Novel Soluplus(®)-TPGS mixed micelles for encapsulation of paclitaxel with enhanced in vitro cytotoxicity on breast and ovarian cancer cell lines.

The aim of this work was to develop mixed micelles based on two biocompatible copolymers of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus(®)) and D-α-tocopheryl polyethylene-glycol 1000 succinate (TPGS), to improve the aqueous solubility and the in vitro anti-tumor activity of paclitaxel (PTX). Pure and mixed nanomicelles were prepared by solvent evaporation method and characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). Solubility of PTX was increased 60,000 and 38,000 times, when it was formulated in pure Soluplus(®) micelles and in mixed micelles (Soluplus(®):TPGS; 4:1 ratio), respectively. The in vitro PTX release profile from micellar systems was characterized employing the dialysis membrane method where all drug-loaded formulations showed a sustained and slow release of PTX. In vitro assays were conducted on human cancer cell lines including ovarian cancer cells SKOV-3, breast cancer cells MCF-7 and triple negative breast cancer cells MDA-MB-231. Cytotoxicity studies showed that mixed micelles exhibited better antitumor activity compared to PTX solution against the three cell lines. Furthermore mixed micelles showed a significant increase on PTX cellular uptake in comparison with pure Soluplus(®) micelles and free drug in all cell lines assayed. More important, blank mixed micelles have shown cytotoxic activity due to the ability of TPGS to induce apoptosis in cancer cells. This effect was associated with the expression levels of cleaved-PARP, an apoptosis-related protein. On the basis of these results, the mixed micelles developed in this study might be a potential nano-drug delivery system for cancer chemotherapy.

Bernabeu E ，Gonzalez L ，Cagel M ，Gergic EP ，Moretton MA ，Chiappetta DA ... -  《-》

A glucose-targeted mixed micellar formulation outperforms Genexol in breast cancer cells.

Breast cancer represents the top cancer among women, accounting 521.000 deaths per year. Development of targeted nanomedicines to breast cancer tissues represents a milestone to reduce chemotherapy side effects. Taking advantage of the over-expression of glucose (Glu) membrane transporters in breast cancer cells, we aim to expand the potential of a paclitaxel (PTX)-loaded mixed micellar formulation based on polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) by its surface decoration with Glu moieties. The glycopolymer (Soluplus(Glu)) was obtained by microwave-assisted ring opening reaction of δ-gluconolactone initiated by Soluplus®. The glycosylation was confirmed by 1H NMR and by agglutination assays employing Concanavalin A. The hydrodynamic diameter of Soluplus(Glu) micelles was characterized by dynamic light scattering (100.3±3.8nm) as well as the critical micellar concentration value (0.0151% w/v). Then, a mixed micelle formulation employing Soluplus®, Soluplus(Glu) and TPGS (3:1:1wt ratio) loaded with PTX (4mg/mL) was developed as a multifunctional nanocarrier. Its in vitro anticancer performance in MCF-7 (1.6-fold) and MDA-MB-231 (14.1-fold) was significantly enhanced (p<0.05) versus the unique commercially available micellar-based PTX-nanoformulation (Genexol®). Furthermore, the in vitro PTX cellular uptake assays revealed that the drug intracellular/cell content was significantly (p<0.05) higher for the Glu-containing mixed micelles versus Genexol® after 6h of incubation with MCF-7 (30.5-fold) and MDA-MB-231 (5-fold). Overall, results confirmed the potential of our Glu-decorated mixed colloidal formulation as an intelligent nanocarrier for PTX-targeted breast cancer chemotherapy.

Moretton MA ，Bernabeu E ，Grotz E ，Gonzalez L ，Zubillaga M ，Chiappetta DA ... -  《-》

Soluplus/TPGS mixed micelles for dioscin delivery in cancer therapy.

Zhao J ，Xu Y ，Wang C ，Ding Y ，Chen M ，Wang Y ，Peng J ，Li L ，Lv L ... -  《-》

Development and evaluation of a novel drug delivery: Soluplus(®)/TPGS mixed micelles loaded with piperine in vitro and in vivo.

Ding Y ，Wang C ，Wang Y ，Xu Y ，Zhao J ，Gao M ，Ding Y ，Peng J ，Li L ... -  《-》

Paclitaxel-loaded PCL-TPGS nanoparticles: in vitro and in vivo performance compared with Abraxane®.

The purpose of this work was to develop Cremophor(®) EL-free nanoparticles (NPs) loaded with Paclitaxel (PTX) in order to improve the drug i.v. pharmacokinetic profile and to evaluate its activity against commercially available formulations such as Taxol(®) and Abraxane(®). PTX-loaded poly(ε-caprolactone)-alpha tocopheryl polyethylene glycol 1000 succinate (PCL-TPGS) NPs were prepared using three different techniques: (i) by nanoprecipitation (NPr-method), (ii) by emulsion-solvent evaporation homogenized with an Ultra-Turrax(®) (UT-method) and (iii) by emulsion-solvent evaporation homogenized with an ultrasonicator (US-method). The NPs prepared by US-method showed the smallest size and the highest drug content. The NPs exhibited a slow and continuous release of PTX. The in vitro anti-tumoral activity was assessed using two human breast cancer cell lines (MCF-7 and MDA-MB-231) with the WTS assay. Cytotoxicity studies with both cell lines showed that PTX-loaded PCL-TPGS NPs exhibited better anti-cancer activity compared to PTX solution and the commercial formulation Abraxane(®) at different concentrations. Importantly, in the case of triple negative MDA-MB-231 breast cancer cells, the IC50 value for PTX-loaded PCL-TPGS NPs was 7.8 times lower than Abraxane(®). Finally, in vivo studies demonstrated that PTX-loaded PCL-TPGS NPs exhibited longer systemic circulation time and slower plasma elimination rate than Taxol(®) and Abraxane(®). Therefore, the novel NPs investigated might be an alternative nanotechnological platform for PTX delivery system in cancer chemotherapy.

Bernabeu E ，Helguera G ，Legaspi MJ ，Gonzalez L ，Hocht C ，Taira C ，Chiappetta DA ... -  《-》