Using a systematic and quantitative approach to generate new insights into drug loading of PLGA nanoparticles using nanoprecipitation.

The synthesis of drug-loaded PLGA nanoparticles through nanoprecipitation in solvent/antisolvent mixtures is well reported but lacks clarity in explaining drug loading mechanisms and the prediction of efficiency of drug entrapment. Various methods using physical parameters such as log P and solid-state drug-polymer solubility aim to predict the intensity of drug-polymer interactions but lack precision. In particular, the zero-enthalpy method for drug/polymer solubility may be intrinsically inaccurate, as we demonstrate. Conventional measurement of loading capacity (LC), expressed in weight ratios, can be misleading for comparing different drugs and we stress the importance of using molar units. This research aims to provide new insights and critically evaluate the established methodologies for drug loading of PLGA nanoparticles. The study employs four model drugs with varying solubilities in solvent/antisolvent mixtures, log P values, and solid-state solubility in PLGA: ketoprofen (KPN), indomethacin (IND), sorafenib (SFN), and clofazimine (CFZ). This study highlights that drug loading efficiency is primarily influenced by the drug's solubilities within the solvent system. We emphasise that both kinetic and thermodynamic factors play a role in the behaviour of the system by considering the changes in drug solubility during mixing. The study introduces a pseudo-constant K* to characterise drug-polymer interactions, with CFZ and SFN showing the highest K* values. Interestingly, while IND and KPN have lower K* values, they achieve higher loading capacities due to their greater solubilities, indicating the key role of solubility in determining LC.

Emerging molecular mechanisms and genetic targets for developing novel therapeutic strategies for treating bladder diseases.

Bladder diseases affect millions of patients worldwide and compromise their quality of life with a substantial economic impact. The not fully understood aetiologies of bladder diseases limit the current diagnosis and therapeutic options to primarily symptomatic treatment. In addition, bladder targeted drug delivery is challenging due to its unique anatomical features and its natural physiological function of urine storage and frequent voiding. Therefore, current treatment options often fail to provide a highly effective, precisely targeted and long-lasting treatment. With the growing maturity of gene therapy, comprehensive studies are needed to provide a better understanding of the molecular mechanisms underpinning bladder diseases and help to identify novel gene therapeutic targets and biomarkers for treating bladder diseases. In this review, molecular mechanisms involved in pathology of bladder cancer, interstitial cystitis and overactive bladder syndrome are reviewed, with focus on establishing potential novel treatment options. Proposed novel therapies, including gene therapy combined with nanotechnology, localised drug delivery by nanoparticles, and probiotics, are discussed in regard to their safety profiles, efficacy, treatment lenght, precise targeting, and in comparison to conventional treatment methods.

Evaluation of the Benefits of Microfluidic-Assisted Preparation of Polymeric Nanoparticles for DNA Delivery.

An effective delivery vehicle of genetic materials to their target site is the key to a successful gene therapy. In many cases, nanoparticles are used as the vehicle of choice and the efficiency of the delivery relies heavily on the physicochemical properties of the nanoparticles. Microfluidics, although being a low throughput method, has been increasingly researched for the preparation of nanoparticles. A range of superior properties were claimed in the literature for microfluidic-prepared platforms, but no evidence on direct comparison of the properties of the nanoparticles prepared by microfluidics and conventional high throughput method exists, leaving the industry with little guidance on how to select effective large-scale nanoparticle manufacturing method. This study used plasmid DNA-loaded PLGA-Eudragit nanoparticles as the model system to critically compare the nanoparticles prepared by conventional and microfluidics-assisted nanoprecipitation. The PLGA-Eudragit nanoparticles prepared by microfluidics were found to be statistically significantly larger than the ones prepared by conventional nanoprecipitation. PLGA-Eudragit nanoparticle prepared conventionally showed higher DNA loading efficiency. Although the DNA-loaded nanoparticles prepared by both methods did not induce significant cytotoxicity, the transfection efficiency was found to be higher for the ones prepared conventionally which has good potential for plasmid delivery. This study for the first time provides a direct comparison of the DNA-loaded nanoparticles prepared by microfluidic and conventional methods. The findings bring new insights into critical evaluation of the selection of manufacturing methods of nanoparticles for future gene therapy.

Microfluidics for pharmaceutical nanoparticle fabrication: The truth and the myth.

Using micro-sized channels to manipulate fluids is the essence of microfluidics which has wide applications from analytical chemistry to material science and cell biology research. Recently, using microfluidic-based devices for pharmaceutical research, in particular for the fabrication of micro- and nano-particles, has emerged as a new area of interest. The particles that can be prepared by microfluidic devices can range from micron size droplet-based emulsions to nano-sized drug loaded polymeric particles. Microfluidic technology poses unique advantages in terms of the high precision of the mixing regimes and control of fluids involved in formulation preparation. As a result of this, monodispersity of the particles prepared by microfluidics is often recognised as being a particularly advantageous feature in comparison to those prepared by conventional large-scale mixing methods. However, there is a range of practical drawbacks and challenges of using microfluidics as a direct micron- and nano-particle manufacturing method. Technological advances are still required before this type of processing can be translated for application by the pharmaceutical industry. This review focuses specifically on the application of microfluidics for pharmaceutical solid nanoparticle preparation and discusses the theoretical foundation of using the nanoprecipitation principle to generate particles and how this is translated into microfluidic design and operation.