Pectolinarigenin ameliorates osteoporosis via enhancing Wnt signaling cascade in PPARß-dependent manner.

BACKGROUND: Osteoporosis is a prevalent metabolic bone disease in older adults. Peroxisome proliferator-activated receptor ß (PPARß), the most abundant PPAR isotype expressed in bone tissues, plays a critical role in regulating the energy metabolism of osteoblasts. However, the botanical compounds targeting PPARß for the treatment of osteoporosis remain largely unexplored. PURPOSE: To discover a potent PPARß agonist from botanical compounds, as well as to investigate the anti-osteoporosis effects and to elucidate the underlying mechanisms of the newly identified PPARß agonist. METHODS: The PPARß agonist effects of botanical compounds were screened by an in vitro luciferase reporter gene assay. The PPARß agonist effects of pectolinarigenin (PEC) in bone marrow mesenchymal stromal cells (BMSCs) were validated by Western blotting. RNA-seq transcriptome analyses were conducted to reveal the underlying osteoporosis mechanisms of PEC in BMSCs. The PPARß antagonist (GSK0660) and Wnt signaling inhibitor (XAV969) were used to explore the role of the PPARß and Wnt signaling cascade in the anti-osteoporosis effects of PEC. PEC or the PEG-PLGA nanoparticles of PEC (PEC-NP) were intraperitoneally administrated in both wild-type mice and ovariectomy-induced osteoporosis mice to examine its anti-osteoporotic effects in vivo. RESULTS: PEC, a newly identified naturally occurring PPARß agonist, significantly promotes osteogenic differentiation and up-regulates the osteogenic differentiation-related genes (Runx2, Osterix, and Bmp2) in BMSCs. RNA sequencing and functional gene enrichment analysis suggested that PEC could activate osteogenic-related signaling pathways, including Wnt and PPAR signaling pathways. Further investigations suggested that PEC could enhance Wnt/ß-catenin signaling in a PPARß-dependent manner in BMSCs. Animal tests showed that PEC-NP promoted bone mass and density, increased the bone cell matrix protein, and accelerated bone formation in wild-type mice, while PEC-NP also played a preventive role in ovariectomy-induced osteoporosis mice via maintaining the expression level of bone cell matrix protein, balancing the rate of bone formation, and slowing down bone loss. Additionally, PEC-NP did not cause any organ injury and body weight loss after long-term use (11 weeks). CONCLUSION: PEC significantly promotes bone formation and reduces bone loss in both BMSCs and ovariectomy-induced osteoporosis mice via enhancing the Wnt signaling cascade in a PPARß-dependent manner, providing a new alternative therapy for preventing estrogen deficiency-induced osteoporotic diseases.

Intranasal delivery of Borneol/R8dGR peptide modified PLGA nanoparticles co-loaded with curcumin and cisplatin alleviate hypoxia in pediatric brainstem glioma which improves the synergistic therapy.

Cisplatin (cis) is a first-line chemotherapeutic used for the treatment of intractable pediatric brainstem glioma (PBSG). Its therapeutic effect in PBSG is, however, critically challenged by the hypoxic microenvironment of the tumor and the presence of the blood brain barrier (BBB). Herein, we report on the intranasal administration of borneol (Bo)/R8dGR peptide modified PLGA based nanoparticles (NP) co-loaded with curcumin and cisplatin (cur/cis). We observed that borneol modification improved the brain penetration of the nanoparticles by reduction of the expression of ZO-1 and occludin in nasal mucosa, while the R8dGR peptide modification allowed the targeting of the NP through the binding on integrin αvß3 receptors which are present on PBSG cells. Following intranasal administration, BoR-cur/cis-NP attenuated hypoxia in the PBSG microenvironment and reduced angiogenesis, which prolonged survival of GL261-bearing PBSG mice. Therefore, intranasal administration of BoR-cur/cis-NP, which deeply penetrate PBSG, is an encouraging strategy to attenuate hypoxia which potentiates the efficacy of cisplatin in the treatment of PBSG.

Traditional herbal medicine and nanomedicine: Converging disciplines to improve therapeutic efficacy and human health.

Traditional herbal medicine (THM), an ancient science, is a gift from nature. For thousands of years, it has helped humans fight diseases and protect life, health, and reproduction. Nanomedicine, a newer discipline has evolved from exploitation of the unique nanoscale morphology and is widely used in diagnosis, imaging, drug delivery, and other biomedical fields. Although THM and nanomedicine differ greatly in time span and discipline dimensions, they are closely related and are even evolving toward integration and convergence. This review begins with the history and latest research progress of THM and nanomedicine, expounding their respective developmental trajectory. It then discusses the overlapping connectivity and relevance of the two fields, including nanoaggregates generated in herbal medicine decoctions, the application of nanotechnology in the delivery and treatment of natural active ingredients, and the influence of physiological regulatory capability of THM on the in vivo fate of nanoparticles. Finally, future development trends, challenges, and research directions are discussed.

Nose-to-brain delivery of borneol modified tanshinone IIA nanoparticles in prevention of cerebral ischemia/reperfusion injury.

Targeted treatment of cerebral ischemia/reperfusion injury (CIRI) remains a problem due to the difficulty in drug delivery across the blood-brain barrier (BBB). In this study, we developed Bo-TSA-NP, a novel tanshinone IIA (TSA) loaded nanoparticles modified by borneol, which has long been proved with the ability to enhance other drugs' transport across the BBB. The Bo-TSA-NP, with a particle size of about 160 nm, drug loading of 3.6%, showed sustained release and P-glycoprotein (P-gp) inhibition property. It demonstrated a significantly higher uptake by 16HBE cells in vitro through the clathrin/caveolae-mediated endocytosis and micropinocytosis. Following intranasal (IN) administration, Bo-TSA-NP significantly improved the preventive effect on a rat model of CIRI with improved neurological scores, decreased cerebral infarction areas and a reduced content of malondialdehyde (MDA) and increased activity of superoxide dismutase (SOD) in rat brain. In conclusion, these results indicate that Bo-TSA-NP is a promising nose-to-brain delivery system that can enhance the prevention effect of TSA on CIRI.

Integrated Pharmacological Analysis on the Mechanism of Fuyou Formula in Treating Precocious Puberty.

Fu-you formula (FY), a Traditional Chinese Medicine (TCM) formula composed of 12 herbs, as an in-hospital preparation, has been used treat to precocious puberty (PP) for decades. However, the lack of phytochemical characterization and mechanism of FY remains the main limitation for its spreading. In this study, we analyze the components and mechanisms of FY in PP, based on the integrated pharmacology. Investigated main constituents, targets, pathways of FY by using an integrative pharmacology, and recognized main constituents by HPLC-MS/MS. Then, observed the levels of Follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (E2) in danazol-induced PP in Sprague-Dawley (SD) rats. Lastly, retrospective study analyzed the clinical data of 575 patients who were diagnosed PP, treated by the FY, and followed-up in our hospital from 2014-2020. The result that total of 116 important candidate targets were selected based on pharmacological analysis. Selected the top 10 values key targets such as the estrogen receptor alpha (ESR1) and insulin-like growth factor 1 (IGF1), were localized and the related gene functions were determined. Gene functions were associated with biological regulation, a cellular process, or signaling pathway, such as the Estrogen signaling pathway, MAPK signaling pathway and PI3K-Akt signaling pathway. By recognizing the five compounds related to the ESR1 and IGF1, which are Quercetin, kaempferol, Luteolin, Apigenin, and Emodin. The results of the molecular docking study further showed that the flavonoids had a strong binding affinity for ESR1 and IGF1 after docking into the crystal structure. The results showed that the FY could effectively reduce E2, LH, and FSH levels in SD rats. Furthermore, the results of the retrospective analysis of medical records showed that the FY could remarkably reduce E2 levels in girls with PP.

Combination of Geniposide and Eleutheroside B Exerts Antidepressant-like Effect on Lipopolysaccharide-Induced Depression Mice Model.

OBJECTIVE: To study the antidepressant-like effect and action mechanism of geniposide and eleutheroside B combination treatment on the lipopolysaccharide (LPS)-induced depression mice model. METHODS: Depression mice model was established by lipopolysaccharide (LPS) injection. Totally 48 mice were randomly divided into 6 groups (8 rats per group) according to a random number table, including normal, model, fluoxetine (20 mg/kg), geniposide (100 mg/kg) + eleutheroside B (100 mg/kg), geniposide + eleutheroside B + WAY 100635 (0.03 mg/kg), geniposide + eleutheroside B+ N-methyl-D-aspartic acid receptor (NMDA, 75 mg/kg) groups, respectively. After continuous administration for 10 days, autonomic activity tests after 30 min of administration were performed on the 10th day. On the 11th day, except for the normal group, the mice in the other groups were intraperitoneally injected with LPS (1 mg/kg), and the behavioral tests were performed 4 h later. Enzyme linked immunosorbent assay was used to detect tumor necrosis factor alpha (TNF- α) and interleukin-1 ß (IL-1 ß) levels in mice serum. The mRNA expression of indoleamine 2,3-dioxygenase (IDO) and nuclear transcription factor (NF- κB) were detected by real-time quantitative polymerase chain reaction. Western-blot analysis was used to detect IDO and NF- κB protein expressions in hippocampus tissue. RESULTS: Compared with the normal group, a single administration of LPS increased the immobility time in the forced swimming test (FST) and tail suspension test (TST, P<0.01), without affecting autonomous activity. Compared with the model group, fluoxetine and geniposide + eleutheroside B administration significantly improved the immobility time of depressed mice in the FST and TST, decreased serum IL-1 ß content, inhibited the expression levels of NF- κ B gene and protein in hippocampus tissues (P<0.05 or P<0.01). Compared with the model group, geniposide + eleutheroside B treatment significantly reduced serum TNF-α content and inhibited IDO mRNA and protein expressions in hippocampus (P<0.05 or P<0.01). In addition, NMDA partly prevented the inhibition of IDO mRNA expression by geniposide + eleutheroside B; NMDA and WAY-100635 also partly prevented the reduction of IL-1 ß content induced by geniposide + eleutheroside B treatment (P<0.05 or P<0.01). CONCLUSIONS: The combination of geniposide and eleutheroside B showed a certain antidepression-like effect. Its main mechanism of action may be contributed to inhibiting the activation of NF- κB, decreasing the proinflammatory cytokines such as TNF-α, IL-1 ß, and inhibiting in the neuroinflammatory reaction. Additionally, it also affects tryptophan metabolism, reduces the expression of a key enzyme of tryptophan metabolism, IDO. And this antidepressant-like effect may be mediated by 5-hydroxytryptamine and glutamate systems.

Natural products remodel cancer-associated fibroblasts in desmoplastic tumors.

Desmoplastic tumors have an abundance of stromal cells and the extracellular matrix which usually result in therapeutic resistance. Current treatment prescriptions for desmoplastic tumors are usually not sufficient to eliminate the malignancy. Recently, through modulating cancer-associated fibroblasts (CAFs) which are the most abundant cell type among all stromal cells, natural products have improved chemotherapies and the delivery of nanomedicines to the tumor cells, showing promising ability to improve treatment effects on desmoplastic tumors. In this review, we discussed the latest advances in inhibiting desmoplastic tumors by modeling CAFs using natural products, highlighting the potential therapeutic abilities of natural products in targeting CAFs for cancer treatment.

Antidepressant-like mechanism of honokiol in a rodent model of corticosterone-induced depression.

Depression is closely linked to hypothalamus-pituitary-adrenal axis hyperactivity. Honokiol, a biphenolic lignan compound obtained from the traditional Chinese medicine Magnolia officinalis, can reduce the activity of the hypothalamus-pituitary-adrenal axis and improve depression-like behavior caused by hypothalamus-pituitary-adrenal axis hyperactivity. The current study investigated the specific mechanism of action of this effect. A depression model was established by repeated injections of corticosterone to study the antidepressant-like effect of honokiol and its potential mechanism. Honokiol prevented the elevated activity of the hypothalamus-pituitary-adrenal axis and the depression-like behavior induced by corticosterone. Treatment with honokiol resulted in greater glucocorticoid receptor mRNA expression, greater glucocorticoid receptor-positive expression, and a greater ratio of glucocorticoid receptor to the mineralocorticoid receptor in the hippocampus. Moreover, honokiol treatment led to lower levels of interleukin-1ß in serum and the positive expression of the interleukin-1ß receptor in the hippocampus. These results demonstrate that the antidepressant-like mechanism of honokiol, which has effects on inflammatory factors, may act through restoring the typical activity of the hypothalamus-pituitary-adrenal axis by regulating the glucocorticoid receptor-mediated negative feedback mechanism and the balance between glucocorticoid and mineralocorticoid receptors.

Study on the Mechanism of Sarsasapogenin in Treating Precocious Puberty by Regulating the HPG Axis.

The present study aims to investigate the effects and mechanisms of sarsasapogenin resistance to precocious puberty. Female Sprague Dawley rats were divided into a normal (N) group, model (M) group, leuprolide (L) group, and sarsasapogenin (Sar) group. Rats at 5 days of age were given a single subcutaneous injection of 300 micrograms of danazol to establish the precocious puberty model. After 10 days of modeling, drug intervention was started. The development of the uterus and ovary was observed by hematoxylin and eosin (HE) staining. The levels of the serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) were determined by radioimmunoassay. Also, the expressions of the hypothalamic gonadotropin releasing hormone (GnRH), Kiss-1, G protein-coupled receptor 54 (GPR54), and pituitary gonadotropin releasing hormone receptor (GnRH-R) were detected by RT-PCR. The results showed that compared with the model group, sarsasapogenin could significantly delay the opening time of vaginal, decreased uterine and ovarian coefficients, and reduced uterine wall thickness. Moreover, it can significantly downregulate the levels of serum hormones and reduce the expression of GnRH, GnRH-R, and kiss-1. In summary, our results indicate that sarsasapogenin can regulate the HPG axis through the kiss-1/GPR54 system for therapeutic precocious puberty.

The Traditional Chinese Medicine Fuyou Formula Alleviates Precocious Puberty by Inhibiting GPR54/GnRH in the Hypothalamus.

The purpose of this study was to explore the effect of the traditional Chinese medicine Fuyou formula on precocious puberty (PP). The Fy formula may exert an effect in female rats with PP and GT-7 cells through the GPR54/GnRH signaling pathway. To confirm the effect of the Fy formula on PP through the GPR54/GnRH signaling pathway, we first treated GT1-7 cells with the Fy formula and observed changes in the expression of related genes and proteins and in GnRH secretion. Then, we randomly divided young female Sprague-Dawley rats into the control group, model group, leuprorelin group and the Fy formula group. A PP model was established by injection of danazol on postnatal day 5, and the Fy formula was administered on PND15. The time of vaginal opening, the wet weights of the ovary and uterus, serum hormone levels and the expression of hypothalamic-related genes were observed. We found that the Fy formula delayed vaginal opening, decreased the wet weights and coefficients of the ovary and uterus, decreased the levels of serum hormones (E2, follicle-stimulating hormone and luteinizing hormone) and the cellular GnRH level, and downregulated the gene expression of Kiss1, GPR54 and GnRH in the hypothalamus and the gene and protein expression of GPR54 and GnRH in GT1-7 cells. In conclusion, the Fy formula may alleviate PP via the GPR54/GnRH signaling pathway.

Antidepressant-Like Effect and Mechanism of Action of Honokiol on the Mouse Lipopolysaccharide (LPS) Depression Model.

There is growing evidence that neuroinflammation is closely linked to depression. Honokiol, a biologically active substance extracted from Magnolia officinalis, which is widely used in traditional Chinese medicine, has been shown to exert significant anti-inflammatory effects and improve depression-like behavior caused by inflammation. However, the specific mechanism of action of this activity is still unclear. In this study, the lipopolysaccharide (LPS) mouse model was used to study the effect of honokiol on depression-like behavior induced by LPS in mice and its potential mechanism. A single administration of LPS (1 mg/kg, intraperitoneal injection) increased the immobility time in the forced swimming test (FST) and tail suspension test (TST), without affecting autonomous activity. Pretreatment with honokiol (10 mg/kg, oral administration) for 11 consecutive days significantly improved the immobility time of depressed mice in the FST and TST experiments. Moreover, honokiol ameliorated LPS-induced NF-κB activation in the hippocampus and significantly reduced the levels of the pro-inflammatory cytokines; tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and interferon γ (IFN-γ). In addition, honokiol inhibited LPS-induced indoleamine 2,3-dioxygenase (IDO) activation and quinolinic acid (a toxic product) increase and reduced the level of free calcium in brain tissue, thereby inhibiting calcium overload. In summary, our results indicate that the anti-depressant-like effects of honokiol are mediated by its anti-inflammatory effects. Honokiol may inhibit the LPS-induced neuroinflammatory response through the NF-κB signaling pathway, reducing the levels of related pro-inflammatory cytokines, and furthermore, this may affect tryptophan metabolism and increase neuroprotective metabolites.

[Development and characterization of TPGS modified proniosomes of docetaxel].

A novel oral delivery system that TPGS modified docetaxel proniosomes, DTX-TPGS-PN, was developed and the characterization after hydration was observed. Firstly, Doce-TPGS-PN was optimized by investing the factors, including the type of surfactant, methods of adding TPGS, content of TPGS and the molar ratio of span40/cholesterol, which may affecting the particle size, encapsulation efficiency and instantaneous release of drug in the formulation. Then, the morphology, particle size, Zeta potential, encapsulation efficiency and in vitro release of the formulation were evaluated. The result showed that hydrated nanoparticles of DTX-TPGS-PNs were (93 ± 6.5) nm in size,(-83.95 ± 3.69) mV in zeta potential, (97.31 ± 0.60)% in encapsulation efficiency, exhibiting spherical morphology and biphasic release process that a low burst effect within the first 0.5 hour and a relative-sustained release for the next several hours in PBS. These results indicate the oral delivery system of DTX-TPGS-PN was successfully built with good properties.

[Progress in regulation effect of aromatic refreshing traditional Chinese medicine on BBB permeability and its mechanism].

The blood-brain barrier (BBB) protects the brain against unwanted substances, while, at the same time, limits the transport of many drugs into the brain. Aromatic refreshing traditional Chinese medicine (TCM) can induce resuscitation and modify the permeability of BBB, promoting other drugs entering into the brain with brain protection effect. This paper mainly reviews the research progress in regulation effects and mechanism of usual aromatic refreshing TCM, such as borneol, moschus, styrax, benzoinum and Tatarinow Sweetflag Rhizome, on BBB permeability. To broaden the application of these drugs in modern pharmaceutics in the future, the relatively research should emphasis on combining aromatic refreshing TCM with new formulations and technologies in pharmaceutics, providing novel promising strategies for brain diseases therapy.

Effects of particle size on the pharmacokinetics of puerarin nanocrystals and microcrystals after oral administration to rat.

Puerarin, which is extracted from traditional Chinese medicine, is widely used in clinic in China and mainly used as a therapeutic agent to cardiovascular diseases. Owing to its poor water solubility and adverse drug reactions caused by cosolvents after intravenous administration, the development of oral formulation is urgently needed. Nowadays, nanocrystals technique has become a preferred way to develop oral dosage form. In this study, we used high pressure homogenization (HPH) to prepare puerarin nanocrystals and microcrystals with different sizes ranged from 525.8 nm to 1875.6 nm and investigated the influence of particle size on pharmacokinetics. The nanocrystals and microcrystals prepared were characterized using DLS, DSC, XRD and SEM, and we found that the crystalline state of puerarin was changed during the preparation process and the drug was dispersed into HPMC. In the pharmacokinetic study, we observed an increasing of Cmax and AUC and a decreasing of CL/F with the decreasing of particle size. The AUC of the puerarin nanocrystals (525.8 nm) was 7.6-fold of that of raw puerarin suspension, with an absolute bioavailability of 21.44%. From the above results, we can conclude that nanocrystal technique is an efficient technology to improve the oral bioavailability of puerarin.

[Tissue distribution of ginsenoside Rg1 before and after modification by PEG].

OBJECTIVE: To investigate targeted distribution of ginsenoside Rg1 in mice tissues before and after modification by the PEG. METHOD: SD mice were randomly divided into two groups and given Rg1 and PEG-Rg1 by intravenous injection respectively. Their samples of blood and organ tissues were taken at different time points. The content of Rg1 in samples were determined by UPLC and used as indicator to observe the targeted distribution of Rg1 in mice tissues. RESULT: The AUC of ginsenoside Rg1 in tissues of the Rg1 group were in the order of liver, kidney, lung, heart and spleen, with the liver targeting coefficient was of 2.01. While the AUC of ginsenoside Rg1 in tissues of the PEG-modified group were in the order of the kidney, liver, lung, heart, spleen, with the liver targeting coefficient was of 9.21. CONCLUSION: PEG modified Rg1 can increase Rg1's targeting selectivity to the liver, kidney and lung in mice.

[Modification and stability of ginsenoside Rg1PEG].

OBJECTIVE: To study the stability of ginsenoside Rg1 before and after being modified by PEG (PEG-Rg1) in isolated rat stomachs. METHOD: SD rats, after 18 h of fasting, were randomly divided into the Rg1 group and the PEG-Rg1 group. Rg1 stomach perfusion fluid and PEG-Rg1 infusion fluid were accurately extracted and injected into their stomachs in vitro, with oscillation at 37 degrees C. Samples were taken in different time points and contents of ginsenoside Rg1 were determined by UPLC to observe and compare the stability of ginsenoside Rg1 and PEG-Rg1 in rat stomachs in vitro. RESULT: Rg1 in rat stomachs showed poor stability, Rg1 was measured to be 26.8% in 2 h, with degradation of 73.2%. Its stability in PEG-Rg1 was improved in rat stomachs, Rg1 was measured to be 81.8% in 2 h, with degradation of only 18.2%. CONCLUSION: PEG-modified ginsenoside Rg1 can enhance the stability of ginsenoside Rg1 in stomach and improve degradation and poor stability of ginsenoside Rg1 in stomach.

Enhanced oral bioavailability of docetaxel by lecithin nanoparticles: preparation, in vitro, and in vivo evaluation.

The aim of this research work was to investigate the potential of lecithin nanoparticles (LNs) in improving the oral bioavailability of docetaxel. Docetaxel-loaded LNs (DTX-LNs) were prepared from oil-in-water emulsions and characterized in terms of morphology, size, zeta potential, and encapsulation efficiency. The in vitro release of docetaxel from the nanoparticles was studied by using dialysis bag method. Caco-2 cell monolayer was used for the in vitro permeation study of DTX-LNs. Bioavailability studies were conducted in rats and different pharmacokinetic parameters were evaluated after oral administration of DTX-LNs. The results showed that DTX-LNs had a mean diameter of 360 ± 8 nm and exhibited spherical shape with smooth surface under transmission electron microscopy. The DTX-LNs showed a sustained-release profile, with about 80% of docetaxel released within 72 hours. The apical to basolateral transport of docetaxel across the Caco-2 cell monolayer from the DTX-LNs was 2.14 times compared to that of the docetaxel solution (0.15 × 10⁻5 ± 0.016 × 10⁻5 cm/second versus 0.07 × 10⁻5 ± 0.003 × 10⁻5 cm/second). The oral bioavailability of the DTX-LNs was 3.65 times that of docetaxel solution (8.75% versus 2.40%). These results indicate that DTX-LNs were valuable as an oral drug delivery system to enhance the absorption of docetaxel.

Improved antitumor efficacy and reduced toxicity of liposomes containing bufadienolides.

Long-circulating liposomes are used extensively nowadays for enhancing the therapeutic effect and reducing the toxicity of anticancer drugs. In this paper, a traditional Chinese medicine, toad venom, which has long been used in the clinic for tumor therapy with unpleasant side effects, was incorporated into poloxamer modified liposomes to increase its antitumor effect and reduce its toxicity. Our preparation of bufadienolides liposomes had a particle size of around 70 nm and an entrapment efficiency of about 87.6%. Lyophilized liposomes well retained their appearance, particle size and encapsulation efficiency for 3 months. The in vitro release results verified the sustained release properties of the bufadienolides liposomes. The concentration of bufadienolides in modified liposomes that caused 50% cell killing was much lower than that of free drug for both Lovo cells and NCI-H157 cells. Compared to the bufadienolides solution and the unmodified liposomes, the bufadienolides liposomes significantly prolonged the retention time and increased the area under the curve in vivo. The antitumor efficiency of the bufadienolides liposomes against mice bearing H22 liver cancer cells and Lewis pulmonary cancer cells were 2.15 and 2.96, respectively, times that of a bufadienolides solution at the same toxicity. The safety test results demonstrated that the bufadienolides liposomes had an LD(50) that was 3.5 times the LD(50) of bufadienolides solution and caused no allergen-related or blood vessel irritation effects. All these results proved that poloxamer modified bufadienolides liposomes have improved antitumor efficacy and safety.