TPN10466 ameliorates Concanavalin A-induced autoimmune hepatitis in mice via inhibiting ERK/JNK/p38 signaling pathway.

Autoimmune hepatitis (AIH) eventually progresses to liver fibrosis, cirrhosis, and even hepatocellular carcinoma, causing irreversible damage to the liver. Concanavalin A-induced hepatitis in mice is a well-established model with pathophysiology similar to that of immune-mediated liver injury in human viral and autoimmune hepatitis, and it has been widely used to explore the pathogenesis and clinical treatment of human immune hepatitis. Artemisinin has been shown to exhibit anti-inflammatory effects through unclear mechanisms. In this study, we aimed to assess the effect of the artemisinin derivative TPN10466 on AIH. In vitro studies showed that TPN10466 dose dependently inhibited the percentage of IFN-γ-producing T cells. Further studies showed that TPN10466 attenuated the disease severity of AIH by downregulating the ability of lymphocytes to secrete IFN-γ and by reducing lymphocyte number in the liver. In addition, we found that TPN10466 treatment reduced T-cell responses by inhibiting JNK, ERK, and p38 pathways. In conclusion, our work suggests that TPN10466 provides protection against the autoimmune disease AIH by suppressing the inflammatory response of T cells, suggesting that TPN10466 may be a promising potential agent for the treatment of AIH.

Design and Antimalarial Evaluation of Polydopamine-Modified Methyl Artelinate Nanoparticles.

Targeted nanodrug delivery systems are highly anticipated for the treatment of malaria. It is known that Plasmodium can induce new permeability pathways (NPPs) on the membrane of infected red blood cells (iRBCs) for their nutrient uptake. The NPPs also enable the uptake of nanoparticles (NPs) smaller than 80 nm. Additionally, Plasmodium maintains a stable, slightly acidic, and reductive internal environment with higher glutathione (GSH) levels. Based on this knowledge, methyl artelinate (MA, a prodrug-like derivative of dihydroartemisinin) nanoparticles (MA-PCL-NPs) were developed using poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-PCL) by a thin-film dispersion method and were further coated with polydopamine (PDA) to obtain MA-PCL@PDA-NPs with a particle size of ∼30 nm. The biomaterial PDA can be degraded in slightly acidic and reductive environments, thereby serving as triggers for drug release. MA could generate reactive oxygen species and decrease GSH levels, consequently causing parasite damage. The in vitro release experiment results indicated that the cumulative release percentage of MA from MA-PCL@PDA-NPs was considerably higher in phosphate buffer with 10 mM GSH at pH 5.5 (88.10%) than in phosphate buffer without GSH at pH 7.4 (16.98%). The green fluorescence within iRBCs of coumarin 6, the probe of NPs (C6-PCL@PDA-NPs), could be reduced significantly after adding the NPP inhibitor furosemide (p < 0.001), which demonstrated that MA-PCL@PDA-NPs could be ingested into iRBCs through NPPs. In vivo antimalarial pharmacodynamics in Plasmodium berghei K173-bearing mice showed that the inhibition ratio of MA-PCL@PDA-NPs (93.96%) was significantly higher than that of commercial artesunate injection (AS-Inj, 63.33%). The above results showed that the developed MA-PCL@PDA-NPs possessed pH-GSH dual-responsive drug release characteristics and targeting efficacy for iRBCs, leading to higher antimalarial efficacy against Plasmodium.

Ring-Contracted Artemisinin Derivatives as Novel CDK 4/6 Inhibitors: Synthesis and Anti-Breast Cancer Evaluation.

The endoperoxide group of artemisinins is universally accepted an essential group for their anti-cancer effects. In this study, a series of D-ring-contracted artemisinin derivatives were constructed by combining ring-contracted artemisinin core with fragments of functional heterocyclic molecules or classical CDK4/6 inhibitors to identify more efficacious breast cancer treatment agents. Twenty-six novel hybridized molecules were synthesized and characterized by HRMS, IR, 1H-NMR and 13C NMR. In antiproliferative activities and kinase inhibitory effects assays, we found that the antiproliferative effects of B01 were close to those of the positive control Palbociclib, with GI50 values of 4.87±0.23 µM and 9.97±1.44 µM towards T47D cells and MDA-MB-436 cells respectively. In addition, the results showed that B01 was the most potent compound against CDK6/cyclin D3 kinase, with an IC50 value of 0.135±0.041 µM, and its activity was approximately 1/3 of the positive control Palbociclib.

Blackwater Fever Treated with Steroids in Nonimmune Patient, Italy.

Causes of blackwater fever, a complication of malaria treatment, are not completely clear, and immune mechanisms might be involved. Clinical management is not standardized. We describe an episode of blackwater fever in a nonimmune 12-year-old girl in Italy who was treated with steroids, resulting in a rapid clinical resolution.

Anti-Cancer Effects of Artesunate in Human 3D Tumor Models of Different Complexity.

The anti-malaria drug Artesunate (ART) shows strong anti-cancer effects in vitro; however, it shows only marginal treatment results in clinical cancer studies. In this study, ART was tested in preclinical 3D cancer models of increasing complexity using clinically relevant peak plasma concentrations to obtain further information for translation into clinical use. ART reduced cell viability in HCT-116 and HT-29 derived cancer spheroids (p < 0.001). HCT-116 spheroids responded dose-dependently, while HT-29 spheroids were affected more strongly by ART than by cytostatics (p < 0.001). HCT-116 spheroids were chemo-sensitized by ART (p < 0.001). In patient-derived cancer spheroids (PDCS), ART led to inhibition of cell viability in 84.62% of the 39 samples tested, with a mean inhibitory effect of 13.87%. Viability reduction of ART was 2-fold weaker than cytostatic monotherapies (p = 0.028). Meanwhile, tumor-stimulation of up to 16.30% was observed in six (15.38%) PDCS-models. In 15 PDCS samples, ART modulated chemotherapies in combined testing, eight of which showed chemo-stimulation (maximum of 36.90%) and seven chemo-inhibition (up to 16.95%). These results demonstrate that ART's anti-cancer efficacy depends on the complexity of the tumor model used. This emphasizes that cancer treatment with ART should be evaluated before treatment of the individual patient to ensure its benefits and prevent unwanted effects.

Efficacy of artemisinin and its derivatives in animal models of type 2 diabetes mellitus: A systematic review and meta-analysis.

Although current evidence suggests that artemisinin and its derivatives play a multitarget therapeutic role in type 2 diabetes mellitus (T2DM), their efficacy and safety remain under debate. This meta-analysis aimed to evaluate the effects and safety of artemisinin and its derivatives in T2DM animal models. Preclinical studies that met the inclusion criteria were retrieved from PubMed, Embase, Web of Science, Scopus, CINAHL, OpenGrey, Google Scholar, Psyclnfo, British Library Ethos, ProQuest Dissertations & Theses, China National Knowledge Internet, VIP Information Chinese Periodical Service Platform, Chinese Biomedicine Literature Database, and Wanfang Data Knowledge Service Platform. Twenty-two studies involving 526 animals were included in the meta-analysis. The RevMan 5.3 and Stata 15.0, were used to perform the statistical analyses. The overall results showed that artemisinin or its derivatives could significantly reduce fasting plasma glucose, 2-h plasma glucose (2hPG) in the intraperitoneal glucose tolerance test (IPGTT), 2hPG in the intraperitoneal insulin tolerance test (IPITT), glycated hemoglobin A1c, under the curve in the IPGTT/IPITT, total cholesterol, triglyceride, low-density lipoprotein cholesterol, free fatty acid, and urine volume. Although increase in body weight was observed due to administration of the compounds, no significant effect was observed regarding serum insulin. In terms of adverse reactions, only two of the included studies reported that high-dose artemether may cause digestive inhibition in mice. Our results suggest that artemisinins could improve several parameters related to glycolipid metabolism in T2DM animal models. However, to evaluate the antidiabetic effects and safety of artemisinins in a more accurate manner, additional preclinical studies are necessary.

Synthesis and biological evaluation of artemisinin derivatives as potential MS agents.

In this paper, a series of artemisinin derivatives were synthesized and evaluated. Studies have shown that IFN-γ produced by Th1 CD4+ T cells and IL-17A secreted by Th17 CD4+ T cells played critical roles in the treatment of multiple sclerosis. We used different concentrations of artemisinin derivatives to inhibit Th1 / Th17 differentiation in naive CD4+ T cells and to characterize IFN-γ / IL-17A in in vitro experiments. The preliminary screening results showed that ester compound 5 exhibited obvious inhibitory activities on Th1 and Th17 (IFN-γ decreased from 41% to 3% and IL-17A decreased from 24% to 8% at the concentration of 10 nM to 10 µM), and carbamate compounds also had obvious inhibitory activities against Th17 at high concentration. Moreover, we investigated the effect of compound 5 on myelin oligodendrocyte glycoprotein (MOG)-induced mice experimental autoimmune encephalomyelitis (EAE) model in vivo. 100 mg/kg compound 5 effectively reduced the disease severity of EAE compared with the vehicle group. This research revealed that compound 5 could be a promising avenue as potential MS inhibitor.

Impact of antimalarial resistance and COVID-19 pandemic on malaria care among pregnant women in Northern Uganda (ERASE): protocol of a prospective observational study.

BACKGROUND: Uganda accounts for 5% of all malaria cases and deaths reported globally and, in endemic countries, pregnancy is a risk factor for both acquisition of P. falciparum infection and development of severe malaria. In recent years, malaria control has been threatened by COVID-19 pandemic and by the emergence, in Northern Uganda, of both resistance to artemisinin derivatives and to sulfadoxine-pyrimethamine. METHODS: In this facility-based, prospective, observational study, pregnant women will be recruited at antenatal-care visits and followed-up until delivery. Collected data will explore the incidence of asymptomatic parasitemia and malaria-related outcomes, as well as the attitudes towards malaria prevention, administration of intermittent preventive treatment, healthcare seeking behavior and use of insecticide-treated nets. A subpopulation of women diagnosed with malaria will be recruited and their blood samples will be analyzed for detection of genetic markers of resistance to artemisinin derivatives and sulfadoxine-pyrimethamine. Also, to investigate the impact of COVID-19 on malaria care among pregnant women, a retrospective, interrupted-time series will be conducted on at the study sites for the period January 2018 to December 2021. DISCUSSION: The present study will explore the impact of COVID-19 pandemic on incidence of malaria and malaria-related adverse outcomes, along with the prevalence of resistance to artemisinin derivatives and to sulfadoxine-pyrimethamine. To our knowledge, this is the first study aiming to explore the combined effect of these factors on a cohort of pregnant women. TRIAL REGISTRATION: This study has been registered on the ClinicalTrials.gov public website on 26th April, 2022. CLINICALTRIALS: gov Identifier: NCT05348746.

Novel artemisinin derivatives with potent anticancer activities and the anti-colorectal cancer effect by the mitochondria-mediated pathway.

Many artemisinin derivatives have good inhibitory effects on malignant tumors. In this work, a novel series of artemisinin derivatives containing piperazine and fluorine groups were designed and synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies. The in vitro cytotoxicity against various cancer cell lines was evaluated. Among the derivatives, compound 12h was found to exhibit not only the best activity against HCT-116 cells (IC50 = 0.12 ± 0.05 µM), but also low toxicity against normal cell line L02 (IC50 = 12.46 ± 0.10 µM). The mechanisms study revealed that compound 12h caused the cell cycle arrest in G1 phase, induced apoptosis in a concentration-dependent manner, significantly reduced mitochondrial membrane potential, increased intracellular ROS and Ca2+ levels, up-regulated the expression of Bax, cleaved caspase-9, cleaved caspase-3, and down-regulated the expression of Bcl-2 protein. A series of analyses confirmed that 12h can inhibit HCT-116 cells migration and induce apoptosis by a mechanism of the mitochondria-mediated pathway in the HCT-116 cell line. The present work indicates that compound 12h may merit further investigation as a potential therapeutic agent for colorectal cancer.

Global research on artemisinin and its derivatives: Perspectives from patents.

BACKGROUND: The isolation of artemisinin in 1971 heralded the beginning of a new era in antimalarial drug therapy, and artemisinin-based combination therapies are currently the mainstay of malaria treatment worldwide. Artemisinin-related studies have been extensively and intensively executed in the last few decades. However, although many purely technological reviews have been completed in this field, studies on artemisinin from the perspective of patents are still very limited. In terms of the importance of patents for academic research and commercial development, this study aims to reveal the overall patent landscape of artemisinin in the temporal, spatial, and technological dimensions. This work may provide a useful reference for relevant decision-making by researchers, investors, and policymakers. METHODS: All available patent data relevant to artemisinin derivatives and artemisinin-based drug combinations developed for use in various therapeutic areas were collected from the Derwent Innovation database. Descriptive statistics and citation analyses were used to analyze the patent landscape. RESULTS: A total of 4594 patent documents and 1450 simple patent families from 1986 to 2019 were analyzed. A comprehensive patent landscape of artemisinin is presented from the aspects of time trends, filing countries, patent ownership, co-patents, technological categories, therapeutic areas, and citation networks and pathways. CONCLUSIONS: China and the United States are mainly responsible for the dramatic increase of artemisinin patents over the last three decades. From the point of view of patents, notable technological issues on artemisinin are chemical and biological synthesis, novel combinations, new formulations and administration routes, drug repositioning, and minimizing the resistance. Furthermore, a critical challenge lies in how to stimulate the industry to develop artemisinin-related drugs by government regulation and public-private partnership.

[Therapeutic progress in the control of uncomplicated Plasmodium falciparum malaria]. / Les dérivés combinés de l'artémisinine : une avancée thérapeutique dans le contrôle du paludisme non compliqué à Plasmodium falciparum.

Malaria is a worldwide public health problem. In Europe, data show an increasing trend of imported cases in the last ten years. Following an alarming observation reporting resistance to anti-malarial drugs, new effective treatments have been developed in early 21st century. These are artemisinin and its derivatives. Artemisinin-based combination therapies (ACT) are now recommended by the World Health Organisation (WHO) since 2006 as the first-line treatment for uncomplicated Plasmodium falciparum malaria. However, resistance phenomena to these new drugs have been described in South-East Asia since 2009. It is thus necessary to use them properly and to monitor their use to preserve their effectiveness in the future.

Le paludisme représente un problème majeur en termes de santé publique mondiale et l'on décèle une augmentation du nombre de cas d'importation en Europe au cours des dix dernières années. Suite au constat alarmant faisant état de phénomènes de résistance aux anciens anti-paludéens et grâce aux recherches activement menées, de nouveaux traitements extrêmement efficaces ont été développés au début du XXIème siècle. Il s'agit de l'artémisinine et de ses dérivés. L'Organisation Mondiale de la Santé (OMS) recommande depuis 2006 l'utilisation en première intention de dérivés semi-synthétiques combinés de l'artémisinine (ACT) dans le traitement des formes non sévères de paludisme à Plasmodium falciparum. Toutefois, des phénomènes de résistance partielle aux ACT sont décrits en Asie du sud-est depuis 2009. Il est donc nécessaire de les utiliser de manière judicieuse et de majorer la surveillance par le biais de programmes de monitoring standardisés afin de maintenir leur efficacité sur le long terme.

Plasmodium falciparum Clearance Is Pitting-Dependent With Artemisinin-Based Drugs but Pitting-Independent With Atovaquone-Proguanil or Mefloquine.

Pitting, the removal of dead parasites from their host erythrocyte, has been studied in patients with severe malaria treated parenterally with quinine or artesunate, and was recently shown to contribute to delayed hemolysis, a frequent adverse event of artesunate. We quantified pitting in 81 travelers treated with oral antimalarial therapy. Pitting rate was high (55.8%) with artemisinin-based combinations, but <10% with the nonartemisinin drugs quinine, mefloquine, and atovaquone-proguanil. This may, in part, explain the slower parasite clearance in patients treated with antimalarial drugs lacking an artemisinin component, as well as the absence of posttreatment hemolysis with these drugs.

[Effects of Artemisinin and Its Derivatives on Oral Microbes].

The oral environment provides suitable conditions for the colonization of various microorganisms. However, the oral microbials could be the initial factors of some kinds of oral infectious diseases, therefore the treatment against oral microbial pathogens has become an effective strategy. Artemisinin, a kind of sesquiterpene lactone extracted from Traditional Chinese Medicine Artemisia annua L., is the first-line therapy to treat tertian malaria, subtertian malaria and anti-chloroquine malaria for its high efficiency and low toxicity. In recent years, artemisinin and its derivatives have also been proven to be effective against bacteria, fungi, viruses, parasites, and tumors, some of which are closely related to oral diseases. In this review, we summarize the potential effects of artemisinin and its derivatives on oral microorganism by analyzing previous research and latest progress to provide the evidence for further improvement, and look forward to the new research directions. Further studies are needed to improve existing technologies and standards to clarify the effects of artemisinin and its derivatives on microorganisms with controversial effects, to expand the detection of microorganisms associated with oral infectious diseases, and to clarify the interaction with existing antifungal agents in the field of antifungal diseases. In addition, in the study of anti-oral infectious diseases, artemisinin and its derivatives' administration scheme, potential drug interactions, toxic and side effects and other aspects are necessary conditions for further research, which is also a new direction of research. With the maturity of the production process, the improvement of relevant research and the potential demand for the treatment of oral infectious diseases, artemisinin and its derivatives have a broad prospect in the field of oral microorganisms, and provide a new opportunity for the research and development of oral drugs.

[Potential therapies for COVID-19 cardiovascular complications using artemisinin and its derivatives intervene based on its cardiovascular protection].

Corona virus disease 2019(COVID-19) has brought untold human sufferings and economic tragedy worldwide. It causes acute myocardial injury and chronic damage of cardiovascular system, which has attracted much attention from researchers. For the immediate strategy for COVID-19, "drug repurposing" is a new opportunity for developing drugs to fight COVID-19. Artemisinin and its derivatives have a wide range of pharmacological activities. Recent studies have shown that artemisinin has clear cardiovascular protective effects. This paper summarizes the research progress on the pathogenesis the pathogenesis of COVID-19 in cardiovascular damage by 2019 novel coronavirus(2019-nCoV) virus from myocardial cell injury directly by 2019-nCoV virus,viral ligands competitively bind to ACE2 and then reduce the protective effect of ACE2 on cardiovascular disease, "cytokine storm" related myocardial damage, arrhythmia and sudden cardiac death induced by the infection and stress, myocardial injury by hypoxemia, heart damage side effects from COVID-19 drugs and summarizing the cardiovascular protective effects of artemisinin and its derivatives have activities of anti-arrhythmia, anti-myocardial ischemia, anti-atherosclerosis and plaque stabilization. Then analyzed the possible multi-pathway intervention effects of artemisinin-based drugs on multiple complications of COVID-19 based on its specific immunomodulatory effects, protective effects of tissue and organ damage and broad-spectrum antiviral effect, to provide clues for the treatment of cardiovascular complications of COVID-19, and give a new basis for the therapy of COVID-19 through "drug repurposing".

In vitro and in vivo evaluation of six artemisinin derivatives against Schistosoma mansoni.

Schistosomiasis is a tropical neglected disease whose socioeconomic impact is surpassed only by malaria. Until recently, praziquantel (PZQ) has been the only available drug, raising concerns that tolerant/resistant strains may appear. Since the discovery of the schistosomicidal potential of artemisinin (ART), new derivatives have been produced and evaluated. In this work, we evaluated the activity of ART derivatives against Schistosoma mansoni, both in vitro and in vivo. In the in vitro assay, worm survival, oviposition, and morphological alterations were evaluated. Further analysis of morphological alterations and membrane integrity was conducted using scanning electron microscopy and a cell-permeable, benzimidazole dye (Hoescht 33258) that binds to the minor groove of double stranded DNA. For the in vivo assay, artesunic acid (AcART) and dihydroartemisinin acetate (AcDQHS) were selected, since they showed the best in vitro results. Infected mice treated 21, 45, or 60 days post-infection (dpi), with a concentration of 100 mg/kg of either AcART or AcDQHS, showed a significant worm reduction (particularly in females), fewer eggs eliminated in feces, and a decrease of immature eggs in the intestinal tissues. Our results indicate that AcART and AcDQHS have some schistosomicidal activity against juvenile and adult stages of S. mansoni.

The Artemisinin Derivative Artemisone Is a Potent Inhibitor of Human Cytomegalovirus Replication.

Human cytomegalovirus (HCMV) is a major cause of disease in immunocompromised individuals and the most common cause of congenital infection and neurosensorial disease. The expanding target populations for HCMV antiviral treatment along with the limitations of the currently available HCMV DNA polymerase inhibitors underscore the need for new antiviral agents with alternative modes of action. The antimalarial artemisinin derivative artesunate was shown to inhibit HCMV in vitro yet has demonstrated limited antiviral efficacy in vivo, prompting our search for more potent anti-HCMV artemisinin derivatives. Here we show that the innovative artemisinin derivative artemisone, which has been screened for its activity against malaria parasites in human clinical studies, is a potent and noncytotoxic inhibitor of HCMV. Artemisone exhibited an antiviral efficacy comparable to that of ganciclovir (50% effective concentration, 1.20 ± 0.46 µM) in human foreskin fibroblasts, with enhanced relative potency in lung fibroblasts and epithelial cells. Significantly, the antiviral efficacy of artemisone was consistently ≥10-fold superior to that of artesunate in all cells. Artemisone effectively inhibited both laboratory-adapted and low-passage-number clinical strains, as well as drug-resistant HCMV strains. By using quantitative viral kinetics and gene expression studies, we show that artemisone is a reversible inhibitor targeting an earlier phase of the viral replication cycle than ganciclovir. Importantly, artemisone most effectively inhibited HCMV infection ex vivo in a clinically relevant multicellular model of integral human placental tissues maintained in organ culture. Our promising findings encourage preclinical and clinical studies of artemisone as a new inhibitor against HCMV.

Design, synthesis and biological evaluation of artemisinin derivatives containing fluorine atoms as anticancer agents.

Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC50 = 2.1 µM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation.

Artemisinins-a Promising New Treatment for Systemic Lupus Erythematosus: a Descriptive Review.

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is a complex, potentially fatal autoimmune disease with no complete cure. Current treatments for SLE are limited by suboptimal efficacy and increased risk of infections and malignancies, and cannot meet the clinical demands of patients with SLE. Artemisinin and its derivatives (artemisinins), a new class of anti-malarial drugs, have recently been reported to have an immunosuppressive effect on lupus patients. In this review, we evaluate the therapeutic properties and potential mechanisms of artemisinins for the treatment of SLE. RECENT FINDINGS: Both clinical and animal studies suggest that artemisinins have potential beneficial effects for SLE. The beneficial effects associated with artemisinin treatment include improving symptoms, reducing level of antibodies and proteinuria, ameliorating renal damage, and diminishing the dosage of prednisone use. Animal studies suggest that mechanisms of action of artemisinins may include regulating T cell subsets, inhibiting activation of B cells and production of inflammatory cytokines, as well as blocking the NF-κB signal transduction pathway, thus playing a role in anti-inflammation and immunomodulation. Artemisinin family drugs are a promising potential new medication that may challenge the current treatment paradigms available for SLE.

[Application of three artemisinin derivatives in neuropathic pain: evaluating co-curation of nociceptive and emotional syndromes in spinal cord ligation mice].

In this study, on aspects of the nociceptive, anxiety and depressive syndromes in neuropathic pain (NP), the effects of dihydroartemisinine (DHA), artesunate (ART) and artemether (ARTN) (40 mg·kg⁻¹) were analyzed in the spinal cord ligation (SNL) mice. Clinical equivalent dose of the first-line drug for NP, pregabalin (PGB, 25 mg·kg⁻¹) and amitriptyline (ARP, 20 mg·kg⁻¹), were used as positive controls. General, from day 7 to 14, significant remissions of the nociceptive, anxiety and depressive behaviors were achieved by DHA, ART and ARTN separately. Moreover, on day 14, on aspects of the nociceptive behaviors, analyzed 1.5 h after the gavage administration, no significant difference between the shamed mice and mice administrated with DHA, ART and ARTN was detected; analyzed 3 h after the gavage, significant decreases of pain thresholds in ARTN, but not in DHA nor ART group, were detected as compared with thresholds measured 1.5 h; analyzed 24 h after gavage, pain thresholds in DHA, ART and ARTN were still higher than PGB, in spite of the significant decreases as compared to Sham group. On aspects of the anxiety and depressive behaviors, no significant difference was detected between the shamed mice and mice administrated with DHA nor ART. However, differences still remained between the shamed ones and ones administrated with ARTN. Preliminarily, the effects of DHA, ART and ARTN were consolidated in SNL mice. On aspects of the duration of analgesic effects and the control of negative emotion, ART and ARTN were proven more favorable than ARTN.

Hybrid Nanoparticle for Co-delivering Paclitaxel and Dihydroartemisinin to Exhibit Synergic Anticancer Therapeutics.

AIM: Anticancer treatment is required to provide effective and safe patient medicines. This research aided in developing and applying nanoparticles (NPs) for cancer treatment. BACKGROUND: The poor solubility of paclitaxel (PTX) restricts its therapeutic efficacy because of allergic side effects caused by formulation excipients. To overcome this, PTX was coupled with artemisinin derivatives and loaded into an NP drug delivery system to enhance its effects while addressing its low solubility. OBJECTIVES: This study prepared and characterized a hybrid PLGA-lecithin NP containing dihydroartemisinin (DHA) and PTX for synergic anticancer therapy. A lyophilization study improved the stability of the NP drug formulations. METHODS: Dual PTX- and DHA-loaded PLGA- and lecithin-based NPs were prepared using a single-step solvent evaporation method. The NP suspensions were lyophilized, and the types and ratios of cryoprotectants were investigated. The physicochemical properties of NPs and lyophilized cakes (Lyo-NPs) were characterized. The stability of the Lyo-NPs was investigated at 2-8°C and room conditions. The anticancer effects of the drug combination, NP suspension, and lyophilized powder were analyzed using an in vitro cytotoxicity assay and an in vivo model. RESULTS: The optimal PTX-DHA loaded PLGA-lecithin-NP was formulated (200 nm, PDI: 0.248 ± 0.003, Zeta potential: -33.60 ± 3.39 mV). Mannitol was selected for lyophilization. Lyo-NPs improved the stability of the NPs (1 year), wherein the physicochemical properties of the NPs were maintained (RDI was close to 1.0). An in-vitro cytotoxicity assay of PTX combined with DHA showed a synergistic anticancer effect (CI <1.0). The suppressive effects of Lyo-NPs on tumor growth in vivo were dose-dependent. While the cocktail of free drugs showed high toxicity (7.5 mg PTX-15 mg DHA/kg) in-vivo, Lyo-NPs showed no statistical differences in hematological and biochemical parameters compared to the control. CONCLUSION: Dual-drug-loaded hybrid PLGA-lecithin NP is a potential system to minimize severe side effects while enhancing antitumor efficacy, in which lyophilization is a key process to increase stability.