Tumor transfection after systemic injection of DNA lipid nanocapsules

With the goal of generating an efficient vector for systemic gene delivery, a new kind of nanocarrier consisting of lipid nanocapsules encapsulating DOTAP/DOPE lipoplexes (DNA LNCs) was pegylated by the post-insertion of amphiphilic and flexible polymers. The aim of this surface modification was to create a long-circulating vector, able to circulate in the blood stream and efficient in transfecting tumoral cells after passive targeting by enhanced permeability and retention effect (EPR effect). PEG conformation, electrostatic features, and hydrophylicity are known to be important factors able to influence the pharmacokinetic behaviour of vectors. In this context, the surface structure characteristics of the newly pegylated DNA LNCs were studied by measuring electrophoretic mobility as a function of ionic strength in order to establish a correlation between surface properties and in vivo performance of the vector. Finally, thanks to this PEGylation, gene expression was measured up to 84-fold higher in tumor compared to other tested organs after intravenous injection. The present results indicate that PEGylated DNA LNCs are promising carriers for an efficient cancer gene therapy

Dose effect activity of ferrocifen-loaded lipid nanocapsules on a 9L-glioma model

Ferrociphenol (Fc-diOH) is a new molecule belonging to the fast-growing family of organometallic anti-cancer drugs. In a previous study, we showed promising in vivo results obtained after the intratumoural subcutaneous administration of the new drug-carrier system Fc-diOH-LNCs on a 9L-glioma model. To further increase the dose of this lipophilic entity, we have created a series of prodrugs of Fc-diOH. The phenol groups were protected by either an acetyl (Fc-diAc) or by the long fatty-acid chain of a palmitate (Fc-diPal). LNCs loaded with Fc-diOH prodrugs have to be activated in situ by enzymatic hydrolysis. We show here that the protection of diphenol groups with palmitoyl results in the loss of Fc-diOH in vitro activity, probably due to a lack of in situ hydrolysis. On the contrary, protection with an acetate group does not affect the strong, in vitro, antiproliferative effect of ferrocifen-loaded-LNCs neither the reduction of tumour volume observed on an ectopic model, confirming that acetate is easily cleaved by cell hydrolases. Moreover, the cytostatic activity of Fc-diOH-LNCs is confirmed on an orthotopic glioma model since the difference in survival time between the infusion of 0.36 mg/rat Fc-diOH-LNCs and blank LNCs is statistically significant. By using LNCs or Labrafac to carry the drug, a dose-effect ranging from 0.005 to 2.5mg of Fc-diOH per animal can be evidenced

Serum-stable, long-circulating paclitaxel-loaded colloidal carriers decorated with a new amphiphilic PEG derivative

The paper describes sterically stabilized lipid nanocapsules (LNC) and multilamellar liposomes (MLV) coated using a new amphiphilic conjugate of PEG2000 with a 2-alkyl-lipoamino acid (LAA). A complement activation assay (CH50) and uptake experiments by THP-1 macrophage cells were used to assess in vitro the effectiveness of the PEG-LAA derivative of modifying the surface behavior of nanocarriers. Administered to rats or Swiss mice, respectively, the PEG2000-LAA—modified LNC and MLV showed plasma half-lives longer than the corresponding naked carriers. To assess the ability of nanocarriers to specifically reach tumor sites, paclitaxel (PTX)—loaded LNC and MLV were administered subcutaneously to rats implanted with a 9L glioma. Animals treated with saline or naked LNC and MLV underwent a quick expansion of tumor mass, up to a volume of 2000 mm3 25 days after the injection of tumor cells. On the contrary, treatment with a PEG-LAA modified LNC carrier reduced the growth of the tumor volume, which did not exceed 1000 mm3 by day 25. Analogous positive results were obtained with the liposomal systems. The experimental findings confirmed that these new PEG-LAA conjugates allow to obtain sterically stable nanocarriers that behave effectively and in a comparable or even better way than the (phospho)lipid PEG derivatives commercially available