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Implementing combination medication through crystal engineering technology receives increasing attention from researchers due to improvements in the clinical treatment effects as well as the physicochemical properties of the drug. Berberine (BER) is commonly used to treat gastroenteritis and bacterial diarrhea, with the problems of poor solubility and low oral bioavailability. Recently, it is found that gallic acid (GA) also has anti‐inflammatory and anti‐bacterial activities. Therefore, if the above‐mentioned two ingredients can be combined, it is possible to enhance the therapeutic effects and physicochemical properties of BER. Inspired by this, 8‐hydroxy‐7,8‐dihydroberberine (8H‐HBER) in this study is employed to react with gallic acid to yield BER gallate dihydrate (2BER‐2GA‐2 W). Furthermore, dissolution experiments demonstrate that the maximum apparent solubility (MAS) of 2BER‐2GA‐2 W in dilute hydrochloric acid solution medium (pH 1.2) has increased by 7 times compared to the commercial form of BER, because of avoiding the common‐ion effect. Moreover, 2BER‐2GA‐2 W has also obviously enhanced stability relative to the commercial form of BER. In addition, 2BER‐2GA‐2 W has a better inhibitory effect on Staphylococcus aureus (S. aureus) relative to the commercial form of BER. Hence, 2BER‐2GA‐2 W will be a promising solid‐state form of BER for its further development. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is used as a first-line chemotherapeutic drug, whereas dihydroartemisinin (DHA) also shows a certain degree of antitumor activity. Disulfide bonds (-SS-) in prodrug molecules can be degraded in highly reducing environments. Thus, heterodimer prodrugs of DOX and DHA linked by a disulfide bond was designed and subsequently prepared as reduction-responsive self-assembled nanoparticles (DOX-SS-DHA NPs). In an in vitro release study, DOX-SS-DHA NPs exhibited reduction-responsive activity. Upon cellular evaluation, DOX-SS-DHA NPs were found to have better selectivity toward tumor cells and less cytotoxicity to normal cells. Compared to free DiR, DOX-SS-DHA NPs showed improved accumulation at the tumor site and even had a longer clearance half-life. More importantly, DOX-SS-DHA NPs possessed a much higher tumor inhibition efficacy than DOX-sol and MIX-sol in 4T1 tumor-bearing mice. Our results suggested the superior antitumor efficacy of DOX-SS-DHA NPs with less cytotoxicity. [Display omitted] • A novel heterodimer prodrug (DOX-SS-DHA) was synthesized to take advantages of the combination therapy. • In vitro efficacy studies of the designed DOX-SS-DHA NPs showed enhanced tumor suppression and improved survival time. • DOX-SS-DHA NPs prepared here had better security to mice and better selectivity to the tumor sites of mice. [ABSTRACT FROM AUTHOR]

There is a strong desire to develop docetaxel (DTX) formulation with good therapeutic effectiveness in view of serious adverse reactions of the commercial formulation of DTX (Taxotere®). In this study, a redox-responsive DTX-vitamin E prodrug was successfully formulated into liposomes with the drug loading of 4.14% ± 0.10%. Compared with DTX liposomes, the DTX prodrug liposomes (DPLs) showed good stability for 30-d shelf life and during dilution with different media.In vitroantitumor activity of DPLs on human prostatic carcinoma PC-3 cells and human lung cancer A549 cells was evaluated using cytotoxicity and apoptosis assays. In spite of a decrease inin vitroantitumor activity, thein vivopharmacokinetic study reveals that DPLs exhibit significantly longer DTX plasma half-life (t1/2, 1.38-fold) and higher bioavailability (AUC0−t, 14.49-fold) compared with DTX liposomes. The antitumor activity of DPLs to the A549 tumor xenograft model showed selective accumulation in tumor tissue, significant inhibition the growth of the tumors and a much lower toxicity as seen in body weight loss, compared with DTX-Solution. Taken together, the results showed that DPLs is a promising strategy for DTX antitumor delivery. [ABSTRACT FROM PUBLISHER]

Three 2-phenylpyridine-Pt complexes were synthesized. All these Pt(II) complexes showed rich photophysical properties. 3 displayed high anticancer activity against human gastric cancer cell lines. [Display omitted] • Pt(II) complexes containing phenylpyridine are presented. • Crystal structures of three new Pt(II) complexes are determined. • These Pt(II) complexes display rich photophysical properties. • Some Pt(II) complexes exhibit certain selectivity toward human gastric cancer cell lines. Three luminescent Pt(II) complexes, [Pt(5-NO 2 - ppy)(H -5-NO 2 - ppy)(Cl)] (1), [Pt(2-(2′,4′-dF)- ppy)(H -2-(2′,4′-dF)- ppy)(Cl)] (2), [Pt(2-(3′,5′-dF)- ppy)(H -2-(3′,5′-dF)- ppy)(Cl)] (3) with 2-phenyl-5-nitropyridyl (5-NO 2 - ppy), 2-(2,4-difluorophenyl)pyridine (2-(2′,4′-dF)- ppy) and 2-(3,5-difluorophenyl)pyridine(2-(3′,5′-dF)- ppy) were synthesized. FT-IR spectroscopy, multinuclear NMR spectroscopy and single-crystal X-ray crystallography were used to determine their structures. The UV–vis absorption and photoluminescence (PL) spectra of 1 – 3 were measured. 1 – 3 displayed rich photophysical properties with the maximum emission wavelengths in the range of 403 to 527 nm in the photoluminescence spectra, which demonstrated 1 – 3 have the potential to become the DNA luminescent probes in living cells. The anticancer activities of these complexes were tested in vitro by MTT assay against four tumor cell lines BGC823, MGC803 (human gastric cancer cell lines), HepG2 (human hepatocellular carcinoma), A549 (human non-small-cell lung cancer cell lines), HL-7702(human normal liver cell line). Moreover, 3 displayed highest cytotoxicity against human gastric cancer cell lines with the values of IC 50 in the range of 13.036–26.594 μM. [ABSTRACT FROM AUTHOR]

Currently, conjugation of artemisinin-derived dimers, trimers, and tetramers is a viable strategy for developing new effective antimalarial candidates. Furthermore, nanotechnology is an effective means to achieve intravenous administration of hydrophobic drugs. In this paper, an ester-linked dihydroartemisinin trimer (DHA3) was synthesized and further prepared as self-assembled nanoparticles (DHA3NPs) by a one-step nanoprecipitation method. The pharmacokinetics and antimalarial pharmacodynamics of DHA3NPs were studied in rats and mice infected with Plasmodium yoelii BY265 (PyBY265). DHA3NPs had a regular spherical shape with a uniform size distribution of 140.27 ± 3.59 nm, entrapment efficiency (EE) of 99.63 ± 0.17%, and drug loading efficiency (DL) of 79.62 ± 0.11%. The in vitro release characterization revealed that DHA3NPs were easily hydrolysed into DHA in an esterase environment. The pharmacokinetics study demonstrated that the area under the concentration–time curve (AUC0-t) of DHA in DHA3NPs group was 2070.52 ± 578.76 h×ng×mL−1, which was higher than that of DHA and artesunate (AS) control groups (AUC0-t values of 724.18 ± 94.32 and 448.40 ± 94.45 h×ng×mL−1, respectively) (P < 0.05). The antimalarial pharmacodynamics in vivo suggested that DHA3NPS (ED90 7.82 ± 1.16 μmol×(kg×day)−1) had a superior antimalarial effect compared with that of control groups (ED90 values of 14.68 ± 0.98 (DHA) and 14.34 ± 1.96 (AS) μmol×(kg×day)−1) (P < 0.05). In addition, DHA3NPS reduced the recurrence ratio and improved the cure ratio and survival time. In summary, DHA3NPs exhibited promising pharmacokinetic characteristics and antimalarial pharmacodynamics in vivo. [ABSTRACT FROM AUTHOR]

The dihydroartemisinin-derived dimer (DHA dimer) was synthesized, and its antimalarial activities were evaluated both in vitro and in vivo. The dimer IC50 value of 0.51 ± 0.12 nM in vitro was significantly lower than that of DHA at 1.81 ± 0.70 nM. The dimer ED50 values were 0.44 ± 0.03 and 0.18 ± 0.03 mg/(kg·day) in vivo for intragastric (i.g.) and intravenous (i.v.) groups, respectively, to Plasmodium yoelii rodent malaria. It also performed better relative to those of DHA which had ED50 values of 0.76 ± 0.03 mg/(kg·day) (i.g.) and 0.32 ± 0.03 mg/(kg·day) (i.v.). Moreover, the recrudescence rate, negative conversion rate, and cure rate of the dimer showed superior performance. Furthermore, the metabolites and major metabolic pathways of the dimer in rats were preliminarily investigated using the HPLC-HRMSn method. Twenty-seven metabolites, including DHA, 11 metabolites of DHA, and 15 other novel metabolites, were detected in rats after i.g. administration of dimer. The metabolic pathways of the 15 novel metabolites were inferred: deoxygenation, hydroxylation, and hydroxylation with dehydration. [ABSTRACT FROM AUTHOR]

Artemisinin (ART) drugs showed declining plasma concentrations after repeated oral dosing, known as time-dependent pharmacokinetics (PK). ART and dihydroartemisinin (DHA) were adopted as representatives to evaluate the roles of first-pass effects and systemic metabolism in time-dependent PK by comparison of oral versus intravenous administration and 1 dose versus 5 consecutive doses PK in rats and dogs, respectively. The hepatic extraction ratio (ER h) and the intestinal elimination changes were further investigated in rats to distinguish the roles of hepatic first-pass effect or intestinal first-pass effect. The induction capacities of ARTs to cytochrome P450 (CYP450) in rats and human cells were evaluated as well. For ART, only the oral groups showed time-dependent PK. A fairly high ER h that obtained for ART was not sensitive to multiple oral doses. An increased elimination and CYP450 expression have also been found in the intestine. For DHA, though a significant CYP450 induction was observed, neither time-dependent PK nor changes in the first-pass effects was found. In conclusion, time-dependent PK of ART was mainly caused by the increased intestinal first-pass effect rather than hepatic first-pass effect or systemic metabolism. DHA was not involved in auto-induction elimination, thus showing no time-dependent PK. [ABSTRACT FROM AUTHOR]

As a quinazolinocarboline alkaloid, dehydroevodiamine (DHED) derived from Evodia rutaecarpa has recently gained attention because it improves memory failure in Alzheimer's mice. However, its solid forms, which have not yet been elucidated, could be a vital factor affecting its bioactivity and dosage form design. In this study, five DHED-related crystals, including DHED, its hydrochloride anhydrate (DHED·HCl), methanol solvate (DHED·HCl·CH3OH), dihydrate (DHED·HCl·2H2O) and trihydrate (DHED·HCl·3H2O), were obtained via re-crystallization. The five crystals fell into four distinct structural types based on the analysis of their similarities, and DHED·HCl·CH3OH and DHED·HCl·2H2O were proven to be isostructural. The water or solvent molecules incorporated into the crystal lattices via hydrogen bonds and π–π interactions were the main causes of formation of the distinct solid DHED hydrochloride forms. After dehydration at a high temperature, DHED·HCl·3H2O was transformed into an amorphous form (DHED·HCl-AM). Stability tests showed that the two isostructural crystals exhibited the same solid forms under all investigated conditions, and the humidity-induced phase transformation of DHED·HCl was closely tied to the moisture content. Solubility experiments showed that DHED achieved the highest solubility of approximately 3.6 μg ml−1, because of the loose molecular arrangements in DHED with the smallest packing coefficient and lack of π–π interactions. Additionally, transformations among evodiamine (EVO), DHED, DHED·HCl·2H2O and rutaecarpine (RUT) were also revealed: EVO was transformed into DHED·HCl·2H2O in hydrochloric acid-acidified acetone, and all of the solid forms of DHED hydrochloride were converted to RUT at 523 K. The transformations provided a novel and reliable approach to prepare these compounds. [ABSTRACT FROM AUTHOR]

Nanostructured lipid carriers (NLC) have been considered as promising vehicles for oral delivery of taxanes, such as docetaxel (DTX). However, the low drug loading capability (∼5%, w/w) has greatly limited their clinical application. In response to this challenge, a novel lipophilic oleate prodrug of DTX (DTX-OA) was synthesized and efficiently encapsulated in NLC using core-match technology, in which liquid lipid (OA) was used as core matrix to enhance compatibility with DTX-OA. DTX-OA-NLC showed uniform particle size of about 100 nm with markedly high drug loading capability (∼23% of DTX, w/w) compared with DTX-NLC (∼5%, w/w). Besides, DTX-OA-NLC showed better colloidal stability and slower drug release property compared with DTX-NLC. The prepared NLC could be accumulated more easily in MDCK cells than drug solution, and clathrin-mediated endocytosis was the main endocytosis pathway. In situ single-pass intestinal perfusion (SPIP) and intestinal biodistribution studies demonstrated the improved membrane permeability and intestinal wall bioadhesion of NLCs. The bioavailability of DTX-OA-NLC showed 4.04-fold and 2.06-fold higher than DTX solution and DTX-NLC, respectively. These results suggest that the core-matched prodrug-NLC is a promising platform to facilitate the oral delivery of DTX. [ABSTRACT FROM AUTHOR]

[Display omitted] Targeting delivery and prolonging action duration of artemisinin drugs are effective strategies for improving antimalarial treatment outcomes. Here, dihydroartemisinin (DHA) loaded poly (lactic- co -glycolic acid) (PLGA) nanoparticles (PDNs) were prepared and further cloaked with red blood cell (RBC) membranes via electrostatic interactions to yield RBC membrane-cloaked PDNs (RPDNs). The prepared RPDNs displayed a notable "core-shell" structure, with a negative surface charge of −29.2 ± 4.19 mV, a relatively uniform size distribution (86.4 ± 2.54 nm, polydispersity index of 0.179 ± 0.011), an average encapsulation efficiency (70.1 ± 0.79%), and a 24-h sustained-release behavior in vitro. Compared with PDNs, RPDNs showed markedly decreased phagocytic activity by RAW 264.7 cells and had prolonged blood circulation duration. The Pearson correlation coefficient of RPDNs distribution in infected red blood cells (iRBCs) was 0.7173, suggesting that RPDNs could effectively target Plasmodium -iRBCs. In Py By265-infected mice, RPDNs showed a higher inhibition ratio (88.39 ± 2.69%) than PDNs (83.13 ± 2.12%) or DHA (58.74 ± 3.78%), at the same dose of 8.8 μmol/kg. The ED 90 of RPDNs (8.13 ± 0.18 μmol/kg) was substantially lower than that of PDNs (14.48 ± 0.23 μmol/kg) and DHA (17.67 ± 3.38 μmol/kg). Furthermore, no apparent abnormalities were detected in routine blood examination, liver function indexes, and pathological analysis of tissue sections of Py By265-infected mice following RPDNs treatment. In conclusion, the prepared RPDNs exhibited enhanced antimalarial efficacy, prolonged circulation, targeted delivery to Plasmodium -iRBCs, and satisfactory biocompatibility. [ABSTRACT FROM AUTHOR]

• DTX-S-S-DHA conjugates were synthesized using two-step reaction and furtherly assembled to nanoparticles (DSDNs). • Reductive sensitive release of the DSDNs. • Nanoconjugates enhanced synergistic effect on tumor cells. • Nanoconjugates protected healthy tissues from drugs toxicity. Co-delivery of anti-tumor agents with outstanding stimulus-triggered drug release in tumor cells, especially with the aid of nanotechnology, provided the possibility to enhance delivery efficiency for targeting tumor cells and antitumor efficacy. In this paper, docetaxel-dihydroartemisinin nanoconjugates linked by disulfide bond were designed to increase co-delivery and anti-tumor efficacy. Docetaxel and dihydroartemisinin were synthesized using two-step reaction and furtherly assembled to nanoconjugates. Nanoprescription was optimized to evaluate its physicochemical properties. In vitro anti-tumor activities of nanoformulation were assessed by MTT. The flow cytometry was adopted to analyze cell apoptosis and cell cycle arrest. The wound healing assay was used to evaluate antimigratory-property. In vivo pharmacokinetic and pharmacodynamic studies were investigated in rats and 4T1 bearing Balb/c mice model after intravenous injection, respectively. The chemical structure of conjugate was confirmed. The prepared nanoparticles possessed uniform size distribution (172.10 ± 1.70 nm, PDI 0.05 ± 0.01), was stable during storage period, sustained release profiles and sensitive reduction responsiveness. MTT assay indicated that the toxicity of nanoconjugates was slightly weak. Flow cytometry studies showed that nanoconjugates could promote early apoptosis significantly and mainly arose from G 0 /G 1 phase. The wound healing assay provided an obvious antimetastatic potential of nanoparticles in 4T1 cells. The result of pharmacokinetic study suggested that nanoconjugates exhibited higher exposure levels. In vivo pharmacodynamic research showed that mice treated with docetaxel-dihydroartemisinin nanoconjugates had lower systemic toxicity and higher survival ratio than those of control groups. This potential of nanoconjugates was developed as a novel nanoplateform to treat tumor. [ABSTRACT FROM AUTHOR]