•An intelligent tropical administration system for skin cancer therapy was developed.•It was made by coating of amphipathic polymer P(BA-co-HBA) on docetaxel (TXT, a model hydrophobic anticancer drug) loaded Fe3O4@ZnO.•Under a safe UV, this system has the potential to change tumor microenvironment through removal of cancerous secretion.•Under a safe UV, the antitumor drug was released and effected to tumor cells.Cancer is a leading fatal disease worldwide. To increase its therapeutic efficiency, more effective with less side effect and patient acceptable administration approach is expected. Moreover, modification of tumor microenvironment is proved to be operative recently. In this paper, a nanocarrier named LDEDDS was developed for intelligent tropical administration of skin cancer, along with removal of hydrophobic cancerous secretion to change tumor microenvironment. It was made by coating of amphipathic polymer P(BA-co-HBA) on docetaxel (TXT, a model hydrophobic anticancer drug) loaded Fe3O4@ZnO. Results showed that an optimal loading rate of TXT in Fe3O4@ZnO was 89.75 ± 0.15%, corresponding to loading capacity of 17.95 ± 2.97% when the mass ratio of Fe3O4@ZnO to TXT was 1:20. The LDEDDS had a narrow distribution size of 115.8 nm in average and was superparamagnetic. Without UV radiation, it had low TXT release (< 7% in 48 h) and cytotoxicity (< 14% in 96 h) to both the normal and carcinoma skin cells. While under a UV with a dose much lower than physiological dose of normal sunlight, LDEDDS released around 60% and 90% of TXT in 1 and 48 h. 1 h UV treated LDEDDS removed up to 62% of cancer secreted epidermal growth factor (EGF), a model hydrophobic secretion in 96 h. Consequently, 1 h UV treated LDEDDS inhibited up to 60% of the growth of skin cancer cells in 96 h, overriding those effects of the same concentration of TXT in in vitro cellular experiments. This is the first study to change tumor microenvironment by removal of cancerous secretion and is proved to be effective. Along with the superparamagnetic property, which provides potential for concentrating, increasing penetration and internalization into cancerated cells as well as removing from body under an external magnetic field, we predict LDEDDS will have potential applications in clinic skin cancer therapy.Download high-res image (109KB)Download full-size image

Manipulation of genes in human embryonic stem cells (hESCs) is imperative for their highly potential applications; however, the transduction efficiency remains very low. Although existing evidence revealed the type, size, and zeta potential of vector affect gene transfection efficiency in cells, the systematic study in hESCs is scarce. In this study, using poly(amidoamine) (PAMAM) dendrimers ended with amine, hydroxyl, or carboxyl as model, we tested the influences of size and surface group as well as cytotoxicity and endocytosis on hESC gene transfection. We found that in culture medium of mTeSR the particle sizes of G5, G7, G4.5COOH, and G5OH were around 5 nm and G1 had a smaller size of 3.14 nm. G5 and G7 had a slight and significant positive zeta potential, respectively, whereas G1 was slightly negative, and G4.5COOH and G5OH were significantly negative. We demonstrated that only amine-terminated dendrimers accomplished gene transfection in hESCs, which is greater than that from Lipofectamine 2000 transfection. Ten micromolar G5 had the greatest efficiency and was better than 1000 μM G1. Only a low concentration (0.5 and 1 μM) of G7 realized gene delivery. Amine-ended dendrimers, especially with higher generations, were detrimental to the growth and pluripotent maintenance of hESCs. In contrast, similarly sized hydroxyl- and carboxyl-terminated dendrimers exerted much lower cytotoxicity, in which carboxyl-terminated dendrimer maintained pluripotency of hESCs. We also confirmed the endocytosis into and significant exocytosis from hESCs using FITC-labeled G5 dendrimer. These results suggested that careful considerations of size, concentration, and zeta potential, particularly the identity and position of groups, as well as minimized exocytosis in the design of a vector for hESC gene delivery are necessary, which helps to better design an effective vector in hESC gene transduction.Keywords: dendrimer; embryonic stem cells; end group; endocytosis; gene transfection; size

•A novel drug delivery has been synthesized which could dual-target to ovarian cancer.•The drug delivery could give sustained inhibition to Skov3 cells.•The drug delivery is of good biocompatibility.In order to improve the therapeutic efficiency and reduce the side effects on nonpathological cells and tissues, targeting drug delivery systems have gained more and more attraction. Here, we report a novel dual-targeting drug delivery system for ovarian cancer therapy. The inner core was made of iron oxide (Fe3O4) nanoparticles, synthesized by co-precipitation method. It was further surface-functionalized with amine groups to link single-chain antibody (scFv) and β-cyclodextrin (β-CD). Docetaxel (TXT) was finally included in the grafted β-CD. FTIR and XPS confirmed the reactions. SEM found that the diameters of these Fe3O4 nanoparticles before and after functionalization were around 40 nm. Magnetization test showed that these particles were superparamagnetic. The in vitro release of TXT was concentration-driven and sustained, depending on the renewal rate of release medium. The in vitro flow chamber experiment revealed its magnetic targeting property; modified ELISA and static binding experiments displayed its good affinity to Endoglin, indicating that our drug delivery system has the potential to be dual-targeted to ovarian cancer tissue by externally applied magnetic field and native active binding of grafted scFv to Endoglin, overexpressed by ovarian cancer tissue. MTT assays showed that the TXT released from this drug delivery system continuously inhibited the growth of Skov3 ovarian cancer cells in 72 h, better than the control raw TXT. All these results demonstrated a promising dual-targeting drug delivery system with great potential for ovarian cancer therapy.

The present study reports a UV and dark-triggered highly intelligent drug delivery system for skin protection. ZnO nanoparticles (NPs), a UV filter, were synthesized and characterized to be the carrier for benzophenone-3 (Bp-3), a UV-absorption medicine, by varying the molar ratio of ZnO NPs to Bp-3 ranging from 300:1 to 20:1. The drug release under three cycles of UV and dark stimulation (each for two hours) and its cytotoxicity to human keratinocyte cells and skin fibroblasts were investigated. SEM studies showed the diameter of ZnO was around 30 to 40 nm, which assembled into loose and large NPs ranging from 500 to 1400 nm. Contact angle tests showed ZnO NPs switched to a more hydrophilic and back to a more hydrophobic state under two hours of UV and dark exposure. The optimized encapsulation efficiency and loading capacity of Bp-3 were 53.68 ± 0.13% and 133.61 ± 0.20% when the molar ratio of ZnO NPs to Bp-3 was 150:1 and 80:1. The Bp-3 was almost completely released from ZnO NPs under 2 hours of UV radiation and was mostly encapsulated in after 2 hours of dark stay in three cycles of UV and dark exposure. The Bp-3 loaded ZnO NPs showed low cytotoxicity to human keratinocyte cells and human skin fibroblasts. Overall, a UV and dark-triggered repetitively on-demand drug delivery system biocompatible to skin cells and potential for skin protection from UV radiation was developed.

It is well accepted that osteoblasts respond to fluid shear stress (FSS) depending on the loading magnitude, rate, and temporal profiles. Although in vivo observations demonstrated that bone mineral density changes as the training intensity gradually increases/decreases, whether osteoblasts perceive such slow temporal changes in the strength of stimulation remains unclear. In this study, we hypothesized that osteoblasts can detect and respond differentially to the temporal gradients of FSS. In specific, we hypothesized that when the temporal FSS gradient is high enough, (i) the increasing FSS inhibits the osteoblastic potential in supporting osteoclastogenesis and enhances the osteoblastic anabolic responses; (ii) on the other hand, the deceasing FSS would have opposite effects on osteoclastogenesis and anabolic responses. To test the hypotheses, stepwise varying FSS was applied on primary osteoblasts and osteogenic and resorption markers were analyzed. The cells were subjected to FSS increasing from 5, 10, to 15 or decreasing from 15, 10, to 5 dyn/cm2 at a step of 5 dyn/cm2 for either 6 or 12 h. In a subset experiment, the cells were stimulated with stepwise increasing or decreasing FSS at a higher step (10 dyn/cm2) for 12 h. Our results showed that, with the step of 5 dyn/cm2, the stepwise increasing FSS inhibited the osteoclastogenesis with a 3- to 4-fold decrease in RANKL/OPG gene expression vs. static controls, while the stepwise decreasing FSS increased RANKL/OPG ratio by 2- to 2.5-fold vs. static controls. Both increasing and decreasing FSS enhanced alkaline phosphatase expression and calcium deposition by 1.0- to 1.8 fold vs. static controls. For a higher FSS temporal gradient (three steps of 10 dyn/cm2 over 12 h stimulation), the increasing FSS enhanced the expression of alkaline phosphatase expression and calcium deposition by 1.3 fold, while the decreasing FSS slightly inhibited them by −10% compared with static controls. Taken together, our results suggested that osteoblasts can detect the slow temporal gradients of FSS and respond differentially in a dose-dependent manner, which may account for the observed bone mineral density changes in response to the gradual increasing/decreasing exercise in vivo. The stepwise FSS can be a useful model to study bone cell responses to long-term mechanical usage or disuse. These studies will complement the short-term studies and provide additional clinically relevant insights on bone adaptation.

Osteoarthritis (OA) is a degenerative joint disease and one of the leading causes of disability in the United States and across the world. As a disease of the whole joint, OA exhibits a complicated etiology with risk factors including, but not limited to, ageing, altered joint loading, and injury. Subchondral bone is hypothesized to be involved in OA development. However, direct evidence supporting this is lacking. We previously detected measurable transport of solute across the mineralized calcified cartilage in normal joints, suggesting a potential cross-talk between subchondral bone and cartilage. Whether this cross-talk exists in OA has not been established yet. Using two models that induced OA by either ageing or surgery (destabilization of medial meniscus, DMM), we tested the hypothesis that increased cross-talk occurs in OA. We quantified the diffusivity of sodium fluorescein (mol. wt. 376 Da), a marker of small-sized signaling molecules, within calcified joint matrix using our newly developed fluorescence loss induced by photobleaching (FLIP) method. Tracer diffusivity was found to be 0.30 ± 0.17 and 0.33 ± 0.20 μm2/s within the calcified cartilage and 0.12 ± 0.04 and 0.07 ± 0.03 μm2/s across the osteochondral interface in the aged (20–24-month-old, n = 4) and DMM OA joints (5-month-old, n = 5), respectively, which were comparable to the control values for the contralateral non-operated joints in the DMM mice (0.48 ± 0.13 and 0.12 ± 0.06 μm2/s). Although we did not detect significant changes in tissue matrix permeability in OA joints, we found i) an increased number of vessels invading the calcified cartilage (and sometimes approaching the tidemark) in the aged (+ 100%) and DMM (+ 50%) joints relative to the normal age controls; and ii) a 60% thinning of the subchondral bone and calcified cartilage layers in the aged joints (with no significant changes detected in the DMM joints). These results suggested that the capacity for cross-talk between subchondral bone and articular cartilage could be elevated in OA. Further studies are needed to identify the direction of the cross-talk, the signaling molecules involved, and to test whether subchondral bone initiates OA development and could serve as a pharmaceutical target for OA treatment.This article is part of a Special Issue entitled “Osteoarthritis”.Highlights► Bone-cartilage cross-talk examined in two models (surgical DMM and ageing) of OA. ► Decreased (but not significant) tissue permeability in mineralized ECM of OA joints. ► Increased vessels invasion in aged (+100%) and DMM (+50%) joints vs. controls. ► 60% thinning of thickness in aged joints and no changes in DMM joints vs. controls. ► Bone-cartilage cross-talk elevated in the two OA models via different mechanisms.