International Journal of Pharmaceutics (v.379, #2)

Preface by Gillian Barratt; Didier Betbeder; Bernard Lebleu (199-200).

Lipid nanocapsules: A new platform for nanomedicine by N.T. Huynh; C. Passirani; P. Saulnier; J.P. Benoit (201-209).
Nanomedicine, an emerging new field created by the fusion of nanotechnology and medicine, is one of the most promising pathways for the development of effective targeted therapies with oncology being the earlier and the most notable beneficiary to date. Indeed, drug-loaded nanoparticles provide an ideal solution to overcome the low selectivity of the anticancer drugs towards the cancer cells in regards to normal cells and the induced severe side-effects, thanks to their passive and/or active targeting to cancer tissues. Liposome-based systems encapsulating drugs are already used in some cancer therapies (e.g. Myocet, Daunoxome, Doxil). But liposomes have some important drawbacks: they have a low capacity to encapsulate lipophilic drugs (even though it exists), they are manufactured through processes involving organic solvents, and they are leaky, unstable in biological fluids and more generally in aqueous solutions for being commercialized as such. We have developed new nano-cargos, the lipid nanocapsules, with sizes below the endothelium fenestration (ϕ  < 100 nm), that solve these disadvantages. They are prepared according to a solvent-free process and they are stable for at least one year in suspension ready for injection, which should reduce considerably the cost and convenience for treatment. Moreover, these new nano-cargos have the ability to encapsulate efficiently lipophilic drugs, offering a pharmaceutical solution for their intravenous administration.The lipid nanocapsules (LNCs) have been prepared according to an original method based on a phase-inversion temperature process recently developed and patented. Their structure is a hybrid between polymeric nanocapsules and liposomes because of their oily core which is surrounded by a tensioactive rigid membrane. They have a lipoprotein-like structure. Their size can be adjusted below 100 nm with a narrow distribution. Importantly, these properties confer great stability to the structure (physical stability > 18 months). Blank or drug-loaded LNCs can be prepared, with or without PEG (polyethyleneglycol)ylation that is a key parameter that affects the vascular residence time of the nano-cargos. Other hydrophilic tails can also be grafted. Different anticancer drugs (paclitaxel, docetaxel, etoposide, hydroxytamoxifen, doxorubicin, etc.) have been encapsulated. They all are released according to a sustained pattern. Preclinical studies on cell cultures and animal models of tumors have been performed, showing promising results.
Keywords: Nanocarriers; Nanotechnology; Anticancer drugs; Targeting;

RNA interference (RNAi) has been named as “breakthrough technology” in 2002 by Science magazine. In a short timespan this technology has conquered life sciences and numerous therapeutic approaches and is now well underway to become an important pilier of novel class of RNA based therapeutics. This mini-review focuses on nanomedicinal delivery approaches for siRNA that have shown promise with small molecules, and have recently been applied with the aim to deliver siRNA to humans for treatment of disease.
Keywords: RNAi; siRNA; Liposomes; Nanomedicine; Formulation; Nanotechnology;

pH-sensitive double-hydrophilic block copolymer micelles for biological applications by Ariane Boudier; Anne Aubert-Pouëssel; Corine Gérardin; Jean-Marie Devoisselle; Sylvie Bégu (212-217).
In the recent years, double-hydrophilic block copolymer (DHBC) micelles have appeared as potential vectors for pharmaceutical applications due to their simple preparation method in aqueous solvent. The present study aims at underscoring the strategy for the choice of the partners in the formulation of DHBC micelles presenting a good stability in physiological conditions (pH 7.4, 0.15 mol/L NaCl) and a pH-sensitivity allowing their disassembly at pH 5. Using light scattering and Laser-Doppler electrophoresis, micelles of polymethacrylic acid-b-polyethylene oxide complexing either poly-l-lysine (PLL) or an oligochitosan were characterised. Whatever the polyamine counter-polyion considered, the micelles were perfectly formed for an amine/methacrylic acid molar charge ratio of one. They were characterised by a hydrodynamic diameter of 28 nm for PLL and 60 nm for oligochitosan and by a neutral zeta potential. The stability study as a function of the pH and of the ionic strength revealed different behaviours. Oligochitosan micelles were stable until pH 7 and unstable at 0.15 mol/L NaCl. On the contrary, PLL micelles were stable in physiological conditions and disassembled at pH 5. As a conclusion, the choice of the partners to formulate double-hydrophilic block copolymer based-micelles is strategic in order to obtain well-adapted vectors applied to the pharmaceutical field.
Keywords: Double-hydrophilic block copolymer micelles; pH-sensitivity; Polymethacrylic acid-b-polyethylene oxide; Oligochitosan; Poly-l-lysine;

In this study, isothermal titration microcalorimetry (ITC) and molecular modeling were used to investigate the mechanism of formation of supramolecular nanoassemblies prepared by mixing aqueous solutions of two associative polymers (i.e. polymerised β-CD (pβ-CD) and dextran grafted with lauryl side chains (MD)). Their capacity to entrap a contrast agent for magnetic resonance imaging (a gadolinium (Gd3+) derivative) has been determined by the same methods. ITC experiments have been employed to evaluate the stoichiometry of interaction (N), association constants (K) and thermodynamic parameter variation associated with complexation between hosts and guests involved in this system. The inclusion compounds studied were: as hosts, β-CD and pβ-CD, and as guests, MD, adamantyl amine, and a Gd3+ complex functionalized with adamantane. It has been demonstrated that pβ-CD cavities tend to interact more favourably with MD (K  = 25,000 M−1) than with adamantly amine (K  = 3650 M−1) and Gd3+ complex (K  = 1460 M−1), forming 1:1 complexes, as also confirmed by molecular modeling. Noteworthy, the Gd3+ derivatives, although incorporated in the supramolecular nanoassemblies (by inclusion into the β-CD cavities of pβ-CD), did not destabilize the pβ-CD–MD inclusion complexes, probably because the interaction between pβ-CD and MD was stronger. Finally, the analysis of thermodynamic parameters revealed that the interaction between MD and pβ-CD was entropy driven (|ΔH| < |TΔS|) while the interactions of adamantly amine and Gd3+ complex with β-CD and pβ-CD were enthalpy driven and dominated by van der Walls forces (|ΔH| > |TΔS|).
Keywords: Cyclodextrin; Gadolinium; MRI contrast agent; Isothermal titration microcalorimetry; Nanoparticles; Non-covalent interactions;

Development and physicochemical characterization of copper complexes-loaded PLGA nanoparticles by T. Courant; V.G. Roullin; C. Cadiou; F. Delavoie; M. Molinari; M.C. Andry; F. Chuburu (226-234).
PLGA nanoparticles were prepared via a modified W/O/W emulsion solvent diffusion process, in which all formulation components were fully biocompatible and biodegradable. Different independent processing parameters were systematically studied. Nanoparticles were characterized by DLS (particle size, polydispersity, ζ-potential) and TEM/AFM (surface morphology). An optimized formulation was used to encapsulate copper complexes of cyclen and DOTA as potential PET imaging agents. Results showed that the predominant formulation factors appeared to be the lactide-to-glycolide (L:G) ratio of PLGA, the nature of the diffusion phase, and the presence of hydroxyl ions in the first-emulsion aqueous phase. By regulating those 3 parameters, PLGA nanoparticles were prepared with very good preparation yields (>95%), a size less than 200 nm and a polydispersity index less than 0.1. TEM pictures showed nanoparticles with a narrow size distribution, a spherical shape and a smooth surface. The optimized formulation allowed to encapsulate Cu–cyclen and Cu–DOTA complexes with an encapsulation efficiency between 20% and 25%.
Keywords: Nanoparticles; Poly(lactide-co-glycolide); Triacetin; Copper; Double-emulsion;

Metabolism evaluation of biomimetic prodrugs by in vitro models and mass spectrometry by Muriel Lalanne; Hania Khoury; Alain Deroussent; Nathalie Bosquet; Henri Benech; Pascal Clayette; Patrick Couvreur; Gilles Vassal; Angelo Paci; Karine Andrieux (235-243).
Glycerolipidic prodrug is an interesting concept to enhance lymphatic absorption of polar drugs intended to oral delivery such as didanosine (ddI). In order to improve ddI bioavailability, two didanosine glycerolipidic prodrugs, the phosphorylated (ProddIP) and the non-phosphorylated derivatives (ProddINP) were synthesized to follow triglyceride metabolism. The biomimetism approach of these prodrugs has been studied in vitro at two steps. First, liposomal formulation of each prodrug was incubated with a lipolysis model based on pancreatin and analysed using liquid chromatography combined with tandem mass spectrometry (LC–MS/MS). These experiments evidenced that both didanosine prodrugs were recognized by the lipases; as expected, they were cleaved at both positions sn-1 and sn-3 of glycerol. ProddIP was metabolised twice more rapidly than ProddINP suggesting an implication of some phospholipases in ProddIP degradation. Secondly, the detection of dideoxyadenosine triphosphate (ddA-TP) into HIV-1 infected cells after their incubation with ProddINP loaded liposomes evidenced their ability to release ddI that could penetrate into the cells and be metabolised by intracellular kinases. These results confirmed that the synthesized glycerolipidic prodrugs of didanosine could be investigated for a biomimetic approach with final aiming of increasing the drug oral bioavailability by enhancing intestinal absorption.
Keywords: Glycerolipidic prodrugs; Biomimetic model; Didanosine; Lipase; In vitro metabolism; LC–MS/MS;

Development and formulation of a 0.2% oral solution of midazolam containing γ-cyclodextrin by Frédéric Marçon; David Mathiron; Serge Pilard; Anne-Sophie Lemaire-Hurtel; Jean-Marc Dubaele; Florence Djedaini-Pilard (244-250).
In absence of dedicated children formulation, intravenous formulations of midazolam, which exhibit strong bitterness, are occasionally used for oral or sublingual administration. In order to improve the quality and the acceptance by children of a midazolam anesthesia premedication, a new 0.2% (w/v) aqueous solution for oral administration has been prepared. The final formulation was obtained by the adjunction of a sweetener (sucralose), an aroma (orange aroma) and γ-cyclodextrin to a citric acid solution of midazolam. The γ-cyclodextrin forms an inclusion complex with the hydrophobic midazolam as evidenced using nuclear magnetic resonance spectroscopy (stoichiometry 1:1, K  = 283 M−1). A sterile filtration method was selected for the formulation microbial preservation using liquid chromatography coupled to high resolution mass spectrometry (LC–HRMS). Finally, a routine high performance liquid chromatography (HPLC) method is proposed for the quantitative determination of global midazolam amount in the pharmaceutical preparation.
Keywords: γ-Cyclodextrin/midazolam inclusion complex; Pre-anesthesia; Oral solution; NMR; LC–HRMS; HPLC quantification;

Removal of ciprofloxacin in simulated digestive media by activated charcoal entrapped within zinc-pectinate beads by Mouhamad Khoder; Nicolas Tsapis; Hélène Huguet; Madeleine Besnard; Claire Gueutin; Elias Fattal (251-259).
Beads made of a zinc-pectinate matrix containing activated charcoal were designed for the adsorption of colonic residual antibiotics responsible of the emergence of resistance. Bead stability was shown to correlate with bead zinc content, 0.08 mg/mg being the minimal amount of zinc that protects the egg-box structure against total disintegration. Moreover, the stability in simulated gastro-intestinal media was shown to be related to the composition of the incubation medium. Indeed, gastric medium was shown to extract a large amount of zinc inducing an early disintegration of the beads in the intestinal medium, making necessary their protection by gastro-resistant capsules. Simulated intestinal medium buffered by phosphate was not adapted for the disintegration studies since the formation of a zinc phosphate precipitate on beads surface enhances their resistance to further degradation by pectinases contained in colonic medium. On the other hand, beads incubated in HEPES were stable in intestinal medium and nicely degraded by pectinases contained in simulated colonic medium. Despite this stability, coating with Eudragit RS® was needed to prevent the early adsorption of antibiotics in intestinal medium. Adsorption studies in the simulated colonic medium show that the adsorption capacity of activated charcoal is not modified after its encapsulation within pectin beads making the elimination of ciprofloxacin reaching the colon clinically feasible.
Keywords: Zinc-pectinate beads; Activated charcoal; Ciprofloxacin; Adsorption;

The gastrointestinal stability of lipid nanocapsules by E. Roger; F. Lagarce; J.-P. Benoit (260-265).
The in vitro gastrointestinal stability of lipid nanocapsules (LNCs) was studied in different media. The size of LNCs was determined in simulated gastric and intestinal media. In updated fasted state simulated intestinal fluid (FaSSIF-V2) and updated fed state simulated intestinal fluid (FeSSIF-V2) media, the encapsulation ratio of paclitaxel-loaded LNCs was also measured. The size of LNCs was not modified after 3 h in simulated gastric fluid and simulated intestinal fluid described by the United States Pharmacopeia, in FaSSIF, FaSSIF-V2, and in FeSSIF. Moreover, in the presence of pancreatin in FeSSIF-V2, a decreased above 30% of the loading of paclitaxel was observed. This was attributed to the presence of lipase in pancreatin that could interact with Lipoid® (a mixture of phosphatidylcholine and phosphatidylethanolamine), present on the shell of LNC. As a conclusion, LNCs were stable on gastric medium and fasted state intestinal medium.
Keywords: Lipid nanocapsules; Paclitaxel; Stability; Gastrointestinal tract; Simulated media;

The adaptation of lipid nanocapsule formulations for blood administration in animals by J. Hureaux; F. Lagarce; F. Gagnadoux; A. Clavreul; J.-P. Benoit; T. Urban (266-269).
In many cell-culture and animal models, the therapeutic effects of the entrapped drugs in lipid nanocapsules (LNCs) were preserved with low toxicity. These results allow foreseeing further preclinical efficiency and toxicity studies in animals. In this article, preliminary studies were performed to check the genetically modified organism (GMO) status of the LNCs components and to determine the effects of the acidity of the LNCs dispersions in acid–base balance in rats. Then, several freezing protocols to store paclitaxel-loaded LNCs dispersions for a 6-month period were compared. Results indicate that the Lipoïd® S75-3 could not be certified GMO-free. The same soya bean lecithin certified to be GMO-free permitted to produce LNCs with expected characteristics. The blood administration of blank LNCs dispersions in rats induced no modifications of blood acidity, but a significant decrease of the base excess was observed. Injections of LNCs dispersions in animals might induce iatrogenic acidosis. We finally demonstrated that the best protocol to store LNCs dispersion for a 6-month period is by freezing in liquid nitrogen. This protocol minimized the characteristics modifications and interrupted the drug-release phenomenon. These original data are expected to prepare of LNCs dispersions well adapted for i.v. administration in animals.
Keywords: Lipid nanocapsule; Paclitaxel; Animal experimentation; Intravenous injections; Plants; Genetically modified; Drug storage;

Formulation and characterization of polyphenol-loaded lipid nanocapsules by A. Barras; A. Mezzetti; A. Richard; S. Lazzaroni; S. Roux; P. Melnyk; D. Betbeder; N. Monfilliette-Dupont (270-277).
The purpose of this study was to design and characterize two flavonoid-loaded lipid nanocapsules (LNC) by applying the phase inversion process, and to enhance their apparent solubility and/or the stability. The flavonoid-loaded LNC were characterized by particle size, encapsulation efficiency, drug leakage rates, stability and spectroscopic studies. It was observed that quercetin-loaded LNC30 (3%) and LNC60 (2%) carried a particle size of 30.3 and 55.1 nm, respectively and significant higher entrapment efficiency. Encapsulation of quercetin (QC) in LNC enabled us to increase its apparent aqueous solubility by a factor of 100. And in view of calculations and results, it seems most probable that QC is arranged at this LNC interface between the oil phase and the hydrophilic polyethylene glycol moieties of the surfactant. In addition, colloidal suspensions proved to be stable in term of encapsulation for at least 10 weeks and QC was not oxidised. With simple chemical modification of (−)-epigallocatechin-3-gallate or (−)-EGCG, it was possible to reach very high encapsulation rates (95%). Thus we obtained stable colloidal suspensions of (−)-EGCG in water over 4 weeks while free (−)-EGCG solubilised in water exhibited 100% degradation within 4 h. The initial problems (solubility and stability) of these flavonoids were resolved thanks to drug-loaded LNC.
Keywords: Polyphenol; Quercetin; (−)-Epigallocatechin gallate; Lipid nanocapsules;

A 3D in vitro spheroid model as a way to study the mechanisms of electroporation by L. Wasungu; J.-M. Escoffre; A. Valette; J. Teissie; M.-P. Rols (278-284).
Electropermeabilization is a physical method to deliver molecules into cells and tissues. Clinical applications have been successfully developed for antitumoral drug delivery and clinical trials for gene electrotransfer are currently underway. However, little is known about the mechanisms involved in this transfer. The main difficulties stem from the lack of single cell models which reliably replicate the complex in vivo environment. In order to increase our understanding of the DNA electrotransfer process, we exploited multicellular tumor spheroids as an ex vivo model of tumor. We used confocal microscopy to visualize the repartition of permeabilized cells in spheroids subjected to electric pulses. Our results reveal that even if cells can be efficiently permeabilized with electric fields, including those cells present inside the spheroids, gene expression is by contrast limited to the external layers of cells. Taken together, these results, in agreement with the ones obtained in tumors, indicate that the spheroid model is more relevant to an in vivo situation than cells cultured as monolayers. They validate the spheroid model as a way to study electro-mediated gene delivery processes.
Keywords: Electroporation; DNA; Spheroid; Electropermeabilization; Confocal microscopy; Delivery;

Characterization of endocytosis of transferrin-coated PLGA nanoparticles by the blood–brain barrier by Jiang Chang; Youssef Jallouli; Maya Kroubi; Xu-bo Yuan; Wei Feng; Chun-sheng Kang; Pei-yu Pu; Didier Betbeder (285-292).
Many studies showed that transferrin increases brain delivery of nanoparticles (NPs) in vivo, however the mechanisms implied in their brain uptake are not yet clearly elucidated. In this study we evaluated the endocytosis of PLGA NPs coated with transferrin on an in vitro model of the blood–brain barrier (BBB) made of a co-culture of brain endothelial cells and astrocytes. PLGA NPs were prepared using DiI as a fluorescent marker and coated with Tween® 20, BSA and transferrin (Tf). Blank and BSA-NPs served as controls. The cellular toxicity on BBB of the different samples was evaluated following tight junction aperture and due to high toxicity NPs prepared with Tween® 20 were discarded. The size of the NPs prepared by the solvent diffusion method, varied from 63 to 90 nm depending on DiI incorporation and surface coating. Proteins adsorption on the surface of the NPs was found to be stable for at least 12 days at 37 °C. Contrary to Blank or BSA-NPs, Tf-NPs were found to be highly adsorbed by the cells and endocytosed using an energy-dependent process. Studies in presence of inhibitors suggest that Tf-NPs interact with the cells in a specific manner and enter the cells via the caveolae pathway.
Keywords: PLGA; Nanoparticles; blood–brain barrier; Transferrin; Caveolae;

Galactosylated DNA lipid nanocapsules for efficient hepatocyte targeting by M. Morille; C. Passirani; E. Letrou-Bonneval; J.-P. Benoit; B. Pitard (293-300).
The main objective of gene therapy via a systemic pathway is the development of a stable and non-toxic gene vector that can encapsulate and deliver foreign genetic materials into specific cell types with the transfection efficiency of viral vectors. With this objective, DNA complexed with cationic lipids of DOTAP/DOPE was encapsulated into lipid nanocapsules (LNCs) forming nanocarriers (DNA LNCs) with a size suitable for systemic injection (109 ± 6 nm). With the goal of increasing systemic delivery, LNCs were stabilised with long chains of poly(ethylene glycol) (PEG), either from a PEG lipid derivative (DSPE-mPEG2000) or from an amphiphilic block copolymer (F108). In order to overcome internalisation difficulties encountered with PEG shield, a specific ligand (galactose) was covalently added at the distal end of the PEG chains, in order to provide active targeting of the asialoglycoprotein-receptor present on hepatocytes. This study showed that DNA LNCs were as efficient as positively charged DOTAP/DOPE lipoplexes for transfection. In primary hepatocytes, when non-galactosylated, the two polymers significantly decreased the transfection, probably by creating a barrier around the DNA LNCs. Interestingly, galactosylated F108 coated DNA LNCs led to a 18-fold increase in luciferase expression compared to non-galactosylated ones.
Keywords: Non-viral carrier; Gene delivery; Galactose; Primary hepatocytes; Liver targeting;

Amphiphilic perfluoroalkyl carbohydrates as new tools for liver imaging by C. Richard; P. Chaumet-Riffaud; A. Belland; A. Parat; C. Contino-Pepin; M. Bessodes; D. Scherman; B. Pucci; N. Mignet (301-308).
The synthesis of three molecules containing a fluorocarbon chain (either C6F13, C8F17 or C10F21), a sugar moiety (derived from lactobionic acid) and a chelate (derived from DTPA) is reported. These molecules (C6F13-Gal-DTPA, C8F17-Gal-DTPA or C10F21-Gal-DTPA) have been dispersed in water and their critical micellar concentration (CMC) as well as their size were determined. Their interaction with serum was weak as evaluated by time resolved fluorimetry of europium complexes. The presence of sugar on the surface of the nanoparticles was confirmed by the agglutination test using ricin. Conditions of pH and concentrations were optimised for in vivo studies. Finally, the nanoparticles formed with C10F21-Gal-DTPA have been complexed with 99mTc and injected to rats in order to follow their biodistribution by scintigraphy while following their stability by transmission electronic microscopy. A majority of the compound was found in the liver post-bolus injection.
Keywords: Galactosylated amphiphiles; Perfluoroalkyl surfactants; Radiolabeled particles; Hepatocyte targeting; Liver scintigraphy;

Drug development in oncology assisted by noninvasive optical imaging by L. Sancey; S. Dufort; V. Josserand; M. Keramidas; C. Righini; C. Rome; A.-C. Faure; S. Foillard; S. Roux; D. Boturyn; O. Tillement; A. Koenig; J. Boutet; P. Rizo; P. Dumy; J.L. Coll (309-316).
Early and accurate detection of tumors, like the development of targeted treatments, is a major field of research in oncology. The generation of specific vectors, capable of transporting a drug or a contrast agent to the primary tumor site as well as to the remote (micro-) metastasis would be an asset for early diagnosis and cancer therapy. Our goal was to develop new treatments based on the use of tumor-targeted delivery of large biomolecules (DNA, siRNA, peptides, or nanoparticles), able to induce apoptosis while dodging the specific mechanisms developed by tumor cells to resist this programmed cell death. Nonetheless, the insufficient effectiveness of the vectorization systems is still a crucial issue. In this context, we generated new targeting vectors for drug and biomolecules delivery and developed several optical imaging systems for the follow-up and evaluation of these vectorization systems in live mice. Based on our recent work, we present a brief overview of how noninvasive optical imaging in small animals can accelerate the development of targeted therapeutics in oncology.
Keywords: Drug delivery; Optical imaging; Tumor targeting;

Dose effect activity of ferrocifen-loaded lipid nanocapsules on a 9L-glioma model by E. Allard; N.T. Huynh; A. Vessières; P. Pigeon; G. Jaouen; J.-P. Benoit; C. Passirani (317-323).
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 2.5 mg of Fc-diOH per animal can be evidenced.
Keywords: Lipid nanocapsule; Bioorganometallic chemistry; Cell survival test; Prodrugs; 9L-tumour model; Iron;

Superparamagnetic nanovector with anti-cancer properties: γFe2O3@Zoledronate by Farah Benyettou; Yoann Lalatonne; Odile Sainte-Catherine; Maelle Monteil; Laurence Motte (324-327).
We elaborate a magnetic nanovector to vectorize Zoledronate, an anti-cancer interest molecule of the hydroxmethylenebisphosphonate's family. In fact, Zoledronate is a powerful adjuvant in the treatment of bone diseases such as osteoporosis and Paget's disease. But, recent studies have shown that in addition to anti-osteoclastic properties, it presents antitumour properties notably in the case of breast and prostate cancer. However, these properties cannot be exploited due to their very high affinity to divalent cations and their preferentially accumulation in bone. To overcome this problem, one strategy is the vectorization trough maghemite nanocrystal functionalization. The specific surface coating permits to consider γFe2O3@Zoledronate as a drug delivery vehicle for therapeutic activity. The anchoring to the nanoparticle's surface allowed to increase their hydrophobicity and also to change the therapeutic target, increasing the Zoledronate intestinal absorption instead of their accumulation in bone. We show that Zoledronate link the nanoparticle surface through phosphonate groups. The biological in vitro tests performed on breast cancer cell line, MDA-MB 231, showed that γFe2O3@Zoledronate have antiproliferative activity. In addition, the γFe2O3 core could be used as MRI contrast agent for a good therapeutic evaluation.
Keywords: Drug nanoparticle; Magnetic nanoparticle; Bisphosphonate; Cancer drugs; Drug targeting; Cell internalization;