Acid-decomposable, luminescent ZnO quantum dots (QDs) have been employed to seal the nanopores of mesoporous silica nanoparticles (MSNs) in order to inhibit premature drug (doxorubicin) release. After internalization into HeLa cells, the ZnO QD lids are rapidly dissolved in the acidic intracellular compartments, and as a result, the loaded drug is released into the cytosol from the MSNs. The ZnO QDs behave as a dual-purpose entity that not only acts as a lid but also has a synergistic antitumor effect on cancer cells. We anticipate that these nanoparticles may prove to be a significant step toward the development of a pH-sensitive drug delivery system that minimizes drug toxicity.

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Regeneratable antioxidant property of nanoceria has widely been explored to minimize the deleterious influences of reactive oxygen species. Limited information is, however, available regarding the biological interactions and subsequent fate of nanoceria in body fluids. This study demonstrates a surprising dissolution of stable and ultrasmall (4 nm) cerium oxide nanoparticles (CeO2 NPs) in response to biologically prevalent antioxidant molecules (glutathione, vitamin C). Such a redox sensitive behavior of CeO2 NPs is subsequently exploited to design a redox responsive drug delivery system for transporting anticancer drug (camptothecin). Upon exposing the CeO2 capped and drug loaded nanoconstruct to vitamin c or glutathione, dissolution-accompanied aggregation of CeO2 nanolids unleashes the drug molecules from porous silica to achieve a significant anticancer activity. Besides stimuli responsive drug delivery, immobilization of nanoceria onto the surface of mesoporous silica also facilitates us to gain a basic insight into the biotransformation of CeO2 in physiological mediums.

BackgroundAcute myeloid leukemia (AML) remains a difficult disease to treat and requires new therapies to improve treatment outcome. Wee1 inhibitors have been used to prevent activation of the G2 cell cycle checkpoint, thus enhancing the antitumor activity of DNA damaging agents. In this study, we investigated MK-1775 in AML cell lines and diagnostic blast samples to identify sensitive subtypes as well as possible mechanisms of resistance.MethodsIn vitro MK-1775 cytotoxicities of AML cell lines and diagnostic blasts were measured using MTT assays. The effects of MK-1775 on cell cycle progression and related proteins were determined by propidium iodide (PI) staining and flow cytometry analysis and Western blotting. Drug-induced apoptosis was determined using annexin V/PI staining and flow cytometry analysis.ResultsWe found that newly diagnosed and relapsed patient samples were equally sensitive to MK-1775. In addition, patient samples harboring t(15;17) translocation were significantly more sensitive to MK-1775 than non-t(15;17) samples. MK-1775 induced apoptosis in both AML cell lines and diagnostic blast samples, accompanied by decreased phosphorylation of CDK1 and CDK2 on Tyr-15 and increased DNA double-strand breaks (DSBs). Time-course experiments, using AML cell lines, revealed a time-dependent increase in DNA DSBs, activation of CHK1 and subsequent apoptosis following MK-1775 treatment, which could be attenuated by a CDK1/2 inhibitor, Roscovitine. Simultaneous inhibition of CHK1 and Wee1 resulted in synergistic anti-leukemic activity in both AML cell lines and primary patient samples ex vivo.ConclusionsOur study provides compelling evidence that CHK1 plays a critical role in the anti-leukemic activity of MK-1775 and highlights a possible mechanism of resistance to MK-1775. In addition, our study strongly supports the use of MK-1775 to treat both newly diagnosed and relapsed AML, especially cases with t(15;17) translocation, and supports the development of combination therapies with CHK1 inhibitors.

Targeted drug delivery systems have attracted a great deal of interest by virtue of their potential use in chemotherapy. In this study, multicomponent halloysite nanotubes (HNTs) have been evaluated as a platform to assist and direct the delivery of anticancer drug doxorubicin (DOX) into cancer cells. Folic acid (FA) and magnetite nanoparticles were successfully grafted onto HNTs via amide reaction whereas the drug has been introduced by capitalizing electrostatic interaction between cationic drug and anionic exterior of HNTs, which eventually leads to pH responsive release. The resultant DOX loaded FA-Fe 3 O 4 @HNTs were well characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and XRD. The clinical efficacy of the system was validated by confocal microscopy and cell cytotoxicity assay (MTT assay). MTT assay results revealed a high biocompatibility up to a concentration of 200 μg/mL of HNTs, while, DOX loaded FA-Fe 3 O 4 @HNTs were markedly cytotoxic to HeLa cells. This multifunctional nanovehicle has a great potential for cancer diagnosis and therapy, and could further advance the clinical use of nanomedicine.