A cascade targeting strategy based on modified bacterial vesicles for enhancing cancer immunotherapy.

BACKGROUND: As an efficient tumor immunotherapy, PD-1 antibody has been gradually used in clinical tumor treatment, but the low response rate and excessive immune response limit its extensive application. RESULTS: Herein, a therapeutic regime for the reinvigoration and activation of the tumor immune microenvironment is introduced to improve the anti-tumor effect of the PD-1 antibody. To comprehensively improve the effect of the immunotherapy and reduce excessive immune response, a biomimetic cascade targeting nanosystem, siRNA@PLOV, which was fused by photothermal sensitive liposomes (PTSLs) and attenuated Salmonella outer membrane vesicles (OMVs), was administered in the tumor therapy for targeting of tumor tissues and T cells within tumor respectively. The fused PLOVs which not only retained the biological character of the OMVs, but also enhanced the drug loading ability. The results demonstrated that the immunogenicity of OMVs and photothermal effects can obviously increase the infiltration of T cells and the silencing of CD38 can effectively improve the T cell cytotoxicity, especially combining with PD-1 antibody. CONCLUSIONS: Interesting, this study revealed that anti-PD-1 administration on the 5th day after siRNA@PLOV treatment had the best performance in killing tumors compared with other groups. In addition, this new therapeutic regime also presents a novel strategy for inducing "vaccine effects", conclusively highlighting its potential in preventing tumor recurrence and improving prognosis.

Size-dependent neurotoxicity of micro- and nanoplastics in flowing condition based on an in vitro microfluidic study.

With the widespread presence of plastic wastes, knowledge about the potential environmental risks and bioavailability of micro- or nanoplastics fragmented from large analogs is of utmost importance. As the particle size matters in mediating endocytic mechanism and particle internalization, we first studied the effects of polystyrene microparticles (PS-MPs, 1 µm) and polystyrene nanoparticles (PS-NPs, 100 nm) of two different sizes at varying concentrations of 5, 25 and 75 µg/mL on the mouse hippocampal neuronal HT22 cells. The in vitro study showed efficient cellular uptake of PS-MPs and PS-NPs of both sizes. The adverse effects of cellular metabolic activity as reflective of excess Reactive Oxygen Species (ROS) and cell cycle S phase arresting were observed especially at the greater concentration of smaller-sized PS particles, consequently leading to mild cytotoxicity. We further evaluated the dynamic particle-cell interaction with a continuous supply of PS particles using a microfluidic device. By recapitulating the in vivo mechanical microenvironments while allowing homogeneous distribution of PS particles, the dynamic exposure to PS particles of both sizes under flowing conditions resulted in much lesser viability of neural cells than the traditional static exposure. As the flowing dynamics may avoid the gravitational settling of particles and allow more efficient cellular uptake, the size distribution, together with the exposure configurations, contributed significantly to the determination of the PS particle cytotoxicity. The on-chip investigation and a better understanding of particle translocation mechanisms would offer very much to the risk assessment of PS particles on human health.

In vivo anti-tumor efficacy of docetaxel-loaded thermally responsive nanohydrogel.

Thermally responsive poly(N-isopropylacrylamide-co-acrylamide) (P(NIPA-co-AAm)) nanohydrogel (NHG) with a diameter of about 50 nm and a lower critical solution temperature (LCST) of about 40 degrees C was synthesized by a previously reported precipitation polymerization method. The physical properties including LCST, diameter and morphology were characterized. Four hydrophobic model drugs (5-fluorouracil (5-FU), fluorescein, docetaxel (DTX) and near-infrared dye-12 (NIRD-12)) with different hydrophilicities were respectively entrapped into the nanoparticles and their in vitro release kinetics from NHG was investigated. DTX was ultimately chosen as the goal anti-tumor drug and optimally entrapped into NHG with a drug loading content (DLC) of 7.38% and encapsulation efficiency (EE) of 73.8%. An in vitro drug release test indicated that DTX-loaded NHG had zero-order release kinetics at 43 degrees C. The respective anti-tumor efficacy of DTX-loaded NHG with or without hyperthermia on tumor tissue was evaluated in Kunming mice-bearing S180 sarcoma. The inhibition rates of DTX-loaded NHG with or without hyperthermia were 78.15% and 48.78%, respectively. DTX-loaded NHG also showed much lower toxicity during the therapeutic procedure. Results indicated that this kind of thermally responsive, drug-loaded NHG could be used as a promising strategy for tumor therapy with the help of local hyperthermia treatment.

Characterization of pH- and temperature-sensitive hydrogel nanoparticles for controlled drug release.

Monodispersed poly (N-isopropylacrylamide) (PNIPA) nanoparticles and their derivative poly (N-isopropylacrylamide-co-acrylic acid) (PNIPA-co-AA) nanoparticles were successfully synthesized. Regulation of the size and the lower critical solution temperature (LCST) of the hydrogel nanoparticles was intensively studied. The results showed that the diameters and LCST of the particles can be arbitrarily manipulated according to different application designs. The relationship between the size of the particles and the amount of surfactant were quantitatively disclosed. It was found that the LCST of PNIPA-co-AA nanoparticles ranging from 35-45 degrees C correlated with the molar fraction of acrylic acid which was copolymerized with NIPA. The pH sensitivity of PNIPA-co-AA nanoparticles was displayed by the transmittance transition of their aqueous solution in various pH conditions. Furthermore, the anti-cancer drug 5-fluorouracil (5-Fu) was first loaded into both PNIPA and PNIPA-co-AA hydrogel nanoparticles with an entrapment efficiency larger than 4%. In vitro release of 5-Fu from PNIPA-co-AA nanoparticle hydrogels was shown to be pH- and temperature-dependent, which demonstrated that the PNIPA-co-AA nanoparticles have great potential in the design of controlled drug delivery systems.

[Preliminary study of wireless biofeedback therapy for treatment of bruxism].

OBJECTIVE: To access the effect of wireless biofeedback therapy on bruxism. METHODS: Ten voluntary bruxers (seven female and three male, mean age 26.1 years) were invited to participate in this clinical research. An electric resistance strain gauge was embedded in the position of canine of a maxillary splint for monitoring the abnormal clenching or grinding movement of teeth during sleep. The relevant details of bruxism events, including value of relative force, occurring time and duration were recorded and analyzed by the receiver device and monitoring program respectively. Meanwhile, for the purpose of nerve system and muscle relaxation, a watch-style device around the patient's wrist will vibrate to alert the patient of teeth grinding or clenching if the value of biting force and duration exceed the threshold. Total average episodes of bruxism and duration was observed during eight hours sleep, and was analyzed with one-way analysis of variance in SPSS 19.0 by the end of 6th week and three months following biofeedback therapy. RESULTS: The average episodes of bruxism has declined dramatically from (9.8 ± 2.2) times to (3.0 ± 1.2) times during one night (P < 0.05), and the average duration of bruxism events was reduced from (20.7 ± 12.2) s to (10.0 ± 3.4) s (P < 0.05) after six weeks biofeedback therapy. By the end of three months, the average episodes declined to (2.9 ± 1.2) times (P < 0.05), and the average duration decline to (9.2 ± 2.9) s (P < 0.05) with contrast to preliminary night. CONCLUSIONS: The pressure-based wireless biofeedback device is able to monitoring clenching and grinding of bruxism. The results suggest that biofeedback therapy may be an effective, novel and convenient measure for treatment of bruxism according to several months therapy.

In vivo NIR imaging with PbS quantum dots entrapped in biodegradable micelles.

In this article, we firstly synthesized oil-soluble PbS quantum dots (QDs) emitting in the near-infrared (NIR) spectral range through a two-phase method, which exhibit a conveniently tunable photoluminescence (PL) emission (from ~750 to 872 nm) with a narrow PL bandwidth, as well as a high (up to 40%) PL quantum yield (QY). Next, the as-prepared oil-soluble NIR PbS QDs were applied to the in vivo imaging of tumors by entrapping in biodegradable micelles (N-succinyl-N'-octyl nanomicelles, SOC) which had hydrophobic inner cores. Transmission electron microscope results show well dispersed spherical shaped QDs-loaded SOC micelles with 100 nm diameter. The QY of PbS QDs entrapped into SOC has no significant change compared to free QDs. Besides, both in vitro and in vivo acute toxicity results demonstrated that the QDs-loaded micelles have low cytotoxicity. Furthermore, in vivo imaging of PbS QDs-loaded SOC injected intravenously into tumor-bearing nude mice showed the NIR QDs-loaded micelles can accumulate in the tumor tissue due to the enhanced permeability and retention effect of SOC micelles. These results confirm that the as-prepared PbS QDs could be used as fluorescence probes to study the biodistribution of nanocarriers and their intracellular pathways, as well as their passive targeted behavior to tumors in preclinical research.

Folate-polyethylene glycol conjugated near-infrared fluorescence probe with high targeting affinity and sensitivity for in vivo early tumor diagnosis.

PURPOSE: The purpose of this study is to synthesize a folate-polyethylene glycol (PEG) conjugated near-infrared fluorescence probe (fPI-01) for diagnosis of folate receptor (FR)-overexpressed tumors with high sensitivity and specificity. PROCEDURES: fPI-01 was synthesized, purified, and characterized. Its cytotoxicity and affinity to tumor cells were determined in vitro. The dynamics and biodistribution of the probe was monitored in normal nude mice. And the tumor-targeting capability was investigated in nude mice bearing different tumor xenograft. RESULTS: fPI-01 was successfully synthesized with strengthened optical properties. Cells experiments showed the probe had high FR affinity and without apparent cytotoxicity. Animal experiments indicated the probe excreted through urine by kidney. And its tumor-targeting ability was demonstrated on different tumor-bearing mice, with high sensitivity and tumor-to-normal tissue contrast ratio (10:1). CONCLUSIONS: fPI-01 is a promising optical agent for diagnosis of FR-positive tumors, especially in their early stage.