Study on the treatment for abnormality of metal ions with EDTA complexing agent-loaded microsphere sustained release system

Abstract

Objective To construct a new sustained-release system, hollow mesoporous silica nanoparticles (HMSNs), to control the release of ethylene diamine tetraacetic acid (EDTA) continuously, effectively and intelligently to treat the abnormal increase of metal ions in vivo. The disulfide bond can be broken or reconstructed with the change of H+ concentration to realize the construction of receptor, and the is constructed by blocking cucurbituril and alpha-cyclodextrin through disulfide bond. Thus, the abnormal increase of chromium and cobalt ions in rats can be accurately controlled and maintained at normal levels. Methods HMSNs-EDTA sensitive to H+ was prepared. HMSNs containing functional groups of alpha-cyclodextrin were constructed. The disulfide bond was formed between the HS group at the end of cucurbituril and the HS group of alpha-cyclodextrin as a switch. Cucurbituril and alpha-cyclodextrin are connected by disulfide bond to form a valve system, which can block silica channels and thus close EDTA. A rat model of elevated chromium and cobalt ions was established by intraarticular injection of CoCrMo nanoparticles suspension into the knee joint. Rat models were randomly divided into three groups: intraperitoneal injection of saline (control group), intraperitoneal injection of traditional drug sustained release (IgG-HMSNs-EDTA group), and intraperitoneal injection of H+ sensitive cucurbituril-HMSNs-EDTA sustained release (intelligent sustained release system group). During this process, nanoparticle suspension was injected continuously to observe the changes of serum chromium and cobalt concentration in rats. Results From the release curve of EDTA, it was found that the higher the concentration of H+ was, the faster the drug release was (H+ concentration group: 2 mmol/L>1 mmol/L>0.5 mmol/L>0.1 mmol/L). It shows that the sensor does control the valve with the change of H+ concentration. Compared with the slow-release body without valve, the release of EDTA in the new intelligent slow-release body is gentler. Within 20 weeks, the concentration of metal ions in the control group increased continuously and slowly due to the absence of EDTA treatment (Chromium 1.08±0.07 ug/L and cobalt 41.14±0.79 ug/L). In the traditional valve group, the metal ions decreased rapidly within 8 weeks and were once lower than the normal values in rats. Subsequently, due to the release of EDTA, metal ions will still increase abnormally (Chromium ion 0.61±0.52 ug/L, cobalt ion 28.72±16.93 ug/L). The intelligent sustained-release system group can more effectively, continuously and accurately control the abnormal changes of chromium and cobalt ions in vivo, and the difference is statistically significant (Chromium ion 0.65±0.13 ug/L, cobalt ion 29.68±3.24 ug/L). Conclusion According to the principle that disulfide bond can be broken or reconstructed with the change of H+ concentration, the application of cucurbituril-HMSNs-EDTA intelligent microsphere sustained release system to treat patients with increased chromium and cobalt ions caused by plants in metal will control the drug release more accurately and intelligently. The intelligent sustained-release system can not only avoid the side effects caused by the rapid and excessive release of drugs, which lead to the disorder of normal trace metal elements in vivo, but also prolong the treatment time, and can maintain the chromium and cobalt ions in rats at normal levels for a long time. Key words: Metal; Coordination complexes; Nanostructures