Transdermal Delivery of Metformin Utilizing Ionic Liquid Technology: Insight Into the Relationship Between Counterion Structures and Properties.

PURPOSE: The purpose of the present study was to explore the feasibility of transdermal delivery of metformin, a commonly used oral antidiabetic drug, by ionic liquid (IL) technology. METHODS: Metformin hydrochloride (MetHCl) was first transformed into three kinds of ILs with different counterions. The physicochemical properties of the obtained ILs were characterized in depth. The simulation of stable configuration and calculation of interaction energies were conducted based on density functional theory (DFT). Skin-PAMPA was used to evaluate the intrinsic transdermal permeation properties. The cytotoxicity assay of these ILs was conducted using HaCaT cells to evaluate the toxicity to skin. These metformin ILs were then formulated into transdermal patch, and the transdermal potential was further evaluated using in vitro dissolution test and skin permeation assay. Finally, the pharmacokinetic profiles of these metformin IL-containing patches were determined. RESULTS: Among all the three Met ILs, metformin dihexyl sulfosuccinate (MetDH) with proper overall physiochemical and biological properties demonstrated the highest relative bioavailability. Metformin docusate (MetD) with the highest lipophilicity and intrinsic transdermal permeability exhibited the most significant sustained release profile in vivo. Both MetDH and MetD were the promising candidates for further clinical investigations. CONCLUSIONS: Overall, the properties of ILs were closely related to the structures of counterion. IL technology provided the opportunities to finely tune the solid-state and biological properties of Metformin and facilitated the successful delivery by transdermal route.

Discovery of potent 2,4-difluoro-linker poly(ADP-ribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy.

Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially in breast and ovarian cancers; tumor cells that are deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, we identified a series of 2,4-difluorophenyl-linker analogs (15-55) derived from olaparib as novel PARP1 inhibitors. Four potent analogs 17, 43, 47, and 50 (IC50=2.2-4.4 nmol/L) effectively inhibited the proliferation of Chinese hamster lung fibroblast V-C8 cells (IC50=3.2-37.6 nmol/L) in vitro, and showed specificity toward BRCA-deficient cells (SI=40-510). The corresponding hydrochloride salts 56 and 57 (based on 43 and 47) were highly water soluble in pH=1.0 buffered salt solutions (1628.2 µg/mL, 2652.5 µg/mL). In a BRCA1-mutated xenograft model, oral administration of compound 56 (30 mg·kg-1·d-1, for 21 d) exhibited more prominent tumor growth inhibition (96.6%) compared with the same dose of olaparib (56.3%); in a BRCA2-mutated xenograft model, oral administration of analog 43 (10 mg·kg-1·d-1, for 28 d) significantly inhibited tumor growth (69.0%) and had no negative effects on the body weights. Additionally, compound 56 exhibited good oral bioavailability (F=32.2%), similar to that of olaparib (F=45.4%). Furthermore, the free base 43 of the hydrochloride salt 56 exhibited minimal hERG inhibition activity (IC50=6.64 µmol/L). Collectively, these data demonstrate that compound 56 may be an excellent drug candidate for the treatment of cancer, particularly BRCA-deficient tumors.

Surface Molecularly Engineered Mitochondria Conduct Immunophenotype Repolarization of Tumor-Associated Macrophages to Potentiate Cancer Immunotherapy.

Reprogramming tumor-associated macrophages (TAMs) to an inflammatory phenotype effectively increases the potential of immune checkpoint blockade (ICB) therapy. Artificial mitochondrial transplantation, an emerging and safe strategy, has made brilliant achievements in regulating the function of recipient cells in preclinic and clinic, but its performance in reprogramming the immunophenotype of TAMs has not been reported. Here, the metabolism of M2 TAMs is proposed resetting from oxidative phosphorylation (OXPHOS) to glycolysis for polarizing M1 TAMs through targeted transplantation of mannosylated mitochondria (mPEI/M1mt). Mitochondria isolated from M1 macrophages are coated with mannosylated polyethyleneimine (mPEI) through electrostatic interaction to form mPEI/M1mt, which can be targeted uptake by M2 macrophages expressed a high level of mannose receptors. Mechanistically, mPEI/M1mt accelerates phosphorylation of NF-κB p65, MAPK p38 and JNK by glycolysis-mediated elevation of intracellular ROS, thus prompting M1 macrophage polarization. In vivo, the transplantation of mPEI/M1mt excellently potentiates therapeutic effects of anti-PD-L1 by resetting an antitumor proinflammatory tumor microenvironment and stimulating CD8 and CD4 T cells dependent immune response. Altogether, this work provides a novel platform for improving cancer immunotherapy, meanwhile, broadens the scope of mitochondrial transplantation technology in clinics in the future.

A mitochondria-targeting dihydroartemisinin derivative as a reactive oxygen species -based immunogenic cell death inducer.

Immunogenic cell death (ICD) can activate the anticancer immune response and its occurrence requires high reliance on oxidative stress. Inducing mitochondrial reactive oxygen species (ROS) is a desirable capability for ICD inducers. However, in the category of ICD-associated drugs, numerous reported ICD inducers are a series of anthracyclines and weak in ICD induction. Herein, a mitochondria-targeting dihydroartemisinin derivative (T-D) was synthesized by conjugating triphenylphosphonium (TPP) to dihydroartemisinin (DHA). T-D can selectively accumulate in mitochondria to trigger ROS generation, leading to the loss of mitochondrial membrane potential (ΔΨm) and ER stress. Notably, T-D exhibits far more potent ICD-inducing properties than its parent compound. In vivo, T-D-treated breast cancer cell vaccine inhibits metastasis to the lungs and tumor growth. These results indicate that T-D is an excellent ROS-based ICD inducer with the specific function of trigging vigorous ROS in mitochondria and sets an example for incorporating artemisinin-based drugs into the ICD field.

2-{[3-Methyl-4-(2,2,2-trifluoro-eth-oxy)pyridin-2-yl]methyl-sulfan-yl}-1H-benzimidazole propan-2-ol monosolvate: a second monoclinic polymorph.

In the crystal structure of the title compound, C16H14F3N3OS·C3H8O, the mol-ecules are linked into chains along [010] via N-H⋯O and O-H⋯N hydrogen bonds. The triclinic form was reported by Ren et al. [(2011). Acta Cryst. E67, o270] and the first monoclinic form by Chen et al. [(2012). Acta Cryst. E68, o2015-o2016]. The fused five-and six-membered rings make a dihedral angle of 1.22 (2)°, while the benzene and pyridine rings make a dihedral angle of 10.15 (2)°.

1,3-Dihy-droxy-2-(hy-droxy-meth-yl)propan-2-aminium formate.

The title compound, C(4)H(12)NO(3) (+)·CHO(2) (-), was obtained from 1,3-dihy-droxy-2-(hy-droxy-meth-yl)propan-2-aminium acetate and ethyl formate. In the crystal, the cations and anions are held together by inter-molecular N-H⋯O and O-H⋯O hydrogen bonds.

Lewis acid catalyzed rearrangement of vinylcyclopropenes for the construction of naphthalene and indene skeletons.

[reaction: see text] The choice of Lewis acid catalyst can result in dramatic differences in the chemoselectivity of the rearrangement reactions of vinylcyclopropenes. When BF3.OEt2 was used as the catalyst, naphthalenes were formed. However, when Cu(OTf)2 was used as the catalyst, indenes were obtained.

PdCl(2)-promoted reactions of diaryl-substituted methylenecyclopropanes.

The PdCl(2)-promoted reactions of methylenecyclopropanes (MCPs) 1 bearing diaryl substituents on the terminal double bond were carefully investigated. The solvents employed significantly affected the reaction outcomes. It was found that dimeric allylpalladium(ii) complexes 2a-2f can be obtained as the sole products in acceptable to good yields under mild reaction conditions with THF as the solvent, while dimeric allylpalladium(ii) complexes 2a-2f along with another type of dimeric allylpalladium(ii) complexes 4a-4e can be obtained in good to high total yields if N,N-dimethylacetamide (DMAc) was used as the solvent. Moreover, using N,N-dimethylformamide (DMF) as the solvent in the presence of water, it was found that water can also participate in the reaction to form another type of dimeric allylpalladium(ii) complex 6 as the minor product. All of these dimeric allylpalladium(ii) complexes reported in the paper have been characterized by X-ray crystal structure diffraction.