Microfluidic preparation and optimization of sorafenib-loaded poly(ethylene glycol-block-caprolactone) nanoparticles for cancer therapy applications.

The use of amphiphilic block copolymers to generate colloidal delivery systems for hydrophobic drugs has been the subject of extensive research, with several formulations reaching the clinical development stages. However, to generate particles of uniform size and morphology, with high encapsulation efficiency, yield and batch-to-batch reproducibility remains a challenge, and various microfluidic technologies have been explored to tackle these issues. Herein, we report the development and optimization of poly(ethylene glycol)-block-(ε-caprolactone) (PEG-b-PCL) nanoparticles for intravenous delivery of a model drug, sorafenib. We developed and optimized a glass capillary microfluidic nanoprecipitation process and studied systematically the effects of formulation and process parameters, including different purification techniques, on product quality and batch-to-batch variation. The optimized formulation delivered particles with a spherical morphology, small particle size (dH < 80 nm), uniform size distribution (PDI < 0.2), and high drug loading degree (16 %) at 54 % encapsulation efficiency. Furthermore, the stability and in vitro drug release were evaluated, showing that sorafenib was released from the NPs in a sustained manner over several days. Overall, the study demonstrates a microfluidic approach to produce sorafenib-loaded PEG-b-PCL NPs and provides important insight into the effects of nanoprecipitation parameters and downstream processing on product quality.

Non-viral nanoparticles for RNA interference: Principles of design and practical guidelines.

Ribonucleic acid interference (RNAi) is an innovative treatment strategy for a myriad of indications. Non-viral synthetic nanoparticles (NPs) have drawn extensive attention as vectors for RNAi due to their potential advantages, including improved safety, high delivery efficiency and economic feasibility. However, the complex natural process of RNAi and the susceptible nature of oligonucleotides render the NPs subject to particular design principles and requirements for practical fabrication. Here, we summarize the requirements and obstacles for fabricating non-viral nano-vectors for efficient RNAi. To address the delivery challenges, we discuss practical guidelines for materials selection and NP synthesis in order to maximize RNA encapsulation efficiency and protection against degradation, and to facilitate the cytosolic release of oligonucleotides. The current status of clinical translation of RNAi-based therapies and further perspectives for reducing the potential side effects are also reviewed.

Evaluation of the effects of nanoprecipitation process parameters on the size and morphology of poly(ethylene oxide)-block-polycaprolactone nanostructures.

Nanoprecipitation is a straightforward method for the production of block copolymer nanoparticles for drug delivery applications. However, the effects of process parameters need to be understood to optimize and control the particle size distribution (PSD). To this end, we investigated the effects of material and process factors on PSD and morphology of nanoparticles prepared from an amphiphilic diblock copolymer, poly(ethylene oxide)-block-polycaprolactone. Using a Design of Experiments approach, we explored the joint effects of molecular weight, block length ratios, water volume fraction, stirring rate, polymer concentration and organic phase addition rate on hydrodynamic size and polydispersity index of the nanostructures and created statistical models explaining up to 94% of the variance in hydrodynamic diameter. In addition, we performed morphological characterization by cryogenic transmission electron microscopy and showed that increasing the process temperature may favor the formation of vesicles from these polymers. We showed that the effects of process parameters are dependent on the polymer configuration and we found that the most useful parameters to fine-tune the PSD are the initial polymer concentration and the stirring rate. Overall, this study provides evidence on the joint effects of material and process parameters on PSD and morphology, which will be useful for rational design of formulation-specific optimization studies, scale-up and process controls.