ABSTRACT
Uveal melanoma (UM) is an intraocular tumor which is almost lethal at the metastatic stage due to the lack of effective treatments. In this regard, we have developed an albumin-based nanostructure (ABN) containing AZD8055 (ABN-AZD), which is a potent mTOR kinase inhibitor, for its efficient delivery to the tumors. The drug has been conjugated to ABN using tailored linkers that have a disulfide moiety, allowing its release selectively and effectively in the presence of an elevated concentration of glutathione, such as inside the tumoral cells. Our therapeutic approach induced significant cellular toxicity in uveal melanoma cells, but not in non-tumoral keratinocytes, highlighting the excellent selectivity of the system. In addition, these nanostructures showed excellent activity in vivo, decreasing the tumor surface compared to the free AZD8055 in mice models. Remarkably, the results obtained were achieved employing a dose 23 times lower than those used in previous reports.
Subject(s)
Melanoma/drug therapy , Morpholines , Nanostructures , Serum Albumin, Human , Uveal Neoplasms/drug therapy , Animals , Feeder Cells , Humans , Melanoma/enzymology , Mice , Mice, Nude , Morpholines/chemistry , Morpholines/pharmacology , Nanostructures/chemistry , Nanostructures/therapeutic use , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Serum Albumin, Human/chemistry , Serum Albumin, Human/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Uveal Neoplasms/enzymology , Xenograft Model Antitumor AssaysABSTRACT
Controlled delivery of multiple chemotherapeutics can improve the effectiveness of treatments and reduce side effects and relapses. Here in, we used albumin-stabilized gold nanoclusters modified with doxorubicin and SN38 (AuNCs-DS) as combined therapy for cancer. The chemotherapeutics are conjugated to the nanostructures using linkers that release them when exposed to different internal stimuli (Glutathione and pH). This system has shown potent antitumor activity against breast and pancreatic cancer cells. Our studies indicate that the antineoplastic activity observed may be related to the reinforced DNA damage generated by the combination of the drugs. Moreover, this system presented antineoplastic activity against mammospheres, a culturing model for cancer stem cells, leading to an efficient reduction of the number of oncospheres and their size. In summary, the nanostructures reported here are promising carriers for combination therapy against cancer and particularly to cancer stem cells.
ABSTRACT
A new class of enantiopure ortho,ortho-disubstituted azobenzene photoswitches has been synthesized from (S)-2-(p-tolylsulfinyl)benzoquinone and arylhydrazines. The sulfoxide acts as a unidirectional controller of the helical chirality that arises in the Zâ isomer after photoisomerization. Highly congested E-azobenzenes 5 c showed two atropisomeric diastereoconformers in the solid state that converged upon irradiation into a unique Zâ isomer with defined helicity (M), as evident in the X-ray structure. The chiroptical properties of this three-state enantiopure switch can be externally tuned both photochemically and/or thermally. Theoretical CD spectra calculated by using time-dependent DFT methods support the existence of two atropoisomeric Eâ isomers and only one Zâ isomer with (M) helicity. Complementary to the classical azobenzene-based switches, the photoswiching event is promoted under green/blue light and do not occur under UV irradiation.
ABSTRACT
The asymmetric synthesis of the natural gamma-tocopherol metabolite (S)-gamma-CEHC (1) is described in 10 steps and 18.4% overall yield starting from 2,3-dimethylhydroquinone. The key step is a stereoselective TiCl(4)-mediated homochiral sulfoxide-directed allylation of ketal (SS)-3 to efficiently generate the challenging C-2 stereogenic carbon of chroman (SS,S)-2 with the correct absolute configuration.
