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.

Development of an Albumin-Polymer Bioconjugate via Covalent Conjugation and Supramolecular Interactions.

Preexisting serum albumin-polymer bioconjugates have been formed either through covalent conjugation or supramolecular interactions. However, the viability of producing a bioconjugate where both covalent conjugation and supramolecular interactions have been adopted is yet to be explored. In this work, the noncovalent interaction of two polymers bearing fatty acid-based end-functionalities were compared and the superior binder was carried forward for testing with serum albumin that possessed a polymer conjugated to its Cys34 residue. The studies demonstrated that an albumin-polymer bioconjugate equipped with polymers via both covalent and supramolecular interactions can be successfully achieved.

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.

Expression of GPX4 by oncolytic vaccinia virus can significantly enhance CD8+T cell function and its impact against pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is currently difficult to treat, even when therapies are combined with immune checkpoint blockade (ICB). A novel strategy for immunotherapy would be to maximize the therapeutic potential of oncolytic viruses (OVs), which have been proven to engage the regulation of tumor microenvironment (TME) and cause-specific T-cell responses. To boost tumor sensitivity to ICB therapy, this study aimed to investigate how glutathione peroxide 4 (GPX4)-loaded OVs affect CD8+ T cells and repair the immunosuppressive environment. Here, we successfully constructed a novel recombinant oncolytic vaccinia virus (OVV) encoding the mouse GPX4 gene. We found the OVV-GPX4 effectively replicated in tumor cells and prompted the expression of GPX4 in T cells. Our research indicated that OVV-GPX4 could reshape the TME, rectify the depletion of CD8+T cells, and enhance the antitumor effects of ICB therapy.

Using network pharmacological analysis and molecular docking to investigate the mechanism of action of quercetin's suppression of oral cancer.

OBJECTIVE: This investigation seeks to explore the mechanism of quercetin in oral cancer by incorporating network pharmacology analysis and molecular docking. METHODS: First, we use the network pharmacology analysis to discover possible core targets for quercetin and oral cancer. We subsequently utilized the docking of molecules techniques to calculate the affinities of critical targets and quercetin for verification. RESULTS: TCMSP and the Swiss Target Prediction database found 190 quercetin action targets, while GeneCards, OMIM, PharmGkb, and the Therapeutic Target Database found 8971 oral cancer-related targets. Venny 2.1.0 online software conducted an intersection analysis of quercetin-related target information with information about oral cancer, and 172 putative quercetin-anti-oral cancer targets were examined. Six prospective core targets for quercetin treatment of oral cancer were identified from the PPI network topology analysis of 172 putative therapeutic targets. These targets include AKT1, PIK3R1, MYC, HIF1A, SRC, and HSP90AA1. GO enrichment function analysis showed that 2372 biological processes, 98 cell components, and 201 molecular functions were involved. Through enrichment analysis of the KEGG pathway, 172 signal pathways were obtained. A few examples are PI3K-AKT, HIF-1, IL-17, and other signaling pathways. The molecular docking scores of quercetin and the primary therapeutic targets AKT1, HIF1A, HSP90AA1, MYC, PIK3R1, and SRC are all less than -0.7 points, demonstrating good compatibility between the medicine and small molecules and suggesting that quercetin may affect oral cancer through the primary target. CONCLUSION: This study explores quercetin's mechanism and possible targets for oral cancer treatment, offering novel approaches. Quercetin may be a multitarget medication against oral cancer in the future.

Microsecond molecular dynamics simulation of the adsorption and penetration of oil droplets on cellular membrane.

The hazardous effects of petroleum contaminants in the soil and water environment are highly associated with their interactions with cellular membranes, but our understanding on the molecular-level mechanisms for the adsorption and penetration of heavy oil mixture on cellular membrane is very limited. In this study, microsecond molecular dynamics simulations were performed to gain insights into the morphological evolution and penetration dynamics of the multi-component and single-component oil droplets on the dipalmitoylphosphatidylcholine lipid membrane. Results highlighted the inhibition effect of the resins on the penetration of alkanes and aromatics, because they would form net structure making it difficult to release the latter two components from the oil droplet to the membrane. It also demonstrated the obviously different patterns of penetration between alkanes and aromatics. The overall steps for the toluene penetration included detachment from oil droplet, dispersion in water, adsorption on membrane surface, structure adjustment and penetration into membrane. By contrast, the step of dispersion in water was not necessary for the alkanes' penetration. Instead, it relied on the adsorption of the whole oil droplet on the membrane surface which resulted in the formation of pores on the membrane surface by local structure deformation in the lipid head group regions.