José L. Arias

Magnetic Nanoparticles: Design and Characterization, Toxicity and Biocompatibility, Pharmaceutical and Biomedical Applications

Biocompatibility, Pharmaceutical and Biomedical Applications L. Harivardhan Reddy,†,‡ Jose ́ L. Arias, Julien Nicolas,† and Patrick Couvreur*,† †Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, Universite ́ Paris-Sud XI, UMR CNRS 8612, Faculte ́ de Pharmacie, IFR 141, 5 rue Jean-Baptiste Cleḿent, F-92296 Chat̂enay-Malabry, France Departamento de Farmacia y Tecnología Farmaceútica, Facultad de Farmacia, Campus Universitario de Cartuja s/n, Universidad de Granada, 18071 Granada, Spain ‡Pharmaceutical Sciences Department, Sanofi, 13 Quai Jules Guesdes, F-94403 Vitry-sur-Seine, France

Synthesis and characterization of poly(ethyl-2-cyanoacrylate) nanoparticles with a magnetic core

A method is described to prepare composite colloidal nanoparticles, consisting of a magnetic core (magnetite) and a biodegradable polymeric shell (poly(ethyl-2-cyanoacrylate) or PE-2-CA). The method is based on the so-called anionic polymerization procedure, often used in the synthesis of PE-2-CA nanospheres designed for drug delivery. In the present work, the heterogeneous structure of the particles can confer both magnetic-field responsiveness and potential applicability as a drug carrier. In order to investigate to what extent this target is achieved, we compare the structure, chemical composition, and surface properties of the core/shell particles with those of both the nucleus and the coating material. This preliminary study shows that the synthetic new material displays an intermediate behavior between that of magnetite and PE-2-CA spheres. Thus, electrophoresis measurements as a function of pH and as a function of KNO3 concentration, show great similarity between the core/shell and pure polymer nanoparticles. A similar conclusion is reached when a surface thermodynamic study is performed on the three types of particles: the electron-donor component of the surface free energy of the solids is the quantity that appears to be most sensitive to the surface composition. The fact that PE-2-CA is close to being a non-polar material gives rise to a measurable decrease in the electron-donor component of the surface free energy of core/shell particles as compared to magnetite.

Novel strategies to improve the anticancer action of 5-fluorouracil by using drug delivery systems.

Because of the fundamental importance of new therapeutic routes for cancer treatment, a number of systems based on colloidal particles as vehicles for the delivery of the anticancer drug 5-fluorouracil have been devised. The target is always to provide the proper dose of the antitumor agent only at the desired locus of action, thus reducing the unwanted side effects. In this review, the main strategies and the more significant results in the development of 5-fluorouracil carriers for cancer treatment are discussed.

Magnetite/poly(alkylcyanoacrylate) (core/shell) nanoparticles as 5-Fluorouracil delivery systems for active targeting.

In this article, a reproducible emulsion polymerization process is described to prepare core/shell colloidal nanospheres, loaded with 5-Fluorouracil, and consisting of a magnetic core (magnetite) and a biodegradable polymeric shell [poly(ethyl-2-cyanoacrylate), poly(butylcyanoacrylate), poly(hexylcyanoacrylate), or poly(octylcyanoacrylate)]. The heterogeneous structure of these carriers can confer them both the possibility of being used as drug delivery systems and the responsiveness to external magnetic fields, allowing an active drug targeting without a concurrent systemic distribution. Zeta potential determinations as a function of ionic strength showed that the surface behaviour of the core/shell particles is similar to that of pure cyanoacrylate particles. The first magnetization curve of both magnetite and magnetite/polymer particles demonstrated that the polymer shell reduces the magnetic responsiveness of the particles, but keeps unchanged their ferrimagnetic character. Two drug loading mechanisms were studied: absorption or entrapment in the polymeric network, and surface adsorption. We found that the acidity of the medium had significant effects on the drug absorption per unit mass of polymer, and needs to be controlled to avoid formation of macroaggregates and to reach significant 5-Fluorouracil absorption. The type of polymer and the drug concentration are also main factors determining the drug incorporation to the core/shell particles. 5-Fluorouracil release evaluations showed a biphasic profile affected by the type of polymeric shell, the type of drug incorporation and the amount of drug loaded.

Synthesis of lidocaine-loaded PLGA microparticles by flow focusing Effects on drug loading and release properties

In the present work, two methods for the preparation of lidocaine-loaded PLGA microparticles are compared. The differences between the polymeric particles obtained by solvent evaporation (SEVM) or flow focusing (FF) were studied by means of scanning electron microscopy and surface thermodynamics determinations. A detailed investigation of the capabilities of the polymer particles to load this drug is described. The physical state of the drug in the polymeric particles and the existence of interactions between both entities were studied by differential scanning calorimetry. The main factors determining the lidocaine incorporation and the release kinetics were the synthesis procedure followed, the amount of drug dissolved in the organic phase during the synthesis routine, the type of polymer (molecular weight and end chemical groups) and the size and the hydrophobic/hydrophilic properties of the particles. The FF technology allowed higher drug incorporations and slower release kinetics. The release studies showed a biphasic profile probably due to diffusion-cum-degradation mediated processes.

Development of iron/ethylcellulose (core/shell) nanoparticles loaded with diclofenac sodium for arthritis treatment

Diclofenac sodium is a non-steroidal anti-inflammatory drug of choice to treat arthritis because of its potential anti-inflammatory and analgesic activity. Because of its shorter biological half-life, it is needed to be given frequently and at high doses to elicit the required therapeutic activity, simultaneously leading to severe side effects. We hypothesized that the efficient delivery of diclofenac sodium to inflammation using a magnetic colloid could reduce the dose required to bring out sufficient therapeutic response. Hence, we have developed a diclofenac sodium-loaded magnetic nanomedicine, consisting of a magnetic core (iron) and a biocompatible polymeric shell (ethylcellulose) for parenteral administration. These core/shell nanoparticles were synthesized by an emulsion solvent evaporation process. Two drug loading methods were analyzed: the first one being drug addition prior to the emulsion solvent evaporation process (leading to drug entrapment into the polymeric network), and the second method based on diclofenac sodium surface adsorption onto the preformed nanoparticles. Compared to drug adsorption, the entrapment of this active agent into the polymeric matrix yielded a higher drug loading and a slower drug release profile. Such nanocomposites possessed very important characteristics such as unusually high drug loading, enhanced magnetic susceptibility and prolonged drug release, indicating their potential use as nanocarriers for efficient delivery of diclofenac sodium to inflammation sites.

Nano-engineering of 5-fluorouracil-loaded magnetoliposomes for combined hyperthermia and chemotherapy against colon cancer.

The present investigation aimed to develop magnetoliposome nanoparticles loaded with 5-fluorouracil by following a reproducible thin film hydration technique. The physicochemical characterization (including electron microscopy analysis, dynamic light scattering, infrared spectrometry, X-ray diffractometry, electrophoresis, and surface thermodynamics) suggested that superparamagnetic magnetite nuclei were successfully embedded into a multilamellar lipid vesicle. Magnetic responsiveness of these nanocomposites was quantitatively analyzed by determining the hysteresis cycle and qualitatively confirmed by microscopic visualizations. A high frequency alternating electromagnetic field was further used to define their heating properties. The absence of cytotoxicity in human colon fibroblast CCD-18 and in human colon carcinoma T-84 cell lines and excellent hemocompatibility of these core/shell particles were demonstrated. Additionally, 5-fluorouracil incorporation was investigated by two procedures: (i) entrapment into the nanoparticulate matrix and (ii) surface deposition onto already formed magnetoliposome particles. The former method reported greater drug loading values and a sustained release profile. Interestingly, 5-fluorouracil release was also triggered by the heating properties of the nanoparticles (hyperthermia-triggered drug release). Hence, we put forward that magnetoliposome particles hold important properties, that is, magnetically targeted delivery, hyperthermia inducing capability, high 5-fluorouracil loading capability, and hyperthermia-triggered burst drug release, suggestive of their potential for a combined antitumor therapy against colon cancer.

Polymeric nanoparticulate system augmented the anticancer therapeutic efficacy of gemcitabine

Gemcitabine hydrochloride is an anticancer nucleoside analogue indicated in clinic for the treatment of various solid tumors. Although this drug has been demonstrated to display anticancer activity against a wide variety of tumors, it is needed to be administered at high doses to elicit the required therapeutic response, simultaneously leading to severe adverse effects. We hypothesized that the efficient delivery of gemcitabine to tumors using a biodegradable carrier system could reduce the dose required to elicit sufficient therapeutic response. Thus, we have developed a nanoparticle formulation of gemcitabine suitable for parenteral administration based on the biodegradable polymer poly(octylcyanoacrylate) (POCA). The nanoparticles were synthesized by anionic polymerization of the corresponding monomer. Two drug loading methods were analyzed: the first one based on gemcitabine surface adsorption onto the preformed nanoparticles, and the second method being gemcitabine addition before the polymerization process leading to drug entrapment in the polymeric network. A detailed investigation of the capabilities of the polymer particles to load this drug is described. Gemcitabine entrapment into the polymer matrix yielded a higher drug loading and a slower drug release profile as compared with drug adsorption procedure. The main factors determining the gemcitabine incorporation to the polymer network were the nanoparticles preparation procedure, the monomer concentration, the surfactant concentration, the pH, and the drug concentration. The release kinetic of gemcitabine was found to be controlled by the pH and the type of drug incorporation. The cytotoxicity studies performed on L1210 tumor cells revealed a similar anticancer activity of the gemcitabine-loaded POCA (GPOCA) nanoparticle as free gemcitabine. Following intravenous administration into the mice bearing L1210 wt subcutaneous tumor, the GPOCA nanoparticles displayed significantly greater anticancer activity compared to free gemcitabine; this has been additionally confirmed by histology and immunohistochemistry studies, suggesting the potential of GPOCA for the efficient treatment of cancer.

Doxorubicin-Loaded Nanoparticles: New Advances in Breast Cancer Therapy

Doxorubicin, one of the most effective anticancer drugs currently known, is commonly used against breast cancer. However, its clinical use is restricted by dose-dependent toxicity (myelosuppression and cardiotoxicity), the emergence of multidrug resistance and its low specificity against cancer cells. Nanotechnology is a promising alternative to overcome these limitations in cancer therapy as it has been shown to reduce the systemic side-effects and increase the therapeutic effectiveness of drugs. Indeed, the numerous nanoparticle-based therapeutic systems developed in recent years have shown low toxicity, sustained drug release, molecular targeting, and additional therapeutic and imaging functions. Furthermore, the wide range of nanoparticle systems available may provide a solution to the different problems encountered during doxorubicin-based breast cancer treatment. Thus, a suitable nanoparticle system may transport active drugs to cancer cells using the pathophysiology of tumours, especially their enhanced permeability and retention effects, and the tumour microenvironment. In addition, active targeting strategies may allow doxorubicin to reach cancer cells using ligands or antibodies against selected tumour targets. Similarly, doxorubicin resistance may be overcome, or at least reduced, using nanoparticles that are not recognized by P-glycoprotein, one of the main mediators of multidrug resistance, thereby resulting in an increased intracellular concentration of drugs. This paper provides an overview of doxorubicin nanoplatform-based delivery systems and the principal advances obtained in breast cancer chemotherapy.

Lipid-Based Drug Delivery Systems for Cancer Treatment

It is a fact that chemotherapy agents have little specificity for cancer cells, this leading to low concentrations into the tumor interstititum and severe side effects on healthy tissues. The formulation of lipid-based nanomedicines against cancer has been hypothesized to improve drug localization into the tumor tissue and to increase the anticancer efficacy of concentional drugs, while minimizing their systemic adverse effects. In this review, special attention is devoted to the analysis of the state-of-the-art in the development of lipid-based drug carriers against cancer. Specifically, the most significant in vitro and in vivo results on the use of niosomes, liposomes, and solid lipid nanoparticles are revised. It is concluded that biodistribution profiles of chemotherapy agents can be controlled by their loading to such nanoplatforms. Lipid-based nanomedicines offer an interesting approach to the delivery of anticancer drugs to brain tumors, and to reverse multi-drug resistance of cancer cells. Finally, a deep evaluation of the applicability of drug delivery strategies in the formulation of lipid-based nanoplatforms is carried out. They involve active drug targeting (including ligand-mediated delivery, and stimuli-sensitive carriers), and passive drug targeting (through the enhanced permeability and retention effect) to tumors.