Delivery Strategies for Colchicine as a Critical Dose Drug: Reducing Toxicity and Enhancing Efficacy.

Colchicine (COL), a widely used natural drug, has potent anti-inflammatory effects; however, as a narrow therapeutic index drug, its clinical application is limited by its serious gastrointestinal adverse effects, and only oral formulations are currently marketed worldwide. Recent studies have shown that transdermal, injection, and oral drug delivery are the three main delivery strategies for COL. This article elaborates on the research progress of different delivery strategies in terms of toxicity reduction and efficacy enhancement, depicting that the transdermal drug delivery route can avoid the first-pass effect and the traumatic pain associated with the oral and injection routes, respectively. Therefore, such a dosage form holds a significant promise that requires the development of further research to investigate effective COL delivery formulations. In addition, the permeation-promoting technologies utilized for transdermal drug delivery systems are briefly discussed. This article is expected to provide scientific ideas and theoretical guidance for future research and the exploration of COL delivery strategies.

Recent Advances in Strategies to Combat Bacterial Drug Resistance: Antimicrobial Materials and Drug Delivery Systems.

Bacterial infection is a common clinical disease. Antibiotics have saved countless lives since their discovery and are a powerful weapon in the fight against bacteria. However, with the widespread use of antibiotics, the problem of drug resistance now poses a great threat to human health. In recent years, studies have investigated approaches to combat bacterial resistance. Several antimicrobial materials and drug delivery systems have emerged as promising strategies. Nano-drug delivery systems for antibiotics can reduce the resistance to antibiotics and extend the lifespan of novel antibiotics, and they allow targeting drug delivery compared to conventional antibiotics. This review highlights the mechanistic insights of using different strategies to combat drug-resistant bacteria and summarizes the recent advancements in antimicrobial materials and drug delivery systems for different carriers. Furthermore, the fundamental properties of combating antimicrobial resistance are discussed, and the current challenges and future perspectives in this field are proposed.

Lymphocyte Membrane- and 12p1-Dual-Functionalized Nanoparticles for Free HIV-1 Trapping and Precise siRNA Delivery into HIV-1-Infected Cells.

Despite the success of small interfering RNA (siRNA) in clinical settings and its potential value in human immunodeficiency virus (HIV) therapy, the rapid clearance and absence of precise delivery to target cells still hinder the therapeutic effect of siRNA. Herein, a new system, which can escape immune recognition, has HIV-1 neutralizing capacity, and the ability to deliver siRNA specifically into HIV-1-infected cells, is constructed by functionalizing siRNA delivery lipid nanoparticles with the lymphocyte membrane and 12p1. The constructed system is shown to escape uptake by the mononuclear phagocyte system. The constructed system exhibits strong binding ability with gp120, thus displaying distinguished neutralizing breadth and potency. The constructed system neutralizes all tested HIV-1 pseudotyped viruses with a geometric mean 80% inhibitory concentration (IC80) of 29.75 µg mL-1 and inhibits X4-tropic HIV-1 with an IC80 of 64.20 µg mL-1 , and R5-tropic HIV-1 with an IC80 of 16.39 µg mL-1 . The new system also specifically delivers siRNA into the cytoplasm of HIV-1-infected cells and exhibits evident gene silencing of tat and rev. Therefore, this new system can neutralize HIV-1 and deliver siRNA selectively into HIV-1-infected cells and may be a promising therapeutic candidate for the precise therapy of HIV.

Biomimetic Antidote Nanoparticles: a Novel Strategy for Chronic Heavy Metal Poisoning.

Chronic lead poisoning has become a major factor in global public health. Chelation therapy is usually used to manage lead poisoning. Dimercaptosuccinic acid (DMSA) is a widely used heavy metal chelation agent. However, DMSA has the characteristics of poor water solubility, low oral bioavailability, and short half-life, which limit its clinical application. Herein, a long-cycle slow-release nanodrug delivery system was constructed. We successfully coated the red blood cell membrane (RBCM) onto the surface of dimercaptosuccinic acid polylactic acid glycolic acid copolymer (PLGA) nanoparticles (RBCM-DMSA-NPs), which have a long cycle and detoxification capabilities. The NPs were characterized and observed by particle size meters and transmission electron microscopy. The results showed that the particle size of RBCM-DMSA-NPs was approximately 146.66 ± 2.41 nm, and the zeta potential was - 15.34 ± 1.60 mV. The homogeneous spherical shape and clear core-shell structure of the bionic nanoparticles were observed by transmission electron microscopy. In the animal tests, the area under the administration time curve of RBCM-DMSA-NPs was 156.52 ± 2.63 (mg/L·h), which was 5.21-fold and 2.36-fold that of free DMSA and DMSA-NPs, respectively. Furthermore, the median survival of the RBCM-DMSA-NP treatment group (47 days) was 3.61-fold, 1.32-fold, and 1.16-fold for the lead poisoning group, free DMSA, and DMSA-NP groups, respectively. The RBCM-DMSA-NP treatment significantly extended the cycle time of the drug in the body and improved the survival rate of mice with chronic lead poisoning. Histological analyses showed that RBCM-DMSA-NPs did not cause significant systemic toxicity. These results indicated that RBCM-DMSA-NPs could be a potential candidate for long-term chronic lead exposure treatment.

A Membrane Curvature Modulated Lipopeptide to Broadly Combat Multidrug-Resistant Bacterial Pneumonia with Low Resistance Risk.

The extensive spread of multidrug resistance to Gram-negative bacteria has become a huge threat to human health, where peptide-based antibacterial agents have emerged as a powerful star weapon. Here we report a lipopeptide (LP-20) constructed nanomicelle with a different antibacterial mechanism of membrane curvature modulation, which induced dynamic membrane fission resulting in acceleration and enhancement of antibacterial activity to clinically isolated ESKAPE strains, including multidrug-resistant (MDR) pathogens. The minimum inhibitory concentration was reduced to 2-10 µM, and the minimum duration for killing was shortened to less than an hour by LP-20. This is an improvement over antimicrobial peptides and traditional antibiotics, such as ciprofloxacin and tetracycline, significantly enhancing antibacterial activity for MDR, and we observed no acquisition of resistance for one month. This accelerated germicidal mechanism was attributed to multitargeting with lipopolysaccharides, phosphoethanolamine, phosphatidylglycerol, and cardiolipin, and the synergetic interactions induced a high curvature of the bacterial membrane, which facilitated simultaneously efficient damage to both inner and outer membrane. The LP-20 effectively prolonged the lifetime of myositis mice with Escherichia coli MDR and pneumonia mice with Klebsiella pneumoniae through a hepatic metabolism with ignorable toxicity. This study provides critical information for the fabrication of lipopeptide-based nano-antibiotics for the efficient control of intractable MDR caused by Gram-negative pathogens.

Formulation and Evaluation of a Drug-in-Adhesive Patch for Transdermal Delivery of Colchicine.

Gout is one of the most prevalent rheumatic diseases, globally. Colchicine (COL) is the first-line drug used for the treatment of acute gout. However, the oral administration of COL is restricted, owing to serious adverse reactions. Therefore, this study aimed to develop a drug-in-adhesive (DIA) patch to achieve transdermal delivery of COL. We investigated the solubility of COL in different pressure-sensitive adhesives (PSAs) using slide crystallization studies. The COL-DIA patches were optimized based on in vitro skin penetration studies and evaluated by in vivo pharmacokinetics and pharmacodynamics. The results showed that the optimized COL-DIA patch contained 10% COL, Duro-Tak 87-2516 as PSA, 5% oleic acid (OA) and 5% propylene glycol (PG) as permeation enhancer, exhibiting the highest in vitro cumulative penetration amount of COL (235.14 ± 14.47 µg∙cm-2 over 48 h). Pharmacokinetic studies demonstrated that the maximum plasma drug concentration (Cmax) was 2.65 ± 0.26 ng/L and the mean retention time (MRT) was 37.47 ± 7.64 h of the COL-DIA patch, effectively reducing the drug side effects and prolonging drug activity. In addition, pharmacodynamic studies showed the patch significantly decreased the expression levels of inflammatory factors of gouty rats and reduced pathological damage in the ankle joint of rats, making it an attractive alternative to the administration of COL for the treatment of gout.

Lung-Targeted Delivery of Cepharanthine by an Erythrocyte-Anchoring Strategy for the Treatment of Acute Lung Injury.

As one of the most frequent complications of critical illness, acute lung injury (ALI) carries a high risk of clinical morbidity and mortality. Cepharanthine (CPA) has significant anti-inflammatory activity, however, due to poor water solubility, low bioavailability, and short half-life, it fails to provide effective clinical management measures. Here, we explored the flexibility of an erythrocyte-anchoring strategy using CPA-encapsulated chitosan-coating nanoparticles (CPA-CNPs) anchored onto circulating erythrocytes for the treatment of ALI. CPA-CNPs adhered to erythrocytes successfully (E-CPA-CNPs) and exhibited high erythrocyte adhesion efficiency (>80%). Limited toxicity and favorable biocompatibility enabled further application of E-CPA-CNPs. Next, the reticuloendothelial system evasion features were analyzed in RAW264.7 macrophages and Sprague-Dawley rats. Compared with bare CPA-CNPs, erythrocyte-anchored CNPs significantly decreased cellular uptake in immune cells and prolonged circulation time in vivo. Notably, the erythrocyte-anchoring strategy enabled CNPs to be delivered and accumulated in the lungs (up to 6-fold). In the ALI mouse model, E-CPA-CNPs attenuated the progression of ALI by inhibiting inflammatory responses. Overall, our results demonstrate the outstanding advantages of erythrocyte-anchored CPA-CNPs in improving the pharmacokinetics and bioavailability of CPA, which offers great promise for a lung-targeted drug delivery system for the effective treatment of ALI.

Bacterial and fungal communities within and among geographic samples of the hemp pest Psylliodes attenuata from China.

The hemp flea beetle Psylliodes attenuata (Coleoptera: Chrysomelidae: Psylliodes) is a common pest of Cannabis sativa, including cultivars of both medicinal marijuana and industrial hemp. Both the larval and adult stages of this beetle can cause significant damages to C. sativa, resulting in substantial crop losses. At present, little is known about the bacterial and fungal community diversity among populations of this pest insect. In the present study, we obtained P. attenuata samples from nine field sites representing broad industrial hemp productions in China and analyzed their microbial communities using DNA metabarcoding. Bacterial sequences of all the samples were assigned to 3728 OTUs, which belonged to 45 phyla, 1058 genera and 1960 known species. The most common genera were Rickettsia, Wolbachia, and Candidatus_Brownia. Fungal sequences of all the samples were assigned to 910 OTUs, which belonged to 9 phyla, 308 genera and 464 known species. The most common fungal genera were Cladosporium, Cutaneotrichosporon, and Aspergillus. Principal coordinate analysis revealed a significant difference in the bacterial and fungal community structure among the nine P. attenuata populations. Understanding the microbial symbionts may provide clues to help develop potential biocontrol techniques against this pest.

Genomic insights into the evolutionary history and diversification of bulb traits in garlic.

BACKGROUND: Garlic is an entirely sterile crop with important value as a vegetable, condiment, and medicine. However, the evolutionary history of garlic remains largely unknown. RESULTS: Here we report a comprehensive map of garlic genomic variation, consisting of amazingly 129.4 million variations. Evolutionary analysis indicates that the garlic population diverged at least 100,000 years ago, and the two groups cultivated in China were domesticated from two independent routes. Consequently, 15.0 and 17.5% of genes underwent an expression change in two cultivated groups, causing a reshaping of their transcriptomic architecture. Furthermore, we find independent domestication leads to few overlaps of deleterious substitutions in these two groups due to separate accumulation and selection-based removal. By analysis of selective sweeps, genome-wide trait associations and associated transcriptomic analysis, we uncover differential selections for the bulb traits in these two garlic groups during their domestication. CONCLUSIONS: This study provides valuable resources for garlic genomics-based breeding, and comprehensive insights into the evolutionary history of this clonal-propagated crop.

Morinda officinalis oligosaccharides increase serotonin in the brain and ameliorate depression via promoting 5-hydroxytryptophan production in the gut microbiota.

Morinda officinalis oligosaccharides (MOO) are an oral drug approved in China for the treatment of depression in China. However, MOO is hardly absorbed so that their anti-depressant mechanism has not been elucidated. Here, we show that oral MOO acted on tryptophan â†’ 5-hydroxytryptophan (5-HTP) â†’ serotonin (5-HT) metabolic pathway in the gut microbiota. MOO could increase tryptophan hydroxylase levels in the gut microbiota which accelerated 5-HTP production from tryptophan; meanwhile, MOO inhibited 5-hydroxytryptophan decarboxylase activity, thus reduced 5-HT generation, and accumulated 5-HTP. The raised 5-HTP from the gut microbiota was absorbed to the blood, and then passed across the blood-brain barrier to improve 5-HT levels in the brain. Additionally, pentasaccharide, as one of the main components in MOO, exerted the significant anti-depressant effect through a mechanism identical to that of MOO. This study reveals for the first time that MOO can alleviate depression via increasing 5-HTP in the gut microbiota.

Canalplasty using underwater bone drilling in transcanal endoscopic myringoplasty for patients with a narrow external auditory canal.

BACKGROUND: Canalplasty is important in microscopic ear surgery, but it has rarely been studied in otoendoscopic surgery. OBJECTIVES: The aim of this study was to investigate the application of canalplasty due to external auditory canal stenosis caused by bony bulges in endoscopic myringoplasty. MATERIALS AND METHODS: The procedures and effects of canalplasties and myringoplasties were analysed. During the canalplasties, depending on the location of the bulges, the meatal skin flaps were elevated in different manners, and the underwater bone drilling technique was adopted to remove the bulges to enlarge the osseous canals. RESULTS: Canalplasties were performed in 18.5% (33/178) of myringoplasties. All surgeries were completed exclusively via the transcanal endoscopic approach. No iatrogenic injuries were found. Most of the canalplasties required drilling off bulges on multiple walls. The mean total duration of the canalplasties and myringoplasties was 76.6 ± 4.5 min, and the proportion of time required for the canalplasties was 47.3 ± 2.4%. CONCLUSION: Only approximately one in five endoscopic myringoplasties require antecedent canalplasties due to concurrent canal stenosis. With the underwater bone drilling technique, transcanal endoscopic canalplasty can be safely and efficiently conducted.

Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs.

Rivaroxaban (RIV) is a direct Factor Xa inhibitor anticoagulant, but the oral bioavailability of RIV is estimated to be only 60% due to its poor solubility. The aim of the present study was to improve the solubility and bioavailability of RIV. Five cocrystals-p-hydroxybenzoic acid (HBA), 2,4-dihydroxybenzoic acid (DBA), nicotinamide (NA), isonicotinamide (IA), and succinic acid (SA)-were used as cofomers and were successfully obtained and characterized by powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectra. RIV-DBA and RIV-HBA cocrystals showed obvious improvements in solubility, dissolution (under sink conditions), and intrinsic dissolution rates versus RIV. Moreover, the dissolution of RIV-HBA, RIV-DBA, and RIV-SA cocrystals under non-sink conditions showed obvious "spring and parachute" patterns. The in vitro permeability levels in a Caco-2 cell model of RIV-DBA and RIV-IA cocrystals were significantly improved versus RIV. Pharmacokinetic studies in beagle dogs showed that RIV-DBA and RIV-HBA cocrystals had higher bioavailability than RIV. The enhancements in solubility and bioavailability indicate the potential of RIV cocrystals as a better candidate for the treatment of thrombosis versus RIV.

Advances in Cellulose-Based Hydrogels for Biomedical Engineering: A Review Summary.

In recent years, hydrogel-based research in biomedical engineering has attracted more attention. Cellulose-based hydrogels have become a research hotspot in the field of functional materials because of their outstanding characteristics such as excellent flexibility, stimulus-response, biocompatibility, and degradability. In addition, cellulose-based hydrogel materials exhibit excellent mechanical properties and designable functions through different preparation methods and structure designs, demonstrating huge development potential. In this review, we have systematically summarized sources and types of cellulose and the formation mechanism of the hydrogel. We have reviewed and discussed the recent progress in the development of cellulose-based hydrogels and introduced their applications such as ionic conduction, thermal insulation, and drug delivery. Also, we analyzed and highlighted the trends and opportunities for the further development of cellulose-based hydrogels as emerging materials in the future.

[Optimization of formulation of paclitaxel nanosuspension encapsulated by erythrocyte membrane based on Box-Behnken method].

In view of the longevity and innate immune escape of red blood cells, this study designed the red blood cell membrane-coated paclitaxel nanosuspension [RBC-(PTX)NS] and investigated its physicochemical properties and antitumor effect in vitro. Paclitaxel nanosuspension [(PTX)NS] was prepared by ultrasonic precipitation and then RBC-(PTX)NS by ultrasonic coating. The formulation of(PTX)NS was optimized with Box-Behnken method and indexes of particle diameter, zeta potential, and stability. The morphology, particle diameter, stability, in vitro dissolution, and antitumor effect of(PTX)NS and RBC-(PTX)NS were characterized. The results showed that the particle diameter and zeta potential were(129.38±0.92) nm and(-22.41±0.48) mV, respectively, for the optimized(PTX)NS, while(142.5±0.68) nm and(-29.85±0.53) mV, respectively, for RBC-(PTX)NS. Under the transmission electron microscope,(PTX)NS was spherical and RBC-(PTX)NS had obvious core-shell structure. RBC-(PTX)NS remained stable for 5 days at 4 ℃. The in vitro dissolution test demonstrated that the cumulative release rate of RBC-(PTX)NS reached 79% within 20 min, which was significantly higher than that(25%) of(PTX)NS(P<0.05). As evidenced by MTT assay, RBC-(PTX)NS highly inhibited the proliferation of HepG2 cells in a dose-dependent manner. The cell membrane-coated nano-preparation preparation method is simple and reproducible. It improves the solubility of PTX and endows RBC-(PTX)NS with higher stability and stronger cytotoxicity. Thus, it is a new method for the delivery of PTX via nanocrystallization.

Genetic Diversity and Population Structure of Fusarium commune Causing Strawberry Root Rot in Southcentral China.

Strawberry plants and fruits are vulnerable to infections by a broad range of pathogens and pests. However, knowledge about the epidemiology of pathogens causing strawberry diseases is limited. In this study, we analyzed Fusarium commune, a major fungal pathogen causing strawberry root rot, from diseased strawberry root tissues in southcentral China. A total of 354 isolates were obtained from 11 locations that spanned about 700 km from both south to north and east to west. Multilocus genotypes of all isolates were obtained using seven polymorphic simple sequence repeat markers developed in this study. Our analyses revealed significant genetic diversity within each of the 11 local populations of F. commune. STRUCTURE analysis revealed that the optimal number of genetic populations for the 354 strains was two, with most local geographic populations containing isolates in both genetic clusters. Interestingly, many isolates showed allelic ancestry to both genetic clusters, consistent with recent hybridization between the two genetic clusters. In addition, though alleles and genotypes were frequently shared among local populations, statistically significant genetic differentiations were found among the local populations. However, the observed F. commune population genetic distances were not correlated with geographic distances. Together, our analyses suggest that populations of F. commune causing strawberry root rot are likely endemic to southcentral China, with each local population containing shared and unique genetic elements. Though the observed gene flow among geographic regions was relatively low, human activities will likely accelerate pathogen dispersals, resulting in the generation of new genotypes through mating and recombination.

Red blood cell-hitchhiking mediated pulmonary delivery of ivermectin: Effects of nanoparticle properties.

Recent studies have demonstrated that ivermectin (IVM) exhibits antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of coronavirus disease 2019 (COVID-19). However, the repurposing of IVM for the treatment of COVID-19 has presented challenges primarily due to the low IVM plasma concentration after oral administration, which was well below IC50. Here, a red blood cell (RBC)-hitchhiking strategy was used for the targeted delivery of IVM-loaded nanoparticles (NPs) to the lung. IVM-loaded poly (lactic-co-glycolic acid) (PLGA) NPs (IVM-PNPs) and chitosan-coating IVM-PNPs (IVM-CSPNPs) were prepared and adsorbed onto RBCs. Both RBC-hitchhiked IVM-PNPs and IVM-CSPNPs could significantly enhance IVM delivery to lungs, improve IVM accumulation in lung tissue, inhibit the inflammatory responses and finally significantly alleviate the progression of acute lung injury. Specifically, the redistribution and circulation effects were related to the properties of NPs. RBC-hitchhiked cationic IVM-CSPNPs showed a longer circulation time, slower accumulation and elimination rates, and higher anti-inflammatory activities than RBC-hitchhiked anionic IVM-PNPs. Therefore, RBC-hitchhiking provides an alternative strategy to improve IVM pharmacokinetics and bioavailability for repurposing of IVM to treat COVID-19. Furthermore, according to different redistribution effects of different NPs, RBC-hitchhiked NPs may achieve various accumulation rates and circulation times for different requirements of drug delivery.

Macrophage membrane- and cRGD-functionalized thermosensitive liposomes combined with CPP to realize precise siRNA delivery into tumor cells.

Despite the success of small interfering RNAs (siRNAs) in clinical settings, their fast clearance and poor delivery efficiency to target cells still hinder their therapeutic effect. Herein, a new treatment system was constructed by combining thermosensitive liposomes with the macrophage membrane, tumor-targeting cyclic Arg-Gly-Asp peptide, a cell-penetrating peptide, and thermotherapy. The constructed system was found to be thermosensitive and stable; the proteins were inherited from the macrophage membrane. This new system combined with thermotherapy displayed the least uptake by macrophages, the greatest uptake by HepG2 cells, the most obvious HepG2 cell apoptosis, and the strongest inhibition of Bcl-2 mRNA and Bcl-2 protein in HepG2 cells. Moreover, 24 h after system administration in tumor-bearing mice, the most prominent distribution of siRNA was observed in tumors, while almost no siRNA was found in other organs. The strongest inhibition of Bcl-2 mRNA, Bcl-2 protein, and tumors was found in mice that had received the proposed system. In summary, when using the constructed system both in vitro and in mice, less uptake by the reticuloendothelial system, greater accumulation in tumor cells, and improved therapeutic efficacy were observed. Therefore, this new system can deliver siRNA selectively and efficiently, and it is a promising therapeutic candidate for precise tumor-targeted therapy.