Preparation and evaluation of liposome with ropivacaine ion-pairing in local pain management.

Local analgesia is one of the most desirable methods for postoperative pain control, while the existing local anesthetics have a short duration of analgesic effect. Nano-drug carriers have been widely used in various fields and provide an excellent strategy for traditional drugs. Although the existing liposomes for local anesthetics have certain advantages, their instability and complexity of the preparation process still cannot be ignored. Here, we developed novel ropivacaine hydrochloride liposomes with improved stability and sustained release performance by combining ropivacaine hydrochloride with sodium oleate in liposomes via hydrophobic ion-pairing (HIP). The liposomes are easy to prepare, inexpensive, and suitable for mass production. The infrared (IR), particle size, and Zeta potential measurements adequately characterized the complex, which showed a diameter of 81.09 nm and a zeta potential of -83.3 mV. Animal behavioral experiments, including the hot plate test and von Frey fiber test, demonstrated that the liposome system had a prolonged analgesic effect of 2 h versus conventional liposome preparations, consistent with the results of in vitro release experiments. In addition, in vitro cytotoxicity evaluations in RAW264.7 cells and in vivo evaluations revealed the biocompatibility and safety of the ropivacaine-sodium oleate ion-paired liposome (Rop-Ole-Lipo) system as a suitable local anesthetic for local pain management. Our findings provide a new idea for the preparation of local anesthetics.

Reduced Toxicity of Liposomal Nitrogen Mustard Prodrug Formulation Activated by an Intracellular ROS Feedback Mechanism in Hematological Neoplasm Models.

Nitrogen mustard (NM) is among the earliest drugs used to treat malignant tumors and it kills tumor cells by cross-linking DNA. Unfortunately, because of the short half-life and unfavorable selectivity, NM causes significant damage to normal tissues. As NM can increase the levels of reactive oxygen species (ROS) in tumor cells, a ROS-activated nitrogen mustard prodrug (NM-Pro) was synthesized and mixed with NM at a specific ratio to obtain an "NM-ROS-NM-Pro-NM" positive feedback system, which ultimately achieves a specific lethal effect on hematological neoplasms. The further encapsulation of NM/NM-Pro in liposomes allows the sustained release of the drug and prolongs the residence time in vivo. Here, we prepared stable liposomes with a uniform particle size of 170.6 ± 2.2 nm. The optimal ratio of NM to NM-Pro in this study was 2:1. The active drug NM in the NM/NM-Pro system continuously stimulated ROS production by the cells, which in turn further activated the NM-Pro to continuously generate NM. The positive feedback pathway between the NM and NM-Pro resulted in the specific death of tumor cells. Furthermore, the K562 hematological neoplasm model was utilized to evaluate the therapeutic effect of NM/NM-Pro liposomes in vivo. After encapsulation in liposomes, the targeting of tumor cells was increased approximately two times compared with that of normal cells, and NM/NM-Pro liposomes exhibited reduced toxicity, without an increase in drug activity compared to the NM/NM-Pro combination. The NM/NM-Pro delivery system exerts a positive feedback effect on ROS production in tumor cells and displays good potential for the specific killing of hematoma cells.

Doxorubicin derivative loaded acetal-PEG-PCCL micelles for overcoming multidrug resistance in MCF-7/ADR cells.

Objective: This study was aimed to develop DOX-TPP loaded acetal-PEG-PCCL micelles to improve the clinical efficacy of drug resistance tumor. Significance: Chemotherapy is one of the main treatments for breast cancer but is plagued by multidrug resistance (MDR). DOX-TPP-loaded micelles can enhance the specific concentration of drugs in the tumor and improve the efficacy and overcome MDR. Methods: In this study, DOX-TPP-loaded micelles based on acetal-PEG-PCCL were prepared and their physicochemical properties were characterized. The cellular uptake and ability to induce apoptosis of the micelles was confirmed by flow cytometry in MCF-7/ADR cells. In addition, cytotoxicity of the micelles was studied in MCF-7 cells and MCF-7/ADR cells. Confocal is used to study the subcellular distribution of DOX. Free DOX-TPP or DOX-TPP-loaded acetal-PEG-PCCL micelles were administered via intravenous injection in the tail vain for the biodistribution study in vivo. Results: The diameter of micelles was about 102.4 nm and their drug-loading efficiency is 61.8%. The structural characterization was confirmed by 1H NMR. The micelles exhibited better antitumor efficacy compared to free doxorubicin in MCF-7/ADR cells by MTT assay. The apoptotic rate and the cellular uptake of micelles were significantly higher than free DOX and DOX-TPP. Micelles can efficiently deliver mitochondria-targeting DOX-TPP to tumor cells. The result of bio-distribution showed that the micelles had stronger tumor infiltration ability than free drugs. Conclusions: In this study, mitochondriotropic DOX-TPP was conjugated to the nanocarrier acetal-PEG-PCCL via ionic interaction to form a polymer, which spontaneously formed spherical micelles. The cytotoxicity and cellular uptake of the micelles are superior to free DOX and exhibit mitochondrial targeting and passive tumor targeting, indicating that they have potential prospects.

Effects of microplastics on the properties of different types of sewage sludge and strategies to overcome the inhibition: A review.

Microplastics have been identified as an emerging pollutant. When microplastics enter wastewater treatment plants, the plant traps most of the microplastics in the sludge during sewage treatment. Therefore, the effects of microplastics on sludge removal performance, and on the physical and chemical properties and microbial communities in sludge, have attracted extensive attention. This review mainly describes the presence of microplastics in wastewater treatment plants, and the effects of microplastics on the decontamination efficiency and physicochemical properties of activated sludge, aerobic granular sludge, anaerobic granular sludge and anaerobic ammonium oxidation sludge. Further, the review summarizes the effects of microplastics on microbial activity and microbial community dynamics in various sludges in terms of type, concentration, and contact time. The mechanisms used to strengthen the reduction of microplastics, such as biochar and hydrochar, are also discussed. This review summarizes the mechanism by which microplastics influence the performance of different types of sludge, and proposes effective strategies to mitigate the inhibitive effect of microplastics on sludge and discusses removal technologies of microplastics in sewage. Biochar and hydrochar are one of the effective measures to overcome the inhibition of microplastics on sludge. Meanwhile, constructed wetland may be one of the important choice for the future removal of microplastics from sewage. The goal is to provide theoretical support and insights for ensuring the stable operation of wastewater treatment plants and reducing the impact of microplastics on the environment.

Remarkable Boron Delivery Of iRGD-Modified Polymeric Nanoparticles For Boron Neutron Capture Therapy.

PURPOSE: Boron neutron capture therapy (BNCT) is an emerging binary radiotherapy, which is limited for application due to the challenge of targeted delivery into tumor nowadays. Here, we propose the use of iRGD-modified polymeric nanoparticles for active targeted delivery of boron and doxorubicin (DOX) in BNCT. METHODS: 10B-enriched BSH was covalently grafted to PEG-PCCL to prepare 10B-polymer, then surface-modified with iRGD. And, DOX was physically incorporated into polymers afterwards. Characterization of prepared polymers and in vitro release profile of DOX from polymers were determined by several methods. Cellular uptake of DOX was observed by confocal microscope. Accumulation of boron in cells and tissues was analyzed by ICP-MS. Biodistribution of DOX was studied by ex vivo fluorescence imaging and quantitative measurement. Tumor vascular normalization of Endostar for promoting delivery efficiency of boron on refractory B16F10 tumor was also studied. RESULTS: The polymers were monodisperse and spheroidal in water with an average diameter of 24.97 nm, which were relatively stable at physiological pH and showed a sustained release of DOX, especially at endolysosomal pH. Enhanced cellular delivery of DOX was found in iRGD-modified polymer group. Cellular boron uptake of iRGD-modified polymers in A549 cells was remarkably raised fivefold (209.83 ng 10B/106 cells) compared with BSH. The polymers represented prolonged blood circulation, enhanced tumor accumulation of 10B against BSH, and favorable tumor:normal tissue boron concentration ratios (tumor:blood = 14.11, tumor:muscle = 19.49) in A549 tumor-bearing mice 24 hrs after injection. Both fluorescence imaging and quantitative measurement showed the highest tumor accumulation of DOX at 24 hrs after injecting of iRGD-modified polymers. Improvement of vascular integrity and reduction of vascular mimicries were found after Endostar injection, and raised tumor accumulation of boron as well. CONCLUSION: The developed nanoparticle is an inspiring candidate for the safe clinical application for BNCT.