New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth

Purpose: Combining molecular therapies with chemotherapy may offer an improved clinical outcome for chemoresistant tumours. Sphingosine-1-phosphate (S1P) receptor antagonist and sphingosine kinase 1 (SK1) inhibitor FTY720 (FTY) has promising anticancer properties, however, it causes systemic lymphopenia which impairs its use in cancer patients. In this study, we developed a nanoparticle (NP) combining docetaxel (DTX) and FTY for enhanced anticancer effect, targeted tumour delivery and reduced systemic toxicity. Methods: Docetaxel, FTY and glucosamine were covalently conjugated to poly(lactic-co-glycolic acid) (PLGA). NPs were characterised by dynamic light scattering and electron microscopy. The cellular uptake, cytotoxicity and in vivo antitumor efficacy of CNPs were evaluated. Results: We show for the first time that in triple negative breast cancer cells FTY provides chemosensitisation to DTX, allowing a four-fold reduction in the effective dose. We have encapsulated both drugs in PLGA complex NPs (CNPs), with narrow size distribution of ~ 100 nm and excellent cancer cell uptake providing sequential, sustained release of FTY and DTX. In triple negative breast cancer cells and mouse breast cancer models, CNPs had similar efficacy to systemic free therapies, but allowed an effective drug dose reduction. Application of CNPs has significantly reversed chemotherapy side effects such as weight loss, liver toxicity and, most notably, lymphopenia. Conclusions: We show for the first time the DTX chemosensitising effects of FTY in triple negative breast cancer. We further demonstrate that encapsulation of free drugs in CNPs can improve targeting, provide low off-target toxicity and most importantly reduce FTY-induced lymphopenia, offering potential therapeutic use of FTY in clinical cancer treatment

Asymmetric synthesis of (R)-(–)-baclofen via asymmetric dihydroxylation

326-330A short and efficient asymmetric synthesis of (R)-(–)-baclofen, a selective GABAB agonist has been described with an overall yield of 14% and 85% ee. The Os-catalyzed Sharpless asymmetric dihydroxylation of ⍺,β-unsaturated olefin constitutes the key step in introducing stereogenic centers into the molecule

Synthesis, characterization and catalytic performance of titanium silicalite-1 prepared in micellar media

Titanium silicalite-1 (TS-1) was synthesized in the presence of small amount of TPAOH using Tween 20, as nonionic surfactant. The procedure gives highly pure nanometer-sized homogeneous crystalline product and higher rate of crystallization. The results are compared with the TS-1 sample prepared without surfactant. Characterization of TS-1 has been carried out by using X-ray diffraction and shows that the samples are fully crystalline, while FTIR spectroscopy shows the presence of characteristic band for TS-1 at 960 cm-1, confirming Si-O-Ti linkages present in the product. The UV-visible spectroscopy of the sample prepared without surfactant at low TPAOH concentration shows the presence of extra framework of TiO2 species. Scanning electron micrograph (SEM) of the sample shows homogeneous particle size (~150 nm), while the sample without surfactant shows the presence of particle size ranging between 150 and 200 nm. Catalytic activity of TS-1 sample was also confirmed for octene epoxidation

Fullerenol−Cytotoxic Conjugates for Cancer Chemotherapy

In the present study, we report the novel application of polyhydroxylated fullerenes (fullerenols) in cancer drug delivery. The facile synthetic procedure for generating multiple hydroxyl groups on the fullerene cage offers scope for high drug loading in addition to conferring hydrophilicity. Doxorubicin, a first line cancer chemotherapeutic, was conjugated to fullerenols through a carbamate linker, achieving ultrahigh loading efficiency. The drug−fullerenol conjugate was found to be relatively stable in phosphate buffer saline but temporally released the active drug when incubated with tumor cell lysate. The fullerenol−doxorubicin conjugate suppressed the proliferation of cancer cell-lines in vitro through a G2-M cell cycle block, resulting in apoptosis. Furthermore, in an in vivo murine tumor model, fullerenol−doxorubicin exhibited comparable antitumor efficacy as free drug without the systemic toxicity of free doxorubicin. Additionally, we demonstrate that the fullerenol platform can be extended to other chemotherapeutic agents, such as the slightly water-soluble cisplatin, and can emerge as a new paradigm in the management of cancer

Fullerenol−Cytotoxic Conjugates for Cancer Chemotherapy

In the present study, we report the novel application of polyhydroxylated fullerenes (fullerenols) in cancer drug delivery. The facile synthetic procedure for generating multiple hydroxyl groups on the fullerene cage offers scope for high drug loading in addition to conferring hydrophilicity. Doxorubicin, a first line cancer chemotherapeutic, was conjugated to fullerenols through a carbamate linker, achieving ultrahigh loading efficiency. The drug−fullerenol conjugate was found to be relatively stable in phosphate buffer saline but temporally released the active drug when incubated with tumor cell lysate. The fullerenol−doxorubicin conjugate suppressed the proliferation of cancer cell-lines in vitro through a G2-M cell cycle block, resulting in apoptosis. Furthermore, in an in vivo murine tumor model, fullerenol−doxorubicin exhibited comparable antitumor efficacy as free drug without the systemic toxicity of free doxorubicin. Additionally, we demonstrate that the fullerenol platform can be extended to other chemotherapeutic agents, such as the slightly water-soluble cisplatin, and can emerge as a new paradigm in the management of cancer