Programmable "triple attack" cancer therapy through in situ activation of disulfiram toxification combined with phototherapeutics.

Effectively and completely eliminating residual tumor cells is the key to reducing the risk of tumor metastasis and recurrence. Designing an "ideal" nanoplatform for programmable cancer therapy has great prospects for completely eliminating residual tumor cells. Herein, an intelligent nanoplatform of disulfiram (DSF)-loaded CuS-tannic acid nanohexahedrons (denoted as "DSF-CuS@TA") with thermal- and pH-sensitive degradation, as well as near-infrared (NIR-II) phototherapeutics properties, was constructed. And then, it was employed for in situ DSF toxification activation programmable "triple attack" cancer therapy. After accumulating in the tumor, DSF-CuS@TA first releases the loaded Cu(DTC)2, and simultaneously degrades and releases Cu2+ and DSF under mildly acidic stimulation to trigger instant intratumoral Cu(DTC)2 chelation, thereby achieving the "first strike." Next, under irradiation by a NIR-II laser, light energy is converted into heat to generate NIR-II photothermal therapy, thereby achieving the second strike. Subsequently, under thermal stimulation, DSF-CuS@TA degrades further, triggering the chelation of Cu(DTC)2 for a second time to reach the third strike. As expected, in vitro and in vivo studies showed that the synergistic integration of DSF-based programmed chemotherapy and NIR-II phototherapeutics could achieve effective tumor removal. Therefore, we propose a novel type of programmed therapy against cancer by designing a nanoplatform via "nontoxicity-to-toxicity" chemical chelation transformation.

Transplantation of induced pluripotent stem cells-derived cardiomyocytes combined with modified Taohong Siwu decoction improved heart repair after myocardial infarction.

Objective: This study aimed to study whether modified Taohong Siwu decoction (MTHSWD) combined with human induced pluripotent stem cells-derived cardiomyocytes (iPS-CMs) transplantation can promote cardiac function in myocardial infarction (MI) nude mouse model and explore its possible mechanism. Methods: The MI mouse model was established by the ligation of left anterior descending coronary artery. After 4 weeks of gavage of MTHSWD combined with iPS-CMs transplantation, the changes in heart function of mice were examined by echocardiography. The histological changes were observed by Masson's trichrome staining. The survival and differentiation of transplanted cells were detected by double immunofluorescence staining of human nuclear antigen (HNA) and cardiac troponin T (cTnT). The number of c-kit-positive cells in the infarct area were evaluated by immunofluorescent staining. The levels of stromal cell-derived factor 1 (SDF-1), stem cell factor (SCF), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor in infarcted myocardium tissues were detected by ELISA. Results: MTHSWD combined with iPS-CMs transplantation can improve the heart function of MI mice, reduce the infarct size and collagen deposition in infarct area. By immunofluorescence double-label detection of HNA and cTnT, it was found that MTHSWD combined with iPS-CMs transplantation can improve the survival and maturation of iPS-CMs. In addition, MTHSWD combined with iPS-CMs transplantation can activate more endogenous c-kit positive cardiac mesenchymal cells, and significantly increase the content of SDF-1, SCF and VEGF in myocardial tissues. Conclusions: The combination of MTHSWD with iPS-CMs transplantation promoted cardiac function of nude mice with MI by improving the survival and maturation of iPS-CMs in the infarct area, activating the endogenous c-kit positive cardiac mesenchymal cells, and increasing paracrine.

Guanxin Danshen Formulation improved the effect of mesenchymal stem cells transplantation for the treatment of myocardial infarction probably via enhancing the engraftment.

Although intravenous injection is the most convenient and feasible approach for mesenchymal stem cells (MSCs) delivery, the proportion of donor stem cells in the target myocardium after transplantation is small. It is believed that TCM enhances the effect of stem cell therapy by improving the hostile microenvironment and promoting the migration and survival of stem cells. Guanxin Danshen (GXDS) formulation is one of the main prescriptions for clinical treatment of ischemic heart diseases in China. The purpose of this study was to evaluate the effects of GXDS formulation administration combined with MSCs transplantation on cardiac function improvement, apoptosis, angiogenesis and survival of transplanted cells in an acute model of acute myocardial infarction (MI). After being labeled with GFP, MSCs were transplanted via intravenous injection. Meanwhile, GXDS dripping pills were given by intragastric administration for 4 weeks from 2 days before MI. Echocardiography showed moderate improvement in cardiac function after administration of GXDS formulation or intravenous transplantation of MSCs. However, GXDS formulation combined with MSCs transplantation significantly improved cardiac function after MI. The myocardial infarct size in rats treated with MSCs was similar to that in rats treated with GXDS formulation. However, GXDS formulation combined with MSCs transplantation significantly reduced infarction area. In addition, GXDS formulation combined with MSCs transplantation not only decreased cell apoptosis according to the TUNEL staining, but also enhanced angiogenesis in the peri-infarction and infarction area. Interestingly, the use of GXDS formulation increased the number of injected MSCs in the infarct area. Furthermore, GXDS formulation combined with MSCs transplantation increased SDF-1 levels in the infarcted area, but did not affect the expression of YAP. Our study provided a more feasible and accessible strategy to enhance the migration of stem cells after intravenous injection by oral administration of GXDS formulation. The combination of GXDS formulation and stem cell therapy has practical significance and application prospects in the treatment of ischemic cardiomyopathy such as MI.

Self-assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction.

The lower cell survival and retention in the hostile microenvironment after transplantation has been implicated as a major bottleneck in the advancement of stem cell therapy for myocardial infarction (MI). In this study, we designed a novel self-assembling peptide (SAP) by attaching prosurvival peptide QHREDGS derived from angiopoeitin-1 to the known SAP, RADA16-I. The mesenchymal stem cells (MSCs) were harvested from male rats and cytoprotective effect of this designer SAP (DSAP) on cultured MSCs was detected by Hoechst 33342 staining after being exposed to oxygen and glucose deprivation (OGD). The cytoprotective effect of MSCs seeded in DSAP (DSAP-MSCs) on OGD treated cardiomyocytes was examined by TUNEL staining, phosphorylated (p-) protein kinase B (Akt) level, and ELISA. The therapeutic potential of MSC transplantation carried in DSAP was evaluated in a female rat MI model. PBS, MSCs alone, MSCs seeded in SAP (SAP-MSCs), or DSAP-MSCs were transplanted into the border of the infarcted area, respectively. DSAP not only increased the proliferation of MSCs and decreased apoptosis of MSCs after OGD treatment but also promoted the secretion of IGF-1 and HGF in MSCs. Treatment with culture supernatant of DSAP-MSCs markedly reduced the percentage of apoptotic cardiomyocytes and increased the level of p-Akt. Compared with the MSC group and SAP-MSC group, DSAP-MSC injection improved cardiac function and reduced infarct size, collagen content, and cell apoptosis. The number of Y chromosome-positive cells and microvessels in the DSAP-MSC group was higher than those in the MSC group and SAP-MSC group. Moreover, DSAP-MSC transplantation down-regulated the expression of IL-6 and IL-1ß and up-regulated the level of VEGF and HGF. Interestingly, miR-21 was enriched in DSAP-MSC-derived exosomes (DSAP-MSC-Exos) and the protection against cardiomyocyte apoptosis by DSAP-MSC-Exos was inhibited when miR-21 was knocked down. Furthermore, miR-21 contributed to the improvement of cardiac function after DSAP-MSC-Exo injection in a rat model of MI. Additionally, the combination of DSAP and cardiotrophin-1 (Ctf1) pretreatment further improved the survival of MSCs and the efficiency of MSC transplantation. We proposed QHREDGS-modified SAP as an effective cell delivery system and demonstrated that MSC transplantation in this DSAP promoted angiogenesis and paracrine, thereby reducing scar size and cell apoptosis as well as improving cardiac function probably via exosome-mediated miR-21 after MI. Furthermore, for the first time, we proposed that DSAP, especially working together with Ctf1 pretreatment, could be a valuable way to improve the survival of MSCs and the efficiency of MSC transplantation after MI.-Cai, H., Wu, F.-Y., Wang, Q.-L., Xu, P., Mou, F.-F., Shao, S.-J., Luo, Z.-R., Zhu, J., Xuan, S.-S., Lu, R., Guo, H.-D. Self-assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction.