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Successful delivery of anticancer drugs to intracellular targets requires different properties of the nanocarrier to overcome multiple transport barriers. However, few nanocarrier systems, to date, possess such properties, despite knowledge about the biological fate of inorganic and polymeric nanocarriers in relation to their fixed size, shape and surface properties. Herein, a polymer-lipid hybrid nanoparticle (PLN) system is described with size and shape transformability and its mechanisms of cellular uptake and intracellular trafficking are studied. Pharmaceutical lipids were screened for use in transformable PLN. Mechanisms of cellular uptake and the role of fatty acid-binding proteins in intracellular trafficking of PLN were investigated in breast cancer cells. Intra-tumoral penetration and retention of doxorubicin (DOX) were evaluated by confocal microscopy. The lead PLNs showed time-dependent size reduction and shape change from spherical to spiky shape. This transformability of PLNs and lipid trafficking pathways facilitated intracellular transport of DOX-loaded PLN (DOX-PLN) into mitochondria and nuclei. DOX-PLN significantly increased DOX penetration and retention over free DOX or non-transformable liposomal DOX particles at 4 h post-intravenous administration. Transformability of PLN and lipid-biology interplay can be exploited to design new nanocarriers for effective drug delivery to tumor cells and intracellular targets.

Anthracyclines, commonly employed for cancer chemotherapy, suffer from dose-limiting cardiotoxicity and poor efficacy due to multidrug resistance (MDR). We previously demonstrated that simultaneous delivery of the synergistic drugs doxorubicin (DOX) and mitomycin C (MMC) by polymer-lipid hybrid nanoparticles (PLN) circumvented MDR, increased efficacy, and reduced cardiotoxicity in immuncompromised mice superior to poly(ethylene glycol)-coated (PEGylated) lipososmal DOX (PLD). Herein it is shown that the DOX-MMC combination was also synergistic in MDR EMT6/AR1 murine breast cancer cells and that their nanoparticle formulations were able to overcome the MDR phenotype. In contrast PLD exhibited little or no effect on the MDR cells. For the first time, these differences in in vitro efficacy are shown to be strongly correlated with cellular uptake and intracellular distribution of DOX brought about by DOX formulations (e.g., free solution, PLN vs PLD). To take into consideration the role of an intact immune system and tumor stroma in the response of host and tumor to chemotherapy, use was made of nonimmunocomprised mouse models to study the dose tolerance, cardiotoxicity, and efficacy of DOX-MMC coloaded PLN (DMsPLN) compared to PLD. DMsPLN treatment at 50 mg/m(2) DOX and 17 mg/m(2) of MMC singly or once every 4 days for 4 cycles were well tolerated by the mice without elevated systemic toxicity blood markers or myocardial damage. In contrast, PLD was limited to a single treatment due to significant total weight loss. The DMsPLN treatment delayed tumor growth up to 312% and 28% in EMT6/WT and EMT6/AR1 models, respectively. This work supports the translational value of DMsPLN for the aggressive management of either naïve or anthracycline-resistant tumors.

Although a great number of studies may be found in literature about the parameters affecting the size of chitosan nanoparticles, no systematic work so far has detailed the factors affecting the polydispersity of chitosan as an important factor determining the quality of many preparations. Herein, using artificial neural networks (ANNs), four independent variables, namely, pH and concentration of chitosan solution as well as time and amplitude of sonication of the solution were studied to determine their influence on the polydispersity of solution. We found that in an ultrasound prepared nanodispersion of chitosan, all the four input parameters have reverse but non-linear relation with the polydispersity of the nanoparticles.

Purpose Artificial neural networks (ANNs) are used to optimize a formulation of poly(lactic acid) (PLA) nanoparticles containing hydrophobic drug molecules through a study of the critical parameters affecting nanoparticle size.

The pharmacokinetic properties of chitosan nanoparticles have been shown to mainly depend on its particle size. The aim of this study was to concurrently evaluate and model the effective parameters, namely, chitosan concentration, buffer pH, amplitude and time of sonication, on the particle size of chitosan nanoparticles. Chitosan solutions were prepared and sonicated with different values for the above mentioned parameters. The data were then modeled using artificial neural networks (ANNs). The results illustrated that all four input parameters affect the size of prepared chitosan nanoparticles. While a reverse effect was observed between the size and the buffer pH as well as time and amplitude of sonication, the concentration was found to directly influence the particle size. The optimum condition to obtain the minimum size of nanoparticles in the range of 50-200 nm was found to be high values of pH and sonication time (i.e. approximately 4.9 and 500 s, respectively) and amplitude values of more than ~55.

This review discusses the reports of alternative dosage forms to suspension formulations of hydrophobic drugs for nebulisers. Suspensions for nebulisers, although widely used over recent years, have several limitations which have led to pharmaceutical researchers looking for alternative, better performing preparations. Particular attention has been directed towards the use of nanoparticles as carriers of hydrophobic active ingredients. Several nanoformulations have been prepared and compared in vitro and/or in vivo with the corresponding microsuspension formulation. It is also clear that future studies in this field should address the parallel important aspects of safety and economical aspects of nanoparticualte formulations.

Multifunctional nanoparticles (NPs) have found important applications in diagnosis, chemotherapy, and image-guided surgery of tumors. In this work, we have developed polymeric theranostic NPs (PTNPs) containing the anticancer drug docetaxel (DTX), a fluorescent dye, and magnetic manganese oxide (MnO) NPs for dual modal imaging and chemotherapy. PTNPs ~150 nm in diameter were synthesized by co-loading hydrophobic DTX and MnO NPs ~5 nm in diameter, into the matrix of a fluorescent dye-labeled amphiphilic polymer. The PTNPs enabled high loading efficiency and sustained in vitro release of DTX. Energy-dependent cellular uptake and extended cytoplasmic retention of the PTNPs in MDA-MB-231 human breast cancer cells were observed by fluorescence microscopy examination. DTX-loaded PTNPs exhibited higher cytotoxicity than free DTX with a 3 to 4.4-fold decrease in drug dose required for 50% cell growth inhibition. The hydrophilic backbone of the amphiphilic polymer improved the fluidity of PTNPs which enhanced the longitudinal relaxivity (r1) of loaded MnO NPs by 2.7-fold with r1=2.4mM(-1)s(-1). Whole body fluorescence imaging (FI) and magnetic resonance imaging (MRI) showed significant accumulation and prolonged retention of PTNPs in orthotopic MDA-MB-231 breast tumors. These results suggest that the new amphiphilic polymer-based PTNP system, able to simultaneously deliver a poorly soluble anticancer drug, enhance MRI contrast, and stain tumor tissue by fluorescence, is a good candidate for cancer theranostic applications.

The aim of this study is to prepare a nanosuspension of budesonide for respiratory delivery using nebuliser by optimising its particle size and characterising its in vitro deposition behaviour. PLA (poly lactic acid)-budesonide nanosuspension (BNS) was prepared using high-pressure emulsification/solvent evaporation method. To optimise particle size, different parameters such as PLA concentration, sonication time, and amplitude were investigated. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and scanning electron microscope (SEM) analyses were performed to characterise the prepared PLA-budesonide nanoparticles. The in vitro aerodynamic characteristics of the PLA-BNS using a jet nebuliser were estimated and compared with that of commercially available suspension formulation of budesonide. Budesonide-loaded PLA nanoparticles with fine particle size (an average size of 224-360 nm), narrow size distribution, and spherical and smooth surface were prepared. The optimum condition for preparation of fine particle size for aerosolisation was found to be at PLA concentration of 1.2 mg/ml and amplitude of 70 for 75 s sonication time. The in vitro aerosolisation performance of PLA-BNS compared to that of commercial budesonide indicated that it has significantly (p 0.05) smaller mass median aerodynamic diameter (MMAD) value with an enhancement in fine particle fraction (FPF) value. Improving the in vitro deposition of budesonide, PLA-BNS could be considered as a promising alternative suspension formulation for deep lung delivery of the drug using nebuliser.

Nasal vaccination is a promising, needle-free alternative route for parenteral vaccination. This study introduces a simple, scalable nasal vaccine delivery formulation for Foot and Mouth Disease virus (FMDv) using chitosan (CS) nanoparticles and assesses the potential of fungal CS for use as nanocarriers for mucosal vaccines. Fungal CS was extracted from fungal biomass and physiochemically characterized. FMDv-loaded CS nanoparticles, prepared using an ionic gelation technique, were characterized for particle size, zeta potential, morphology, loading efficiency and virus particle release. The immunogenicities of nasally applied FMDv-loaded fungal or commercial shrimp CS were compared with intraperitoneally administered fluid vaccine in guinea pigs. The nanoparticles had varied sizes (221.9-281.2 nm), positive electrical charge (+7 to +13 mV) and excellent antigen-loading capacity (93-97%). In vitro release studies revealed a biphasic virus particle release for all CS nanoparticles. Higher serum titers were developed with CS formulations than with free virus and were comparable with the titers for intraperitoneally administered fluid vaccine. Significantly higher IgA levels were found after the administration of nasal vaccine than after fluid vaccine or free virus. Overall, CS-FMDv nanoparticles stimulated humoral and mucosal immunity following intranasal administration. Fungal CS polymers were potent mucosal immunoadjuvants and showed promise as alternative sources of CS for mucosal vaccine formulations.

The purpose of this study was to find an artificial neural networks model for determining major factors impacting the stability of an acetaminophen nanosuspansion that was prepared using nanoprecipitation in microfluidic reactors. Four variables, namely concentration of surfactant, solvent and antisolvent flow rate and solvent temperature were used as input variables and time of sedimentation of nanoparticles was considered as output variable. The particle size of optimized formulation was measured by transmission electron microscope and dynamic light scattering. Comparing the 3D graphs from the model showed that antisolvent flow rate and temperature have direct relation with time of sedimentation, whereas solvent flow rate generally has reverse relation with the time of sedimentation. Concentration of surfactant was found to be the most important factor in determining the stability of nanosuspension.