New derivatives of vitamin E as nanovectors for poorly soluble drugs and anticancer agents

The aim of this work was to develop novel vitamin E conjugates for the vectorization of active pharmaceutical ingredients through nanotechnologies. The physico-chemical and biological properties of vitamin E derivatives offer multiple advantages in drug delivery like biocompatibility, improvement of drug solubility and anticancer activity. Nanomedicines have shown high potential in drug delivery since (i) they are appropriate to all route of administration, (ii) they may offer better drug biopharmaceutical properties such as longer half-life or better bioavailability and (iii) they have shown benefits in cancer therapy by improving anticancer drug therapeutic index. Vitamin E based nanovectors were developed to combine the pharmaceutical properties of both vitamin E and nanomedicine for two purposes: (i) to improve water solubility of hydrophobic drugs by using vitamin E-based polymeric micelles and (ii) to enhance the therapeutic efficiency of anticancer agents by using vitamin E-based prodrug nanoparticles. The first part of the thesis aimed at evaluating a new tocol modified chitosan able to self-assemble in micelles and to carry poorly soluble drugs. As most of the new drug candidates are sparingly soluble in water, there is a need to develop efficient and safe solutions to increase their water solubility allowing a better bioavailability. Among these solutions, drug nanocarriers have been investigated due to their ability to be tailored to get specific pharmaceutical and biological properties. Hydrophobically modified chitosan has received increasing attention owing to the biocompatibility, non-toxicity and low-immunogenicity of chitosan. Grafting of vitamin E of chitosan backbone was based on the physico-chemical properties of vitamin E derivatives to improveme of drug solubility (tocophily). In this work we have demonstrated that tocopherol succinate glycol chitosan (GC-TOS) conjugates spontaneously formed micelles in aqueous solution at low critical micelle concentration. AFM and TEM analysis showed that spherical micelles were formed. The GC-TOS increased water solubility of 2 model class II drugs. GC-TOS was non-cytotoxic at concentrations up to 10 mg/mL. GC-TOS increased the apparent permeation coefficient of ketoconazole across a Caco-2 cell monolayer. The second part of the thesis aimed at evaluating whether new vitamin E based anticancer prodrugs could self-organize in nanoparticle to enhance therapeutic index of anticancer drugs. We exploit the numerous advantages of nanotechnologies in cancer therapy, like targeting ability of solid tumor and bypassing resistance, and of the chemosensitizing and anticancer properties of some vitamin E derivatives. To achieve this goal, doxorubicin was chemically conjugated to D-α-tocopherol succinate through an amide bond to form N-doxorubicin-α-D-tocopherol succinate (N-DOX-TOS). The prodrug self-assembled in water into 250 nm nanostructures when stabilized with D-α-tocopherol polyethylene glycol 2000 succinate. Cryo-TEM analysis revealed the formation of nanoparticles with a highly ordered lamellar inner structure. NMR spectra of the N-DOX-TOS nanoparticles indicated that N-DOX-TOS is located in the core of the nanoparticles while PEG chains and part of the tocopherol is in the corona. High drug loading (34% w/w) and low in vitro drug release were achieved. In vitro biological assessment showed significant anticancer activity and cellular uptake of N-DOX-TOS nanoparticles.