Drug molecules transformed into nanoparticles or endowed with nanostructures with or without the aid of carrier materials are referred to as "nanomedicines" and can overcome some inherent drawbacks ...of free drugs, such as poor water solubility, high drug dosage, and short drug half-life in vivo. However, most of the existing nanomedicines possess the drawback of low drug-loading (generally less than 10%) associated with more carrier materials. For intravenous administration, the extensive use of carrier materials might cause systemic toxicity and impose an extra burden of degradation, metabolism, and excretion of the materials for patients. Therefore, on the premise of guaranteeing therapeutic effect and function, reducing or avoiding the use of carrier materials is a promising alternative approach to solve these problems. Recently, high drug-loading nanomedicines, which have a drug-loading content higher than 10%, are attracting increasing interest. According to the fabrication strategies of nanomedicines, high drug-loading nanomedicines are divided into four main classes: nanomedicines with inert porous material as carrier, nanomedicines with drug as part of carrier, carrier-free nanomedicines, and nanomedicines following niche and complex strategies. To date, most of the existing high drug-loading nanomedicines belong to the first class, and few research studies have focused on other classes. In this review, we investigate the research status of high drug-loading nanomedicines and discuss the features of their fabrication strategies and optimum proposal in detail. We also point out deficiencies and developing direction of high drug-loading nanomedicines. We envision that high drug-loading nanomedicines will occupy an important position in the field of drug-delivery systems, and hope that novel perspectives will be proposed for the development of high drug-loading nanomedicines.
A safe and effective vaccine adjuvant is important in modern vaccines. Various Chinese herbal polysaccharides can activate the immune system. Cistanche deserticola (CD) is a traditional Chinese herb ...and an adjuvant candidate. Here, we confirmed that water-extractable polysaccharides of CD (WPCD) could modulate immune responses in vitro and in vivo. In a dose-dependent manner, WPCD significantly promoted the maturation and function of murine marrow-derived dendritic cells (BM-DCs) through up-regulating the expression levels of MHC-II, CD86, CD80, and CD40, allogenic T cell proliferation, and the yields of IL-12 and TNF-α via toll-like receptor4 (TLR4), as indicated by in vitro experiments. In addition, its immunomodulatory activity was also observed in mice. WPCD effectively improved the titers of IgG, IgG1 and IgG2a and markedly enhanced the proliferation of T and B cells, the production of IFN-γ and IL-4 in CD4+ T cells and the expression level of IFN-γ in CD8+ T cells better than Alum. Furthermore, WPCD could markedly up-regulate the expression levels of CD40 and CD80 on DCs in spleen and down-regulate the Treg frequency. The study suggests that polysaccharides of Cistanche deserticola are a safe and effective vaccine adjuvant for eliciting both humoral immunity and cellular immunity by activating DCs via TLR4 signaling pathway.
Abstract Brain homeostasis is maintained by the blood–brain barrier (BBB), which prevents the entrance of circulating molecules and immune cells into the central nervous system. The BBB is formed by ...specialized brain endothelial cells that are connected by tight junctions (TJ). Previous studies have proven that the Tat protein of human immunodeficiency virus type 1 (HIV-1) alters TJ protein expression. However, the mechanisms by which the alterations occur have not been characterized in detail. In this study, primary human brain microvascular endothelial cells (HBMEC) were exposed to recombinant HIV-1 Tat protein, and the effects on occludin were observed. Tat treatment decreased occludin mRNA and protein levels. This effect was partially abrogated by addition of the RhoA inhibitor C3 exoenzyme and the p160-Rho-associated coiled kinase (ROCK) inhibitor Y-27632. Meanwhile, Tat also induced MMP-9 expression. RNA interference targeting MMP-9 reduced both the paracellular permeability of Tat-treated HBMEC and the concentration of soluble occludin in supernatants from the cells. Taken together, these results show that the HIV-1 Tat protein disrupts BBB integrity, at least in part by decreasing the production of occludin.
Safety evaluations in preclinical studies are needed to confirm before translating a cell-based product into clinical application. We previously developed a serum-free, xeno-free, and chemically ...defined media (S&XFM-CD) for the derivation of clinical-grade umbilical cord-derived MSCs (UCMSCs), and demonstrated that intraperitoneal administration of UCMSCs in S&XFM-CD (UCMSC
) exhibited better therapeutic effects than UCMSCs in serum-containing media (SCM, UCMSC
). However, a comprehensive investigation of the safety of intraperitoneal UCMSC
treatment should be performed before clinical applications.
In this study, the toxicity, immunogenicity and biodistribution of intraperitoneally transplanted UCMSC
were compared with UCMSC
in rats via general vital signs, blood routine, blood biochemistry, subsets of T cells, serum cytokines, pathology of vital organs, antibody production and the expression of human-specific gene. The tumorigenicity and tumor-promoting effect of UCMSC
were compared with UCMSC
in nude mice.
We confirmed that intraperitoneally transplanted UCMSC
or UCMSC
did not cause significant changes in body weight, temperature, systolic blood pressure, diastolic blood pressure, heart rate, blood routine, T lymphocyte subsets, and serum cytokines, and had no obvious histopathology change on experimental rats. UCMSC
did not produce antibodies, while UCMSC
had very high chance of antibody production to bovine serum albumin (80%) and apolipoprotein B-100 (60%). Furthermore, intraperitoneally injected UCMSC
were less likely to be blocked by the lungs and migrated more easily to the kidneys and colon tissue than UCMSC
. In addition, UCMSC
or UCMSC
showed no obvious tumorigenic activity. Finally, UCMSC
extended the time of tumor formation of KM12SM cells, and decreased tumor incidence than that of UCMSC
.
Taken together, our data indicate that UCMSC
display an improved safety performance and are encouraged to use in future clinical trials.
Nowadays, brain tumors are challenging problems, and the key of therapy is ensuring therapeutic drugs cross the blood-brain barrier (BBB) effectively. Although the efficiency of drug transport across ...the BBB can be increased by innovating and modifying nanomedicines, they exert insufficient therapeutic effects on brain tumors due to the complex environment of the brain. It is worth noting that ultrasound combined with the cavitation effect of microbubbles can assist BBB opening and enhance brain delivery of nanomedicines. This ultrasound-assisted brain delivery (UABD) technology with related nanomedicines (UABD nanomedicines) can safely open the BBB, facilitate the entry of drugs into the brain, and enhance the therapeutic effect on brain tumors. UABD nanomedicines, as the main component of UABD technology, have great potential in clinical application and have been an important area of interest in the field of brain tumor therapy. However, research on UABD nanomedicines is still in its early stages despite the fact that they have been associated with many disciplines, including material science, brain science, ultrasound, biology, and medicine. Some aspects of UABD theory and technology remain unclear, especially the mechanisms of BBB opening, relationship between materials of nanomedicines and UABD technology, cavitation and UABD nanomedicines design theories. This review introduces the research status of UABD nanomedicines, investigates their properties and applications of brain tumor therapy, discusses the advantages and drawbacks of UABD nanomedicines for the treatment of brain tumors, and offers their prospects. We hope to encourage researchers from various fields to participate in this area and collaborate on developing UABD nanomedicines into powerful tools for brain tumor therapy.
The hydrophobic long-chain dialkylcarbocyanine 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) is an important near infrared (NIR) fluorescent dye, which has a satisfactory ...photo stability for continuous excitation. During the past decade, it has been widely used for in vivo monitoring of cells. With the fast emergence of novel tumor-targeted nanocarriers, the applications of DiR in the development of fluorescent or multifunctional nano-probes for in vivo tumor imaging are also reported. In these studies, DiR-loaded nanocarriers have resulted in good fluorescence images, indicating the great potential of this dye. However, some important issues about DiR-loaded nanocarriers were often overlooked. These issues include the in vivo fluorescent properties, stability, toxicity, retention and metabolization of DiR-loaded nanocarriers. This review introduced the current use and the properties of DiR-loaded nanocarriers for in vivo tumor imaging. The perspective outlook at the last section highlights the future application of DiR-loaded nanocarriers.
Quantitative detection of different types of reactive oxygen species (ROS) is vital for understanding the crucial roles of them in biological processes. However, few researches achieved the ...detection of multiple types of ROS with one probe until now. Given this, we designed and prepared fluorescent gold nanoclusters capped by dual ligand bovine serum albumin and lysozyme (BSA-LYS-AuNCs), which could detect 3 specific types of ROS based on its different fluorescent responses to H
2
O
2
, •OH and ClO
−
, respectively. The limit of detection (LOD) of H
2
O
2
, •OH, and ClO
−
was as low as 0.82 μM, 0.45 μM, and 0.62 μM. Moreover, as an important ROS type, ClO
−
was detected with high sensitivity and low LOD by BSA-LYS-AuNCs. It was also proved that the crosslinking of protein mainly contributed to the unique fluorescent characteristics of the probe exposing to ClO
−
. Furthermore, the fluorescent probe achieved the smart detection of hROS (including •OH and ClO
−
) and wROS (the form of H
2
O
2
) in the real sample, which could also been applied specifically to the detection of antioxidants, e.g. ascorbic acid. The gold nanoclusters developed have high potential for the smart detection of multiple ROS in the body fluid of organisms.
Graphical abstract
Based on the impulse radar and the spread-spectrum (SS) radar, the through-wall imaging with three stationary targets or a moving target in a room are obtained, respectively, and compared in this ...paper. We then analyze the influences of different analog-to-digital converters (ADCs) and noise levels on imaging quality. Results show that the SS radar has a great advantage over the impulse radar in some ways, such as covert waveform, engineering realization, excellent anti-noise performance, and accurate tracking. Furthermore, the target localization accuracy is much easier to be affected by sampling frequencies of ADC. Besides, the stationary targets can still be recognized accurately in the image, even when one target is very close to the wall, and the receiving signals of the SS radar are added with 0-dB noise and sampled by a 4-bit 3-GHz ADC.
A glucoamylase-immobilized system based on cross-linked gelatin nanoparticles (CLGNs) was prepared by coacervation method. This system exhibited characteristics of temperature-triggered phase ...transition, which could be used for enzyme immobilization and release. Their morphology and size distribution were examined by transmission electron microscopy and dynamic light scattering particle size analyzer. Their temperature-triggered glucoamylase immobilization and release features were also further investigated under different temperatures. Results showed that the CLGNs were regularly spherical with diameters of 155±5 nm. The loading efficiencies of glucoamylase immobilized by entrapment and adsorption methods were 59.9% and 24.7%, respectively. The immobilized enzyme was released when the system temperature was above 40°C and performed high activity similar to free enzyme due to the optimum temperature range for glucoamylase. On the other hand, there was no enzyme release that could be found when the system temperature was below 40°C. The efficiency of temperature-triggered release was as high as 99.3% for adsorption method, while the release of enzyme from the entrapment method was not detected. These results indicate that CLGNs are promising matrix for temperature-triggered glucoamylase immobilization and release by adsorption immobilization method.
Tissue hypoxia may occur in many diseases, specifically during the occurrence and growth of malignant solid-tumors. Targeting hypoxia is one of the most significant characteristics of tumors in ...diagnosis, monitoring, and treatment. This review summarizes the current oxygen-sensitive imaging agents used to target tumor hypoxia, including positron-emission computed tomography/single photon-emission computed tomography radionuclide labeled tracers, magnetic resonance imaging contrast agents for hypoxia detection, and hypoxia-sensitive optical imaging probes. Researchers have utilized nanotechnology as a useful toolkit to improve the effects of oxygen-sensitive imaging agents. We emphasize the progress and influence of nanotechnology in these materials and technologies. This review demonstrates that hypoxia imaging agents have promising prospects, and may provide helpful information for tumor diagnosis and prognosis.
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