site, the author found that DOX @ AuNPs can enrich more drugs to the tumor site After one hour, the drug content in the tumor site was 3.35 ± 0.17% ID / g, 1.6 times of DOX group, 12 times of DOX group after 12 hours, and 4.8 times of DOX group after 48 hours (Figure 3a) The results show that DOX @ AuNPs can carry more drugs out of tumor blood vessels and into deep tissues (Figure 3B, c) These results show that DOX @ AuNPs has better antitumor effect than DOX because more drugs are concentrated in the tumor site and penetrate into the deep part of the tumor for a longer time (image source: angelw Chem Int ed.) finally, the author analyzed the drug content of other healthy tissues and organs and the side effects of drugs on other organs The quantitative analysis of drugs in various tissues showed that DOX @ AuNPs carried drugs more easily and faster from muscle tissue, heart, lung and other organs, and the corresponding drug concentration was significantly lower than that in DOX group (Figure 4e-h) The analysis of hepatorenal toxicity shows that DOX can significantly increase the levels of AST and ALT in blood, which means the acute injury of liver parenchyma cells; at the same time, DOX can significantly increase the contents of bun and crea in blood, which means the acute renal injury On the contrary, DOX @ AuNPs caused the rise of the above four indexes significantly lower than DOX, which indicated that the side effects of DOX @ AuNPs on liver and kidney were significantly lower than DOX (Figure 4a-d) (image source: angelw Chem Int ed.) to sum up, this study shows that carrying anticancer drugs with gold nanoparticles that can be removed by the kidney can not only achieve high tumor penetration and enrichment of the drug, but also make the retention time of the drug in the tumor site longer than that of small molecule drugs through the rapid renal clearance of the drug In addition, DOX @ AuNPs significantly reduced DOX enrichment and toxic side effects in healthy organs due to rapid renal clearance and reduced drug-tissue interaction These results show that the renal removable nanoparticles can achieve high vascular permeability and low systemic toxicity at the same time, thus significantly enhancing the anti-cancer effect and anti metastasis effect of the drug.