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Cocktail treatment has become an effective multidrug medication therapy for many diseases, because of the additive or synergistic effect of each medicine and relief from adverse effects of drugs. Nanotechnology offers an unparalleled opportunity for co-delivery strategies with the ability to simultaneously release various drugs and controllably unify the pharmacokinetics. In this work, we formulated a cocktail composed of hydrogen sulfide-releasing aspirin (HS-ASP) and paclitaxel (PTX) in a single delivery system, which is fabricated by a biodegradable block copolymer (i.e., methoxy poly(ethylene glycol)–polycaprolactone). The resulting drug cocktail-loaded nanoparticles possess small and narrow size distribution (∼44 nm), high dual-drug encapsulation efficiency, pH-sensitivity and simultaneous drug release capability. The co-delivery of HS-ASP and PTX has significantly decreased the IC50 value of PTX on LL/2 cells by 17.7-fold compared with single free PTX and by 5.4-fold compared with PTX NPs. Meanwhile, its cellular uptake is improved by 2.67-fold compared with free HS-ASP/FITC-PTX, and it enhanced the cellular apoptosis (53.62%) as well as the cell cycle blocking at G2/M phase (47.9%) relative to other formulations. Confocal laser scanning results show that HS-ASP inhibited the mitosis of LL/2 cells, thereby sensitizing the cells to the tubulin disruption effect, which is a major apoptosis mechanism of PTX. Overall, such a combinational and controlled release strategy is expected to hold great potential for clinical use in cancer therapy.

Background Ischemic vascular diseases are the major cause of death worldwide. In recent years, endothelial cell (EC)-based approaches to vascular regeneration are increasingly viable strategies for treating ischemic diseases, but their applications are challenged by the difficulties in their efficient generation and stable maintenance. Here, we show an alternative protocol that facilitates the generation of functional and expandable ETS variant 2 (ETV2)-induced endothelial-like cells (EiECs) from human adipose-derived stem cells (hADSCs), providing a potential source of cells for autologous ECs to treat ischemic vascular diseases. Methods hADSCs were obtained from fresh human adipose tissue. Passage 3 hADSCs were transduced with doxycycline (DOX)-inducible ETV2 transcription factor; purified ETV2-hADSCs were induced into endothelial-like cells using a two-stage induction culture system composed of small molecule compounds and cell factors. EiECs were evaluated for their surface markers, proliferation, gene expression, secretory capacity, and effects on vascular regeneration in vivo. Results We found that short-term ETV2 expression combined with TGF-β inhibition is sufficient for the generation of kinase insert domain receptor (KDR)+ cells from hADSCs within 10 days. KDR+ cells showed immature endothelial characteristics, and they can gradually mature in a chemically defined induction medium at the second stage of induction. Futher studies showed that KDR+ cells deriving EC-like cells could stably self-renew and expand about 106-fold in 1 month, and they exhibited expected genome-wide molecular features of mature ECs. Functionally, these EC-like cells significantly promoted revascularization in a hind limb ischemic model. Conclusions We isolated highly purified hADSCs and effectively converted them into functional and expandable endothelial-like cells. Thus, the study may provide an alternative strategy to obtain functional EC-like cells with potential for biomedical and pharmaceutical applications. Electronic supplementary material The online version of this article (10.1186/s13287-018-1088-6) contains supplementary material, which is available to authorized users.

Brain drug delivery is still facing significant challenges due to the low permeability of the blood–brain barrier (BBB). To overcome such an insurmountable obstacle, we developed gemini quaternary ammonium (GQA) as a cell penetrating molecule incorporated into biodegradable multiblock poly(e-caprolactone urethanes)s (BMPUs) drug nanocarriers for improvement of drug accumulation in brain parenchyma. The zeta potential of Dox-loaded GQA-BMPUs micelles was around 26 mV with a mean particle size near 100 nm. It was found that GQA-BMPUs micelles achieved steadily time-dependent and concentration-dependent Dox accumulation in human brain microvascular endothelial cells (HBMECs) much higher than GQA-free BMPUs micelles and free Dox, as confirmed by flow cytometry and confocal laser scanning microscopy (CLSM) experiments. Meanwhile, no pronounced cytotoxicity was noticed in GQA-BMPUs micelles and GQA-free BMPUs micelles, and Dox associated cytotoxicity might be reduced once encapsulated into micelles. More importantly, CLSM of brain sections showed higher accumulation of Dox-loaded GQA-BMPUs micelles in the subcortical area after administrated intravenously, while no Dox accumulation was observed in either Dox-BMPUs micelles or free Dox formulation. Coupling with in vivo pharmacokinetics, biodistribution and histological toxicity studies, the results show that GQA introduced into drug nanocarriers is a promising avenue to transport therapeutic agents across BBB and improve brain drug accumulation.

Anti-angiogenesis has been a promising strategy for cancer therapy. However, many signal pathways are activated during anti-angiogenic treatment to counteract the therapeutic efficacy. Among these pathways, evidence has directly pointed to the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway, whose activation resulted in tolerance to the absence of nutrients and oxygen when tumor angiogenesis has been inhibited. In the present study, we investigated the effects of blocking activation of the PI3K/Akt pathway on cell survival in vitro and tumor growth in vivo during anti-angiogenesis therapy. In modeled microenvironments in vitro, we observed that the phosphorylation of Akt in tumor cells was increased gradually in the absence of serum and oxygen in a time-dependent manner. The specific inhibitors of PI3K inhibited the proliferation of tumor cells in a dose-dependent manner in vitro. Moreover, inhibition was enhanced gradually with increased serum deprivation and/or hypoxia. In a mouse tumor model, we found the phosphorylation of Akt obviously increased following anti-angiogenic therapy using plasmids encoding soluble vascular endothelial growth factor receptor-2, but significantly reduced after treatment with LY294002. Consequently, the combinational treatment exhibited better antitumor effects compared with single treatments, presenting larger necrosis-like areas, more apoptotic cells, less microvessel density and less phosphorylated Akt in tumors. These results suggest that blocking activation of the PI3K/Akt pathway during anti-angiogenesis therapy could enhance antitumor efficacy. Thus, targeting the PI3K/Akt pathway might be a promising strategy to reverse tumor resistance to anti-angiogenesis therapy. (Cancer Sci 2011; 102: 1469–1475)