Nakamura, TakashiHaloha, Sion Elisabeth ElfainaturHarashima, Hideyoshi
12页
查看更多>>摘要：Adjuvant loaded nanoparticles are a potent strategy for developing effective combined cancer immunotherapies. A polyinosinic-polycytidylic acid (poly I:C) is a ligand for toll-like receptor 3 and a promising cancer adjuvant. However, regarding intravenous administration, the potential for and the mechanism of poly I:C loaded nano particles as a cancer vaccine are largely unknown. We investigated the effects of using a combination of poly I:C and an antigen loaded liposome for cancer immunotherapy and a key process for achieving effective antitumor immunity of the liposome system under conditions of intravenous vaccination. A poly I:C and ovalbumin (OVA) loaded octaarginine (R8) modified liposome (PoIC/OVA-R8L) drastically inhibited the systemic cytokine production derived from the poly I:C intravenous injection. Treatment with PoIC/OVA-R8L improved the immune status in B16-OVA tumors to an inflamed immune status and induced a significant combined antitumor effect with the anti-programmed cell death 1 ligand (PD-L1). In a mechanistic analysis compared with a high dose of the free form of poly I:C, interestingly, local cytokine production, maturation of antigen presenting cells and antigen presentation were comparable. Conversely, significant differences were identified in the processes after OVA-specific CTL generation. Collectively, our findings have implications for the development of intravenous liposomal vaccines.
查看更多>>摘要：Understanding the composition and function of the blood brain barrier (BBB) enables the development of novel, innovative techniques for administering central nervous system (CNS) medications and technologies for improving the existing models. Scientific and methodological interest in the pathology of the BBB resulted in the formation of numerous in vitro BBB models. Once successfully studied and modelled, it would be a valuable tool for elucidating the mechanism of action of the CNS disorders prior to their manifestation and the pathogenic factors. Understanding the rationale behind the selection of the models as well as their working may enable the development of state-of-the-art drugs for treating and managing neurological diseases. Hence, to have realistic simulation of the BBB and test its drug permeability the microfluidics-based BBB-on-Chip model has been developed. To summarise, we aim to evaluate the advanced, newly developed and frequently used in vitro BBB models, thereby providing a brief overview of the components essential for in vitro BBB formation, the methods of chip fabrication and cell culturing, its applications and the recent advances in this technological field. This will be critical for developing CNS treatments with improved BBB penetrability and pharmacokinetic properties.
查看更多>>摘要：Glycemic control through titration of insulin dosing remains the mainstay of diabetes mellitus treatment. Insulin therapy is generally divided into dosing with long -and short-acting insulin, where long-acting insulin provides basal coverage and short-acting insulin supports glycemic excursions associated with eating. The dosing of short-acting insulin often involves several steps for the user including blood glucose measurement and integration of potential carbohydrate loads to inform safe and appropriate dosing. The significant burden placed on the user for blood glucose measurement and effective carbohydrate counting can manifest in substantial effects on adherence. Through the application of computer vision, we have developed a smartphone-based system that is able to detect the carbohydrate load of food by simply taking a single image of the food and converting that information into a required insulin dose by incorporating a blood glucose measurement. Moreover, we report the development of comprehensive all-in-one insulin delivery systems that streamline all operations that peripheral devices require for safe insulin administration, which in turn significantly reduces the complexity and time required for titration of insulin. The development of an autonomous system that supports maximum ease and accuracy of insulin dosing will transform our ability to more effectively support patients with diabetes.
查看更多>>摘要：Transdermal delivery of solid nanoparticles remains a big problem. Microneedle administration and subcutaneous injection are the only two feasible approaches. Here, we developed a noninvasive strategy for the transdermal delivery of mesoporous silica nanoparticles (MSNs) using deep eutectic solvent (DES) from amino acid (AA) and citric acid (CA), which showed a substantial enhancement in skin penetration ability. MSNs were surface modified by CA and then reacted with Lysine (Lys) to form the DES-MSNs system. The covalent linkage of MSNs to the surrounding DES immobilized the nanoparticles and provided strong interactions. We used intradermal and transdermal penetration assays to identify that the AACA DES could synchronously drive the MSNs to penetrate across the entire skin via a "Drag" effect. Furthermore, this is the first study to detect the nanoparticles in the blood by topical administration routes. Thus, we achieved the transdermal delivery of the MSNs into blood circulation. This work would extend the application of the MSNs drug carrier system and provide a novel strategy for the controlled and sustained delivery of nanoparticles.
查看更多>>摘要：Dicer substrate RNA is an alternative gene silencing agent to canonical siRNA. Enhanced in vitro gene silencing can be achieved with RNA substrates by facilitating Ago2 loading of dsRNA after Dicer processing. However, the in vivo use of Dicer substrate RNA has been hindered by its instability and immunogenicity in the body due to the lack of proper chemical modification in the structure. Here, we report a universal chemical modification approach for Dicer substrate RNA nanostructures by optimizing protein-RNA interactions in the RNAi pathway. Proteins involved in the RNAi pathway were utilized for evaluating their recognition and binding of substrate RNA. It was found that conventional chemical modifications could severely affect the binding and processing of substrate RNA, consequently reducing RNAi activity. Protein-RNA interaction guided chemical modification was introduced to RNA nanostructures, and their gene silencing activity was assessed. The optimized RNA nano structures showed excellent binding and processability with RNA binding proteins and offered the enhancement of in vivo EC50 up to 1/8 of its native form.
查看更多>>摘要：The inhibition of autophagy is a feasible clinical strategy in tumor therapy. Traditional autophagy inhibitors are limited in clinical tumor therapy due to nonspecific biodistribution, systemic toxicity and limited antitumor effect. Herein, the autophagy inhibitor hydroxychloroquine (HCQ)-loaded nanodroplets (NDs) are synthesized to overcome these drawbacks. HCQ-NDs are endowed with endogenous pH-and exogenous ultrasound-responsive drug release and contrast enhanced ultrasound imaging performance. The combined application of ultrasound targeted microbubble destruction (UTMD) and HCQ-NDs can severely break the homeostasis of tumor cells, simultaneously releasing HCQ rapidly to block autophagic flux and thus abolish the cytoprotective function. This strategy presents strong synergistic antitumor efficacy with the tumor growth inhibition value of 80.02% and synchronously inhibits tumor lung metastasis by inhibition of MMP2 and MMP9 production, eventually leading to tumor suppression. In addition, HCQ-NDs show excellent tumor-targeting, biocompatibility, biosafety and contrast-enhanced ultrasound imaging properties. Based on the above findings, this combined strategy rationally regulates the autophagic process of tumor cells and could be instructive for the design of clinical treatment modalities.
查看更多>>摘要：Tumor-associated macrophages (TAMs), which dampen the therapeutic efficacy of cancer immunotherapy, are the key players in the immunosuppressive tumor microenvironment (TME). Therefore, reprogramming TAMs into tumoricidal M1 macrophages possesses considerable potential as a novel immunotherapy. However, the low bioavailability of polarization agents and limited accumulation of TAMs restrict their anti-tumor efficacy. In this study, we developed a polymer-based hypoxia-responsive nanocomplex to target TAMs in hypoxia for enhanced cancer immunotherapy. We synthesized a hypoxia-cleavable polymer poly(ethylene glycol)-azo-poly((L)-lysine) (PEG-azo-PLL) and formulated a nanocomplex by simple mixing PEG-azo-PLL and poly(I:C). By mimicking in vitro hypoxia conditions, PEG-azo-PLL/poly(I:C) complexes could transform the physicochemical properties to enhance the delivery efficiency of poly(I:C) to tumor hypoxia, where M2-like TAMs are accumulated. Furthermore, PEG-azo-PLL/poly(I:C) could successfully reduce the population of M2-like TAMs in hypoxic tumors and promoted infiltration of CD8(+) T cells in vivo, resulting in the favorable conversion of immunosuppressive TME. Finally, PEG-azo-PLL/poly(I:C) could elicit a significant in vivo anti-tumor effect in B16F10-bearing mice in addition to a prolonged survival time, demonstrating that the hypoxia-responsive nanocomplex PEG-azo-PLL/ poly(I:C) is a promising approach for TAM reprogramming immunotherapy for solid tumors.
查看更多>>摘要：As the major energy supplier in cells, mitochondria play a significant role in regulating cellular processes. The pathogenesis of various diseases is found to be associated with dysfunctional mitochondria, and supplement of functional mitochondria has been regarded as a potential therapeutic strategy. To achieve mitochondrial replenishment, transplantation of isolated mitochondria or utilization of cells as selective mitochondrial carriers have been developed. On the one hand, isolated mitochondria can be internalized into injured cells to restore impaired functions. On the other hand, the natural process of intercellular mitochondrial transfer can replace the dysfunctional mitochondria with functional mitochondria, providing a safe and effective way to rescue damaged tissues. Cell mediated mitochondrial transfer can serve as a promising targeted therapy with mitochondria being high-efficient biotherapeutics. In this review, we summarize the updated findings of mitochondrial delivery strategies, offering an overview of the role of mitochondria, mechanisms of intercellular mitochondrial transfer, therapeutic benefits, challenges and prospects of mitochondrial delivery. The understanding of mitochondrial delivery helps to improve the therapeutic outcomes of mitochondrial dysfunctional diseases in the future.
查看更多>>摘要：Exosomes as nanosized membrane vesicles, could targeted deliver therapeutic agents by modification with target ligands. Exosome-derived non-coding RNAs play a vital role in the development of tumors. Previous evidences reveal that long non-coding RNA maternally expressed gene 3 (lncRNA MEG3) has anti-tumor properties. Whereas, the inhibitory effects of exosome-derived lncRNA MEG3 in osteosarcoma (OS) remain largely un-known. In this study, we utilize the engineering technology to combine exosome and lncRNA for tumor-targeting therapy of OS. We elucidated the anti-OS effects of lncRNA MEG3, and then prepared the c(RGDyK)-modified and MEG3-loaded exosomes (cRGD-Exo-MEG3). The engineered exosomes cRGD-Exo-MEG3 could deliver more efficiently to OS cells both in vitro and in vivo. In this way, cRGD-Exo-MEG3 facilitate the anti-OS effects of MEG3 significantly, with the help of enhanced tumor-targeting therapy. This study elucidates that engineered exosomes as targeted lncRNA MEG3 delivery vehicles have potentially therapeutic effects for OS.
查看更多>>摘要：Dietary uptake of folic acid (FA) improves cartilage regeneration. In this work, we discovered that three days of FA treatment is highly effective for promoting chondrogenic differentiation of tonsil-derived mesenchymal stem cells (TMSCs). In a three-dimensional pellet culture, the levels of typical chondrogenic biomarkers, sulfated glycosaminoglycan, proteoglycan, type II collagen (COL II), SRY box transcription factor 9 (SOX 9), cartilage oligomeric matrix protein (COMP), and aggrecan (ACAN) increased significantly in proportion to FA concentration up to 30 mu M. At the mRNA expression level, COL II, SOX 9, COMP, and ACAN increased 3.6-6.0-fold with FA treatment at 30 mu M compared with the control system that did not receive FA treatment, and the levels with FA treatment were 1.6-2.5 times greater than those in the kartogenin-treated positive control system. FA treatment did not increase type I collagen alpha 1 (COL I alpha 1), an osteogenic biomarker which is a concern with most chondrogenic promoters. At the high FA concentration of 100 mu M, significant decreases in chondrogenic bio-markers were observed, which might be related to DNA methylation. A thermogel system incorporating TMSCs and FA provided sustained release of FA over several days, similar to the FA treatment. The thermogel system confirmed the efficacy of FA in promoting chondrogenic promotion of TMSCs. The increased nuclear trans-location of core-binding factor beta subunit (CBF beta) and the runt-related transcription factor 1 (RUNX1) expression after FA treatment, together with molecular docking studies, suggest that the chondrogenic enhancement mechanism of FA is mediated by CBF beta and RUNX1.
NSTL
Elsevier