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

Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy

Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O → Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 ± 0.16 μM) comparable to that of free cisplatin (3.87 ± 0.37 μM), and superior to carboplatin (14.75 ± 0.38 μM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-rasLSL/+/Ptenfl/fl ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer

Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity

Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC50 values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-RasLSL/+/Ptenfl/fl ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics.United States. Dept. of Defense (Breast Cancer Research Program Era of Hope Scholar Award W81XWH-07-1- 0482)United States. Dept. of Defense (Collaborative Innovator Grant)National Institutes of Health (U.S.) (Grant R01 CA135242-01A2)Medical Foundation, inc. (Charles A. King Trust Postdoctoral Research Fellowship Program)United States. Dept. of Defense (Breast Cancer Research Program Postdoctoral Fellowship Award)Dana-Farber/Harvard Cancer Center (Ovarian Cancer SPORE award)Canary FoundationMary Kay FoundationV Foundation for Cancer Researc

Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis

Therapeutic angiogenesis is an emerging paradigm for the management of ischemic pathologies. Proangiogenic Therapy is limited, however, by the current inability to deliver angiogenic factors in a sustained manner at the site of pathology. In this study, we investigated a unique nonglycosylated active fragment of hepatocyte growth factor/scatter factor, 1K1, which acts as a potent angiogenic agent in vitro and in a zebrafish embryo and a murine matrigel implant model. Furthermore, we demonstrate that nanoformulating 1K1 for sustained release temporally alters downstream signaling through the mitogen activated protein kinase pathway, and amplifies the angiogenic outcome. Merging protein engineering and nanotechnology offers exciting possibilities for the treatment of ischemic disease, and furthermore allows the selective targeting of downstream signaling pathways, which translates into discrete phenotypes