Regulation of drug release performance using mixed doxorubicin-doxorubicin dimer nanoparticles as a pH-triggered drug self-delivery system.

A mixed drug self-delivery system (DSDS) with high drug content (>50%) was developed to regulate pH-triggered drug release, based on two doxorubicin (DOX)-DOX dimmers: D-DOXADH and D-DOXcar conjugated with acid-labile dynamic covalent bonds (hydrazone and carbamate, respectively) and stabilized with PEGylated D-DOXADH (D-DOXADH-PEG). Owing to the different stability of the dynamic covalent bonds in the two dimers and the noncovalent interaction between them, pH-triggered drug release could be easily regulated by adjusting the feeding ratios of the two DOX-DOX dimers in the mixed DSDS. Similar in vitro cellular toxicity was achieved with the mixed DSDS nanoparticles prepared with different feeding ratios. The mixed DSDS nanoparticles had a similar DOX content and diameter but different drug releasing rates. The MTT assays revealed that a high anti-tumor efficacy could be achieved with the slow-release mixed DSDS nanoparticles.

Regulation of drug release performance using mixed doxorubicin-doxorubicin dimer nanoparticles as a pH-triggered drug self-delivery system / 药物分析学报

A mixed drug self-delivery system(DSDS)with high drug content(＞50％)was developed to regulate pH-triggered drug release,based on two doxorubicin(DOX)-DOX dimmers:D-DOXADH and D-DOXcar con-jugated with acid-labile dynamic covalent bonds(hydrazone and carbamate,respectively)and stabilized with PEGylated D-DOXADH(D-DOXADH-PEG).Owing to the different stability of the dynamic covalent bonds in the two dimers and the noncovalent interaction between them,pH-triggered drug release could be easily regulated by adjusting the feeding ratios of the two DOX-DOX dimers in the mixed DSDS.Similar in vitro cellular toxicity was achieved with the mixed DSDS nanoparticles prepared with different feeding ratios.The mixed DSDS nanoparticles had a similar DOX content and diameter but different drug releasing rates.The MTT assays revealed that a high anti-tumor efficacy could be achieved with the slow-release mixed DSDS nanoparticles.

Remodeling the periodontitis microenvironment for osteogenesis by using a reactive oxygen species-cleavable nanoplatform.

Modestly removing the excessive reactive oxygen species (ROS) plays a crucial role in regulating the microenvironment of periodontitis and provides favorable conditions for osteogenesis. However, the current strategy for scavenging ROS is not controllable, substantially limiting the outcomes in periodontitis. Herein, we introduced a controllable ROS-scavenging nanoplatform by encasing N-acetylcysteine (NAC, (a well-known ROS scavenger) into tailor-made ROS-cleavable amphiphilic polymer nanoparticles (PEG-ss-PCL NPs) as an intracellular delivery carrier. The existing ROS in the inflammatory microenvironment facilitated polymer degradation via breakage of thioketal bonds, and then led to encapsulated NAC release. NAC eliminated all ROS induced by lipopolysaccharide (LPS), while PssL-NAC adjusted the ROS level slightly higher than that of the control group. The percentage of apoptotic cells cultured with NAC and PssL-NAC decreased observably compared with that of cells cultured with 10 µg/ml LPS. The microenvironment regulated by PssL-NAC was highly suitable for osteogenic differentiation based on PCR and Western blot results, which showed higher expression levels of BMP2, Runx2, and PKA. Analysis of ALP activity and Alizarin red S staining showed consistent results. Additionally, the injection of PssL-NAC into the periodontitis area could alleviate the tissue destruction induced by ligation of the maxillary second molar. PssL-NAC showed a better ability to decrease osteoclast activity and inflammation, consequently improving the restoration of destroyed tissue. Our study suggests that ROS-responsive polymer nanoparticles loaded with NAC (PssL-NAC) can be new promising materials for the treatment of periodontitis. STATEMENT OF SIGNIFICANCE: More and more studies indicate that periodontal tissue damage is closely related to the high reactive oxygen species (ROS) environment. Excessive ROS will aggravate periodontal tissue damage and is not conducive to tissue repair. However, as an essential signal molecule in human physiological activities, ROS absence is also useless for tissue repair. In this study, we proposed to improve ROS imbalance in the environment of periodontitis as a strategy to promote periodontal regeneration and successfully synthesized a smart drug-releasing nanoplatform that can respond to ROS. Besides, we validated its ability to regulate the ROS environment and promote osteogenesis through experimental data in vivo and in vitro.