Comparative evaluation of novel biodegradable nanoparticles for the drug targeting to breast cancer cells.

Nanomedicine formulations such as biodegradable nanoparticles (nps) and liposomes offer several advantages over traditional routes of administration: due to their small size, nanocarriers are able to selectively accumulate inside tumours or inflammatory tissues, resulting in improved drug efficacy and reduced side effects. To further augment targeting ability of nanoparticles towards tumour cells, specific ligands or antibodies that selectively recognise biomarkers over-expressed on cancer cells, can be attached to the surface either by chemical bond or by hydrophilic/hydrophobic interactions. In the present work, Herceptin (HER), a monoclonal antibody (mAb) able to selectively recognise HER-2 over-expressing tumour cells (such as breast and ovarian cancer cells), was absorbed on the surface of nanoparticles through hydrophilic/hydrophobic interactions. Nps were prepared by a modified single emulsion solvent evaporation method with five different polymers: three commercial polyesters (poly(ε-caprolactone) (PCL), poly (D,L-lactide) (PLA) and poly (D,L-lactide-co-.glycolide) (PLGA)) and two novel biodegradable polyesterurethanes (PURs) based on Poly(ε-caprolactone) blocks, synthesised with different chain extenders (1,4-cyclohexane dimethanol (CDM) and N-Boc-serinol). Polyurethanes were introduced as matrix-forming materials for nanoparticles due to their high chemical versatility, which allows tailoring of the materials final properties by properly selecting the reagents. All nps exhibited a small size and negative surface charge, suitable for surface functionalisation with mAb through hydrophilic/hydrophobic interactions. The extent of cellular internalisation was tested on two different cell lines: MCF-7 and SK-BR-3 breast cancer cells showing a normal and a high expression of the HER-2 receptor, respectively. Paclitaxel, a model anti-neoplastic drug, was encapsulated inside all nps, and release profiles and cytotoxicity on SK-BR-3 cells were also assessed. Interestingly, PUR nps were superior to commercial polyester-based nps in terms of higher cellular internalisation and cytotoxic activity on the tested cell lines. Results obtained warrants further investigation on the application of these PUR nps for controlled drug delivery and targeting.

Effect of a disintegration mechanism on wetting, water absorption, and disintegration time of orodispersible tablets.

The aim of this study was to evaluate the influence of disintegration mechanism of various types of disintegrants on the absorption ratio (AR), wetting time (WT), and disintegration time (DT) of orodispersible tablets (ODTs). ODTs were prepared by direct compression using mannitol as filler and disintegrants selected from a range of swellable, osmotic, and porous disintegrants. Tablets formed were characterized for their water AR, WT, and DT. The porosity and mechanical strength of the tablets were also measured. Results show that the DT of formulated ODTs was directly related to the WT and was a function of the disintegration mechanism of the disintegrant used. The lowest WT and DT were observed for tablets formulated using the osmotic disintegrant sodium citrate and these tablets also showed the lowest AR and porosity. The wetting and disintegration of tablets containing the highly swellable disintegrant, sodium starch glycollate, was slowest despite their high water AR and high tablet porosity. Rapid wetting and disintegration of ODTs were therefore not necessarily related to the porosity of the tablets.

Influence of particle size and dissolution conditions on the degradation properties of polylactide-co-glycolide particles.

Polymer degradation usually plays a crucial role in drug release from sustained release polyester systems, therefore in order to elucidate the mechanism governing release, it appears essential to analyse the in vitro degradation behaviour of these devices. In this study the influence of processing conditions, particle characteristics and release media temperature on the degradation of PLGA spherical particles were examined. It was found that a linear relationship between the degradation rate and particle size existed, with the larger particles degrading fastest. In smaller particles degradation products formed within the particle can diffuse easily to the surface while in larger particles degradation products have a longer path to the surface of the particle during which autocatalytic degradation of the remaining polymer material can occur. The influence of release media temperature on the degradation of PLGA particles was also examined. At lower incubation temperatures PLGA microparticles showed an induction period after which polymer degradation proceeded. The rate of polymer degradation was found to increase with increasing incubation temperature. The polymer erosion profile was fitted to the Prout-Tompkins equation and the rate constants were used to determine the activation energy of PLGA hydrolysis.

Binding and uptake of biodegradable poly-DL-lactide micro- and nanoparticles in intestinal epithelia.

The use of biodegradable particles as oral delivery vehicles for macromolecular drugs was investigated. We evaluated the binding, uptake and absorption of poly-dl-lactide (PLA) micro- and nanoparticles in Caco-2 monolayers and in ileal tissue and gut associated lymphoid tissue (GALT) of anaesthetised rats and rabbits. Using a range of experimental techniques, we found that approximately 10% of administered micro- and nanoparticles were adsorbed to the apical membranes of each of the five intestinal models. Nanoparticles were found to be absorbed better than microparticles. Overall, little discrimination in uptake patterns was evident between Peyer's patch (PP) and non-PP tissue while rat ileum showed a greater uptake capacity than rabbit. Our results show that uptake of PLA particles was low capacity, size-dependent and predominantly transcellular in all systems. A low proportion of the apically-bound particles was absorbed, with uptake exclusion evident for particles >4microm. The affinity of PLA particles for intestinal epithelia and GALT needs to be greatly enhanced in order to achieve improved oral bioavailability of macromolecules.

Influence of formulation variables on the morphology of biodegradable microparticles prepared by spray drying.

The preparation of microparticles of the biodegradable poly-DL-lactide (PLA) and polylactide-co-glycolide (PLGA) polymers using spray-drying technology was studied. Formulation parameters investigated include polymer type, polymer molecular weight, polymer concentration, and viscosity. Microparticles were characterized using electron microscopy, particle size analysis, and gel permeation chromatography. Kinematic viscosity was determined for each of the sprayed polymer solutions. Polymer molecular weight and polymer concentration were found to be important parameters when preparing PLA and PLGA microparticles using spray-drying technology.

Release kinetics of fluphenazine from biodegradable microspheres.

Fluphenazine-loaded microspheres were prepared using biodegradable lactide and lactide-co-glycolide polymers. Sustained release of fluphenazine was achieved with fluphenazine loadings of up to 30 per cent in both the lactide and lactide-co-glycolide polymers. Fluphenazine release from microspheres was found to increase with increasing drug loading and was most rapid from the poly-L-lactide-co-glycolide microspheres. The release profiles showed a 'lag' period followed by an accelerating release phase and in some cases a decay period, i.e. the release profiles were sigmoidal and fitted the Prout-Tomkins equation (Prout and Tompkins 1944). Consequently it was considered that polymer degradation, the primary rate-determining step controlling drug release, occurred by a mechanism involving propagation of active sites, drug release reflecting the spread of this degradation throughout the polymer.