Natural saponin and cholesterol assembled nanostructures as the promising delivery method for saponin.

The application of saponins has been restricted by problems such as hemolysis, low bioavailability, and poor solubility. So it is imperative to find a strategy to deliver saponins safely and efficiently. Here, through bottom-up technique, we design and prepare two saponin-cholesterol (Cho) nano-complex: dioscin (Dio, steroid saponin)-Cho nanofibers (NFs) and escin Ia (EIa, triterpene saponin)-Cho nanoparticles (NPs). It is found that the hydrophobic force and hydrogen bonding drive the two pairs of molecules to bind in different directions (the 3ß-OH of Cho face the sugar chain of EIa and the 22α-O of Dio, respectively) and finally show spherical NPs (EIa-Cho) and fibrous NFs (Dio-Cho). The equimolar saponin-Cho complex, Dio NFs and EIa NPs, reveal potent cytotoxicities against mouse breast cancer cells (4T1) in vitro. In vivo results confirm the antitumor (4T1 mice model) efficacy of PEGylation Dio NFs (10 mg/kg, i.v.) with a tumor inhibition rate of 61%, meanwhile, it does not cause extreme irritation and pain as free Dio does to mice. Moreover, compared with the free drug, the prepared nano-complex can significantly reduce hemolysis and organ toxicity. Our research reduces the toxicity of saponins while retaining their antitumor activity, providing a new strategy for the delivery of saponins.

Pharmacokinetic and tissue distribution studies of cassane diterpenoids, in rats through an ultra-high-performance liquid chromatography-Q exactive hybrid quadrupole-Orbitrap high-resolution accurate mass spectrometry.

Cassane diterpenoids (CA) are considered as the main active constituents of medicinal plants belonging to the Caesalpinia genus. Three cassane derivatives, bonducellpin G (BG), 7-O-acetyl-bonducellpin C (7-O-AC) and caesalmin E (CE), isolated from Caesalpinia minax Hance seeds, showed strong anti-inflammatory activity. In this paper, pharmacokinetics (BG, 7-O-AC, CE) and tissue distribution (7-O-AC, CE) properties were studied for the first time using a reliable, sensitive and rapid UHPLC-Q-Orbitrap HR-MS to develop new anti-inflammatory agents. A novel quantitative method with full scan in positive ion mode was used to determine the contents of compounds. They were separated using acetonitrile-water (0.1% formic acid) as gradient mobile phase. The calibration curve displayed good linearity and the lower limit of quantitation was 0.005-0.02 µg/mL for all analytes. Meanwhile, the absorption, distribution, metabolism, excretion (ADME) property was predicted using PreADMET web. The pharmacokinetic parameters indicated that they were absorbed quickly, eliminated rapidly together with high blood concentration. The results of tissue distribution demonstrated that CE was distributed rapidly and widely among tissues, and stomach was the main tissue site of CE and 7-O-AC, followed by small intestine/liver. This study indicates that the structures and dosages of active CA should be modified to help improve the absorption rate and residence time, and the findings are helpful for the pharmaceutical design of CA derivatives.

16-Tigloyl linked barrigenol-like triterpenoid from Semen Aesculi and its anti-tumor activity in vivo and in vitro.

Barrigenol-like triterpenoids (BATs) showed promising anti-tumor, anti-inflammatory and anti-Alzheimer's activities, while, the inhibitory strength was usually affected by their states with aglycones or glycosides. In order to find more BATs as new anti-tumor agents with much more efficiency, the chemical and pharmaceutical studies were carried out on the acid hydrolysate product (AHP) of Semen Aesculi crude extract. Thirteen BATs, including three new aglycones (1-3), two new glycosides (4, 5) and eight known glycosides (6-13) were obtained. Compound 1, as the main product in AHP, with a tigloyl unit linked at the C-16 position was an unusual aglycone. All compounds exhibited various degrees of inhibitory activity against human breast cell line (MCF-7) and cervical cancer cell line (HeLa) growth, moreover, new aglycones 1 and 2, and the known glycoside 6 (escin Ia) and 9 were found to exhibit potent inhibitory activity which were similar to the positive control (doxorubicin hydrochloride). Compound 1, named 16-tigloyl-O-protoaescigenin, could suppress tumor progression and decreased lung metastasis focuses in mice, and no pathological change was observed at the end of the treatment course. Besides that, the hemolysis experiment between 1 and 6 revealed that the hemolysis toxicity of 1 was much less than that of 6. According to these results, 16-tigloyl-O-protoaescigenin, with the powerful anti-tumor activity and cancer cell apoptosis induction, might be considered as a new promising anti-tumor agent.

"Gate" engineered mesoporous silica nanoparticles for a double inhibition of drug efflux and particle exocytosis to enhance antitumor activity.

"Gate" engineered mesoporous silica nanoparticles (MSN) have been extensively applied in cancer theranostics. Due to the complexity of tumor development and progression, with chemotherapy alone, it has often been difficult to achieve a good therapeutic effect. Currently, it has been shown that the combination with photothermal therapy overcomes the shortcoming of chemotherapy. In most studies, the photothermal effect has proven to accelerate drug release from nanocarriers and ablate malignant cells directly, but the influence on the intracellular fate of nanocarriers remains unknown. Herein, a lipophilic cyanine dye Cypate acting as a photothermal converting agent was conjugated on the external surface of MSN through a disulfide bond (MSN-Cy) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) was coated on the outside of the MSN-Cy via a hydrophobic interaction (TCMSN) to cover the pores, preventing drug preleakage in the circulation. The TCMSN underwent exocytosis through the lysosome-mediated pathway. Moderate heat induced by near-infrared light promoted lysosome disruption, which thus partly inhibited lysosome-mediated particle exocytosis. In the meantime, TPGS, as a P-glycoprotein inhibitor, blocked the drug efflux. This research elaborated the photothermal effect from a new perspective-inhibiting particle exocytosis. The as-designed "gate" engineered MSN realized a double inhibition of drug efflux and particle exocytosis from cancer cells, thus sustaining the drug action time and enhancing the antitumor activity.

Thermosensitive Lipid Bilayer-Coated Mesoporous Carbon Nanoparticles for Synergistic Thermochemotherapy of Tumor.

Thermochemotherapy exhibits a synergistic therapeutic efficiency for cancer, and the sensitivity of cancer cells to chemical drugs could be increased to a large extent at elevated temperature. In this work, a biocompatible nanocomposite thermosensitive mesoporous carbon nanoparticles (TSMCN) was prepared by covering a liposome on mesoporous carbon nanoparticles (MCN). The TSMCN had good photothermal efficiency and photostability. The doxorubicin (DOX)-loaded TSMCN (DOX/TSMCN) showed a slower release than the DOX-loaded MCN-COOH (DOX/MCN-COOH) both in simulated tumor environment and physiological environment. And release curves of DOX/TSMCN exposed to NIR laser exhibited the fast release property. The confocal laser scanning microscopy results illustrated that cellular uptake of DOX for DOX/TSMCN can be enhanced by NIR laser. The temperature of the tumor site reached up to 51.9 °C within 3 min after exposure to laser at 1.25 W/cm2 power density, which is above the phase transition temperature ( Tm) of liposome (40.7 °C). The biodistribution of DOX in vivo indicated that NIR laser can prolong the retardation time of DOX in the tumor site. The results of both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and antitumor efficiency elucidated that the DOX/TSMCN under NIR irradiation had a synergistic therapeutic effect for cancer. Thus, the TSMCN could be explored as a powerful nanoplatform that shows great prospect in thermochemotherapy of tumor therapy.

Hydrophobic interaction mediated coating of pluronics on mesoporous silica nanoparticle with stimuli responsiveness for cancer therapy.

In this research, a novel method was used to successfully stably coat Pluronic P123 on mesoporous silica nanoparticles (MSNs). Co-constructing a drug delivery system (DDS) with P123 and MSNs has not been previously reported. In this DDS, the coating of P123 was realized through a hydrophobic interaction with octadecyl chain-modified MSNs. The experiments found only Pluronic with an appropriate ratio of hydrophilic and lipophilic segments could keep the nanoassemblies stable. For comparison, nanoassemblies consisting of P123 and octadecyl chain-modified MSNs with or without a disulfide bond were prepared, which were denoted as PSMSNs and PMSNs, respectively. The disulfide bond was expected to endow the system with redox-responsiveness to enhance the therapeutic effect meanwhile decreasing the toxicity. A series of experiments including characterization of the nanoparticles, in vitro drug release, cell uptake and cellular drug release, in vitro cytotoxicity, cell migration and biodistribution of the nanoparticles were carried out. Compared with the PMSNs, PSMSNs displayed a redox-responsive drug release property not only in in vitro release text, but also on the cellular level. In addition, the cell migration experiments proved that the coating of P123 endowed the system with the ability of anti-metastasis. The accumulation of P123 in the tumor was enhanced after coating the MSNs by virtue of the 'EPR' effect of nanoparticles compared with the solution form.