Maximizing Aqueous Drug Encapsulation: Small Nanoparticles Formation Enabled by Glycopolymers Combining Glucose and Tyrosine.

Highly potent heterocyclic drugs are frequently poorly water soluble, leading to limited or abandoned further drug development. Nanoparticle technology offers a powerful delivery approach by enhancing the solubility and bioavailability of hydrophobic therapeutics. However, the common usage of organic solvents causes unwanted toxicity and process complexity, therefore limiting the scale-up of nanomedicine technology for clinical translation. Here, we show that an organic-solvent-free methodology for hydrophobic drug encapsulation can be obtained using polymers based on glucose and tyrosine. An aqueous solution based on a tyrosine-containing glycopolymer is able to dissolve solid dasatinib directly without adding an organic solvent, resulting in the formation of very small nanoparticles of around 10 nm loaded with up to 16 wt % of drug. This polymer is observed to function as both a drug solubilizer and a nanocarrier at the same time, offering a simple route for the delivery of insoluble drugs.

Collapsed Star Copolymers Exhibiting Near Perfect Mimicry of the Therapeutic Protein "TRAIL".

Here we introduce amphiphilic star polymers as versatile protein mimics capable of approximating the activity of certain native proteins. Our study focuses on designing a synthetic polymer capable of replicating the biological activity of TRAIL, a promising anticancer protein that shows very poor circulation half-life. Successful protein mimicry requires precise control over the presentation of receptor-binding peptides from the periphery of the polymer scaffold while maintaining enough flexibility for protein-peptide binding. We show that this can be achieved by building hydrophobic blocks into the core of a star-shaped polymer, which drives unimolecular collapse in water. By screening a library of diblock copolymer stars, we were able to design structures with IC50's of ∼4 nM against a colon cancer cell line (COLO205), closely approximating the activity of the native TRAIL protein. This finding highlights the broad potential for simple synthetic polymers to mimic the biological activity of complex proteins.

Streamlined Formation and Manipulation of Charged Polymersomes.

Charged polymersomes are attractive for advanced material applications due to their versatile encapsulation capabilities and charge-induced functionality. Although desirable, the pH-sensitivity of charged block copolymers adds complexity to its self-assembly process, making it challenging to produce charged polymersomes in a reliable manner. In this work, a flow approach to control and strike a delicate balance between solvent composition and pH for self-assembly is used. This allows for the identification of a phase window to reliably produce of charged polymersomes. The utility of this approach to streamline downstream processes, such as morphological transformation or in-line purification is further demonstrated. As proof-of-concept, it is shown that the processed polymersomes can be used for surface modifications facilitated by charge complexation.

Effects of Drug Conjugation on the Biological Activity of Single-Chain Nanoparticles.

The field of single-chain nanoparticles (SCNPs) continues to mature, and an increasing range of reports have emerged that explore the application of these small nanoparticles. A key application for SCNPs is in the field of drug delivery, and recent work suggests that SCNPs can be readily internalized by cells. However, limited attention has been directed to the delivery of small-molecule drugs using SCNPs. Moreover, studies on the physicochemical effects of drug loading on SCNP performance is so far missing, despite the accepted view that such small nanoparticles should be significantly affected by the drug loading content. To address this gap, we prepared a library of SCNPs bearing different amounts of a covalently conjugated therapeutic drug-sulfasalazine (SSZ). We evaluated the impact of the conjugated drug loading on both the synthesis and biological activity of SCNPs on pancreatic cancer cells (AsPC-1). Our results reveal that covalent drug conjugation to the side chains of the SCNP polymer precursor interferes with chain collapse and cross-linking, which demands optimization of reaction conditions to reach high degrees of cross-linking efficiencies. Small-angle neutron scattering and diffusion-ordered spectroscopy nuclear magnetic resonance (DOSY NMR) analyses reveal that SCNPs with a higher drug loading display larger sizes and looser structures, as well as increased hydrophobicity associated with a higher SSZ content. Increased SSZ loading led to reduced cellular uptake when assessed in vitro, whereby SCNP aggregation on the surface of AsPC-1 cells led to reduced toxicity. This work highlights the effects of drug loading on the drug delivery efficiency and biological behavior of SCNPs.

Smart Galactosidase-Responsive Antimicrobial Dendron: Towards More Biocompatible Membrane-Disruptive Agents.

Antimicrobial resistance is a global healthcare challenge that urgently needs the development of new therapeutic agents. Antimicrobial peptides and mimics thereof are promising candidates but mostly suffer from inherent toxicity issues due to the non-selective binding of cationic groups with mammalian cells. To overcome this toxicity issue, this work herein reports the synthesis of a smart antimicrobial dendron with masked cationic groups (Gal-Dendron) that could be uncaged in the presence of ß-galactosidase enzyme to form the activated Enz-Dendron and confer antimicrobial activity. Enz-Dendron show bacteriostatic activity toward Gram-negative (P. aeruginosa and E. coli) and Gram-positive (S. aureus) bacteria with minimum inhibitory concentration values of 96 µm and exerted its antimicrobial mechanism via a membrane disruption pathway, as indicated by inner and outer membrane permeabilization assays. Crucially, toxicity studies confirmed that the masked prodrug Gal-Dendron exhibited low hemolysis and is at least 2.4 times less toxic than the uncaged cationic Enz-Dendron, thus demonstrating the advantage of masking the cationic groups with responsive immolative linkers to overcome toxicity and selectivity issues. Overall, this study highlights the potential of designing new membrane-disruptive antimicrobial agents that are more biocompatible via the amine uncaging strategy.

Polymersomes with micellar patches.

Hollow block copolymer particles called polymer vesicles (polymersomes) serve as versatile containers for compartmentalization in synthetic biology and drug delivery. Recently, there has been growing interest in using polymersomes as colloidal building blocks for creating higher-order clustered structures. Most reports thus far rely on the use of DNA base-pairing interactions to "glue" polymersomes with other colloidal components. In this study, we present two alternative electrostatically driven approaches to assemble polymersomes and model colloids (micelles) into hybrid clusters. The first approach uses pH to manipulate electrostatic interactions and effectively control the clustering extent of micellar subunits on polymersomes, while the second approach relies on the hydrolysis of an acid trigger, glucono delta-lactone (GDL), to introduce temporal control over clustering. We envisage our approaches and structures reported herein will help inspire the creation of new prospects for materials science and biomedical applications.

Metal ion interference therapy: metal-based nanomaterial-mediated mechanisms and strategies to boost intracellular "ion overload" for cancer treatment.

Metal ion interference therapy (MIIT) has emerged as a promising approach in the field of nanomedicine for combatting cancer. With advancements in nanotechnology and tumor targeting-related strategies, sophisticated nanoplatforms have emerged to facilitate efficient MIIT in xenografted mouse models. However, the diverse range of metal ions and the intricacies of cellular metabolism have presented challenges in fully understanding this therapeutic approach, thereby impeding its progress. Thus, to address these issues, various amplification strategies focusing on ionic homeostasis and cancer cell metabolism have been devised to enhance MIIT efficacy. In this review, the remarkable progress in Fe, Cu, Ca, and Zn ion interference nanomedicines and understanding their intrinsic mechanism is summarized with particular emphasis on the types of amplification strategies employed to strengthen MIIT. The aim is to inspire an in-depth understanding of MIIT and provide guidance and ideas for the construction of more powerful nanoplatforms. Finally, the related challenges and prospects of this emerging treatment are discussed to pave the way for the next generation of cancer treatments and achieve the desired efficacy in patients.

Mix and Shake: A Mild Way to Drug-Loaded Lysozyme Nanoparticles.

Biocompatible nanoparticles as drug carriers can improve the therapeutic efficiency of hydrophobic drugs. However, the synthesis of biocompatible and biodegradable polymeric nanoparticles can be time-consuming and often involves toxic solvents. Here, a simple method for protein-based stable drug-loaded particles with a narrow polydispersity is introduced. In this process, lysozyme is mixed with hydrophobic drugs (curcumin, ellipticine, and dasatinib) and fructose to prepare lysozyme-based drug particles of around 150 nm in size. Fructose is mixed with the drug to generate nanoparticles that serve as templates for the lysozyme coating. The effect of lysozyme on the physicochemical properties of these nanoparticles is studied by transmission electron microscopy (TEM) and scattering techniques (e.g., dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS)). We observed that lysozyme significantly stabilized the curcumin fructose particles for 7 days. Moreover, additional drugs, such as ellipticine and dasatinib, can be loaded to form dual-drug particles with narrow polydispersity and spherical morphology. The results also reveal that lysozyme dual ellipticine/dasatinib curcumin particles enhance the cytotoxicity and uptake on MCF-7 cells, RAW 264.7 cells, and U-87 MG cells due to the larger and rigid hydrophobic core. In summary, lysozyme in combination with fructose and curcumin can serve as a powerful combination to form protein-based stable particles for the delivery of hydrophobic drugs.

The flow of anisotropic nanoparticles in solution and in blood.

The alignment of anisotropic nanoparticles in flow has been used for a range of applications such as the preparation of strong fibres and the assembly of in-plane aligned 1D-nanoobjects that are used for electronic devices, sensors, energy and biological application. Important is also the flow behaviour of nanoparticles that were designed for nanomedical applications such as drug delivery. It is widely observed that non-spherical nanoparticles have longer circulation times and a more favourable biodistribution. To be able to understand this behaviour, researchers have turned to analyzing the flow of non-spherical nanoparticles in the blood stream. In this review, an overview of microfluidic techniques that are used to monitor the alignment of anisotropic nanoparticles in solution will be provided, which includes analysis by small angle X-ray scattering (SAXS) and polarized light microscopy. The flow of these nanoparticles in blood is then discussed as the presence of red blood cells causes margination of some nanoparticles. Using fluorescence microscopy, the extent of margination can be identified, which coincides with the ability of nanoparticles to adhere to the cells grown along the wall. While these studies are mainly carried out in vitro using blood, initial investigations in vivo were able to confirm the unusual flow of anisotropic nanoparticles.