Knowledge-Based Design of Multifunctional Polymeric Nanoparticles.

Conventional drug delivery systems (DDS) today still face several drawbacks and obstacles. High total doses of active pharmaceutical ingredients (API) are often difficult or impossible to deliver due to poor solubility of the API or undesired clearance from the body caused by strong interactions with plasma proteins. In addition, high doses lead to a high overall body burden, in particular if they cannot be delivered specifically to the target site. Therefore, modern DDS must not only be able to deliver a dose into the body, but should also overcome the hurdles mentioned above as examples. One of these promising devices are polymeric nanoparticles, which can encapsulate a wide range of APIs despite having different physicochemical properties. Most importantly, polymeric nanoparticles are tunable to obtain tailored systems for each application. This can already be achieved via the starting material, the polymer, by incorporating, e.g., functional groups. This enables the particle properties to be influenced not only specifically in terms of their interactions with APIs, but also in terms of their general properties such as size, degradability, and surface properties. In particular, the combination of size, shape, and surface modification allows polymeric nanoparticles to be used not only as a simple drug delivery device, but also to achieve targeting. This chapter discusses to what extent polymers can be designed to form defined nanoparticles and how their properties affect their performance.

Ethoxy acetalated dextran nanoparticles for drug delivery: A comparative study of formulation methods.

Dextran-based polymers, such as ethoxy acetalated dextran (Ace-DEX), are increasingly becoming the focus of research as they offer great potential for the development of polymer-based nanoparticles as drug delivery vehicles. Their major advantages are the facile synthesis, straightforward particle preparation and the pH-dependent degradation of the particles that can be fine-tuned by the degree of acetalation of the polymer. In this study we have shown that Ace-DEX can not only compete against the commonly used and FDA-approved polymer poly(lactic-co-glycolic acid) (PLGA), but even has the potential to outperform it in its encapsulation properties, e.g., for the herein used anti-inflammatory leukotriene biosynthesis inhibitor BRP-187. We used three different methods (microfluidics, batch nanoprecipitation and emulsion solvent evaporation) for the preparation of BRP-187-loaded Ace-DEX nanoparticles to investigate the influence of the formulation technique on the physicochemical properties of the particles. Finally, we evaluated which production method offers the greatest potential for achieving the demands for a successful translation from research into pharmaceutical production by fulfilling the basic requirements, such as reaching a high loading capacity of the particles and excellent reproducibility while being simple and affordable.

Self-assembled PEGylated amphiphilic polypeptides for gene transfection.

In the present study, three biodegradable block copolymers composed of a poly(ethylene glycol) block and a copolypeptide block with varying compositions of cationic L-lysine (L-Lys) and hydrophobic benzyl-L-glutamate (Bzl-L-Glu) were designed for gene delivery applications. The polypeptides were synthesized by ring opening polymerization (ROP) and after orthogonal deprotection of Boc-L-Lys side chains, the polymer exhibited an amphiphilic character. To bind or encapsulate plasmid DNA (pDNA), different formulations were investigated: a nanoprecipitation and an emulsion technique using various organic solvents as well as an aqueous pH-controlled formulation method. The complex and nanoparticle (NP) formations were monitored by dynamic light scattering (DLS), and pDNA interaction was shown by gel electrophoresis and subsequent controlled release with heparin. The polypeptides were further tested for their cytotoxicity as well as biodegradability. The complexes and NPs presenting the most promising size distributions and pDNA binding ability were subsequently evaluated for their transfection efficiency in HEK293T cells. The highest transfection efficiencies were obtained with an aqueous formulation of the polypeptide containing the highest L-Lys content and lowest proportion of hydrophobic, helical structures (P1*), which is therefore a promising candidate for efficient gene delivery by biodegradable gene delivery vectors.

Optimized Encapsulation of the FLAP/PGES-1 Inhibitor BRP-187 in PVA-Stabilized PLGA Nanoparticles Using Microfluidics.

The dual inhibitor of the 5-lipoxygenase-activating protein (FLAP) and the microsomal prostaglandin E2 synthase-1 (mPGES-1), named BRP-187, represents a promising drug candidate due to its improved anti-inflammatory efficacy along with potentially reduced side effects in comparison to non-steroidal anti-inflammatory drugs (NSAIDs). However, BRP-187 is an acidic lipophilic drug and reveals only poor water solubility along with a strong tendency for plasma protein binding. Therefore, encapsulation in polymeric nanoparticles is a promising approach to enable its therapeutic use. With the aim to optimize the encapsulation of BRP-187 into poly(lactic-co-glycolic acid) (PLGA) nanoparticles, a single-phase herringbone microfluidic mixer was used for the particle preparation. Various formulation parameters, such as total flow rates, flow rate ratio, the concentration of the poly(vinyl alcohol) (PVA) as a surfactant, initial polymer concentration, as well as presence of a co-solvent on the final particle size distribution and drug loading, were screened for best particle characteristics and highest drug loading capacities. While the size of the particles remained in the targeted region between 121 and 259 nm with low polydispersities (0.05 to 0.2), large differences were found in the BRP-187 loading capacities (LC = 0.5 to 7.29%) and drug crystal formation during the various formulations.

Investigation of the Adrenergic and Opioid Binding Affinities, Metabolic Stability, Plasma Protein Binding Properties, and Functional Effects of Selected Indole-Based Kratom Alkaloids.

Selected indole-based kratom alkaloids were evaluated for their opioid and adrenergic receptor binding and functional effects, in vivo antinociceptive effects, plasma protein binding, and metabolic stability. Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), had higher affinity at opioid receptors than at adrenergic receptors while the vice versa was observed for corynantheidine. The observed polypharmacology of kratom alkaloids may support its utilization to treat opioid use disorder and withdrawal.