Engineering of stealth (maghemite/PLGA)/chitosan (core/shell)/shell nanocomposites with potential applications for combined MRI and hyperthermia against cancer.

(Maghemite/poly(d,l-lactide-co-glycolide))/chitosan (core/shell)/shell nanoparticles have been prepared reproducibly by nanoprecipitation solvent evaporation plus coacervation (production performance ≈ 45%, average size ≈ 325 nm). Transmission electron microscopy, energy dispersive X-ray spectroscopy, electrophoretic determinations, and X-ray diffraction patterns demonstrated the satisfactory embedment of iron oxide nanocores within the solid polymer matrix and the formation of an external shell of chitosan in the nanostructure. The adequate magnetic responsiveness of the nanocomposites was characterized in vitro by hysteresis cycle determinations and by visualization of the nanosystem under the influence of a 0.4 T permanent magnet. Safety and biocompatibility of the (core/shell)/shell particles were based on in vitro haemocompatibility studies and cytotoxicity tests against HFF-1 human foreskin fibroblasts and on ex vivo toxicity assessments on tissue samples from Balb/c mice. Transversal relaxivities, determined in vitro at a low magnetic field of 1.44 T, demonstrated their capability as T2 contrast agents for magnetic resonance imaging, being comparable to that of some iron oxide-based contrast agents. Heating properties were evaluated in a high frequency alternating electromagnetic gradient: a constant maximum temperature of ≈46 °C was generated within ≈50 min, while antitumour hyperthermia tests on T-84 colonic adenocarcinoma cells proved the relevant decrease in cell viability (to ≈ 39%) when treated with the nanosystem under the influence of that electromagnetic field. Finally, in vivo magnetic resonance imaging studies and ex vivo histology determinations of iron deposits postulated the efficacy of chitosan to provide long-circulating capabilities to the nanocomposites, retarding nanoparticle recognition by the mononuclear phagocyte system. To our knowledge, this is the first study describing such a type of biocompatible and long-circulating nanoplatform with promising theranostic applications (biomedical imaging and hyperthermia) against cancer.

Nano-engineering of biomedical prednisolone liposomes: evaluation of the cytotoxic effect on human colon carcinoma cell lines.

OBJECTIVES: Liposomes have attracted the attention of researchers due to their potential to act as drug delivery systems for cancer treatment. The present investigation aimed to develop liposomes loaded with prednisolone base and the evaluation of the antiproliferative effect on human colon carcinoma cell lines. METHODS: Liposomes were elaborated by following a reproducible thin film hydration technique. The physicochemical characterization of liposomes included photon correlation spectroscopy, microscopy analysis, Fourier transform infrared spectroscopy, rheological behaviour and electrophoresis. On the basis of these data and drug loading values, the best formulation was selected. Stability and drug release properties were also tested. KEY FINDINGS: Resulting liposomes exhibited optimal physicochemical and stability properties, an excellent haemocompatibility and direct antiproliferative effect on human colon carcinoma T-84 cell lines. CONCLUSIONS: This study shows direct antitumour effect of prednisolone liposomal formulation, which opens the door for liposomal glucocorticoids as novel antitumour agents.

Magnetic solid lipid nanoparticles in hyperthermia against colon cancer.

A reproducible double emulsion/solvent evaporation procedure is developed to formulate magnetic solid lipid nanoparticles (average size≈180 nm) made of iron oxide cores embedded within a glyceryl trimyristate solid matrix. The physicochemical characterization of the nanocomposites ascertained the efficacy of the preparation conditions in their production, i.e. surface properties (electrokinetic and thermodynamic data) were almost indistinguishable from those of the solid lipid nanomatrix, while electron microscopy characterizations and X-ray diffraction patterns confirmed the satisfactory coverage of the magnetite nuclei. Hemocompatibility of the particles was established in vitro. Hysteresis cycle determinations defined the appropriate magnetic responsiveness of the nanocomposites, and their heating characteristics were investigated in a high frequency alternating gradient of magnetic field: a constant maximum temperature of 46 °C was obtained within 40 min. Finally, in vitro tests performed on human HT29 colon adenocarcinoma cells demonstrated a promising decrease in cell viability after treatment with the nanocomposites and exposure to that alternating electromagnetic field. To the best of our knowledge, this is the first time that such type of nanoformulation with very promising hyperthermia characteristics has been developed for therapeutic aims.

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.

Multifunctional anticancer nanomedicine based on a magnetically responsive cyanoacrylate polymer.

The therapeutic effect of antitumor molecules (efficacy and safety) is severely limited by their poor pharmacokinetic characteristics. Recently, the use of colloids has been proposed for the delivery of anticancer drugs to tumor cells, thereby providing a significant advance toward new treatments with improved specificity. In this respect, magnetically responsive nanopolymers are probably one of the most promising materials. In this contribution, we describe the basic steps to be followed in the development of such composite nanoplatforms. Starting from the formulation procedure, we detail the physicochemical engineering of these nanomedicines for combined antitumor activities (anticancer drug delivery plus hyperthermia effect). The key features determining drug incorporation to the nanomaterial are analyzed. Such stimuli-sensitive nanoparticles have promising properties (e.g., blood compatibility, hyperthermia, magnetic targeting capabilities, high drug loading, and little burst drug release), which could be used for efficient multifunctional anticancer therapy.

Kollidon SR colloidal particles as vehicles for oral morphine delivery in pain treatment.

Due to the great importance of new therapeutic routes for morphine in pain treatment, several investigations are under development. In this way, the design of a liquid system for the oral administration of morphine would be of great help, especially in patients with difficulties in swallowing (children and elderly people). The systems studied in this work are kollidon SR microparticles, a biodegradable polymer classically used as excipient in the design of solid dosage forms, as vehicles for morphine. A detailed investigation of the capabilities of the polymer particles to load this drug at their surface is described. Electrophoretic mobility and optical absorbance determinations were used with this aim. The main factors determining the drug incorporation, after incubation of the microparticles in the morphine solutions, were the adsorption time, the type of electrolyte and its concentration, and the drug concentration. The optimum loading conditions were used to perform morphine release evaluations, finding that the release profiles were biphasic since the drug adsorbed was slowly released during 24h after an initial burst release phase.

Influence of conducting polymers based on carboxylated polyaniline on in vitro CaCO3 crystallization.

Conducting polymers are interesting materials of technological applications, while the use of polymers as additives controlling crystal nucleation and growth is a fast growing research field. In the present article, we make a first step in combining both topics and report the effect of conducting polymer derivatives, which are based on carboxylated polyanilines (c-PANIs), on in vitro CaCO3 crystallization by the Kitano and gas diffusion method. This is the first example of the mineralization control of CaCO3 by a rigid carboxylated polymer. Both the concentration of c-PANI and the presence of carboxylate groups have a strong influence on the CaCO3 crystallization behavior and crystal morphology. X-ray diffraction (XRD) analysis shows crystalline calcite particles confirmed by FTIR spectra. pH and Ca2+ measurements during CaCO3 crystallization utilizing the Kitano and a constant-pH approach show a defined nucleation period of CaCO3 particles. The measurements allow for the calculation of the supersaturation time development, and the kinetic data can be combined with time-dependent light microscopy. The presence of c-PANIs delays the time of nucleation indicative of calcite nucleation inhibition. Microscopy illustrates the morphologies of CaCO3 crystals at all crystallization stages, from homogeneous spherical amorphous CaCO3 (ACC) particles corresponding to the first steps of crystallization to transition stage calcite crystals also involving a dissolution-recrystallization process in a late stage of crystallization. The data show that it is not possible to conclude the crystallization mechanism even for a very simple additive controlled crystallization process without time-resolved microscopic data supplemented by the analysis of the species present in the solution. Finally, fluorescence analysis indicates that conducting polymer derivatives can be incorporated into precipitated calcite particles. This gives rise to CaCO3 particles with novel and interesting optical properties.