Alternative approaches to treating subcutaneous abscesses—especially those associated with antibiotic‐resistant pathogenic bacterial strains—that eliminate the need for antibiotics are urgently ...needed. This work descibes a chitosan (CS) derivative with self‐doped polyaniline (PANI) side chains that can self‐assemble into micelles in an aqueous environment and be transformed into colloidal gels in a process that is driven by a local increase in pH. These self‐doped PANI micelles can be utilized as nano‐localized heat sources, remotely controllable using near‐infrared (NIR) light. To test the in vivo efficacy of the CS derivative as a photothermal agent, an aqueous solution thereof is directly injected at the site of infected abscesses in a mouse model. The injected polymer solution eventually becomes distributed over the acidic abscesses, forming colloidal gels when it meets the boundaries of healthy tissues. After treatment with an 808 nm laser, the colloidal gels convert NIR light into heat, causing the thermal lysis of bacteria and repairing the infected wound without leaving residual implanted materials. This approach has marked potential because it can provide colloidal gels with tunable spatial stability, limiting localized heating to the infected sites, and reducing thermal damage to the surrounding healthy tissues.
An injected polymer solution exhibits a rapid nanostructure transformation over a narrow range of pH values and forms a colloidal gel at the site of the abscess, providing tunable spatial stabilization. The formed colloidal gel converts near‐infrared (NIR) light energy into heat and causes thermal lysis of the bacteria, reducing thermal damage to the surrounding tissues.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Bubbling over: After endocytosis and intracellular trafficking to lysosomes, liposomes containing ammonium bicarbonate can be thermally triggered to generate CO2 bubbles (see scheme). These bubbles ...grow rapidly and collapse violently to induce transient cavitation, a process that can disrupt the lysosomal membrane and release lysosomal proteases, thus leading to cell necrosis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Chemotherapy research highly prioritizes overcoming the multi-drug resistance (MDR) effect in cancer cells. To overcome the drug efflux mediated by P-glycoprotein (P-gp) transporters, we ...developed pH-responsive poly(D,L-lactic-co-glycolic acid) hollow particles (PLGA HPs), capable of delivering doxorubicin (DOX) into MDR cells (MCF-7/ADR). The shell wall of PLGA HPs contained DiO (a hydrophobic dye), and their aqueous core carried DOX hydrochloride salt and sodium bicarbonate, a gas-generating agent when present in acidic environments. Both DiO and DOX could serve as fluorescence probes to localize HPs and visualize their intracellular drug release in real-time. Real-time confocal images provided visible evidences of the acid-responsive intracellular release of DOX from PLGA HPs in MDR cells. Via the macropinocytosis pathway, PLGA HPs taken up by cells experienced an increasingly acidic environment as they trafficked through the early endosomes and then matured into more acidic late endosomes/lysosomes. The progressive acidification of the internalized particles in the late endosomes/lysosomes generated CO2 bubbles, leading to the disruption of HPs, prompt release of DOX, its accumulation in the nuclei, and finally the death of MDR cells. Conversely, taken up via a passive diffusion mechanism, free DOX was found mainly at the perimembrane region and barely reached the cell nuclei; therefore, no apparent cytotoxicity was observed. These results suggest that the developed PLGA HPs were less susceptible to the P-gp-mediated drug efflux in MDR cells and is a highly promising approach in chemotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Photodynamic therapy (PDT) has received considerable attention as a therapeutic treatment for cancer and other diseases; however, it is frequently accompanied by prolonged phototoxic ...reaction of the skin due to slow clearance of synthetic photosensitizers (PSs) administered externally. This study was designed to investigate the genetic use of pKillerRed-mem, delivered using complexes of chitosan (CS) and poly(γ-glutamic acid) (γPGA), to intracellularly express a membrane-targeted KillerRed protein that can be used as a potential PS for PDT. Following transfection with CS/pKillerRed/γPGA complexes, a red fluorescence protein of KillerRed was clearly seen at the cellular membranes. When exposed to green-light irradiation, the KillerRed-positive cells produced an excessive amount of reactive oxygen species (ROS) in a time-dependent manner. Data from viability assays indicate that ROS have an important role in mediating KillerRed-induced cytotoxicity, apoptosis, and anti-proliferation, suggesting that KillerRed can be used as an intrinsically generated PS for PDT treatments. Notably, the phototoxic reaction of KillerRed toward cells gradually became negligible over time, presumably because of its intracellular degradability. These experimental results demonstrate that this genetically encoded KillerRed is biodegradable and has potential for PDT-induced destruction of diseased cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
As of 2020, hepatocellular carcinoma (HCC), a form of liver cancer, stood as the third most prominent contributor to global cancer-related mortality. Combining immune checkpoint inhibitors (ICI) with ...other therapies has shown promising results for treating unresectable HCC, offering new opportunities. Recombinant adeno-associated viral type 2 (AAV2) virotherapy has been approved for clinical use but it efficacy is stifled through systemic administration. On the other hand, iron oxide nanoparticles (ION) can be cleared via the liver and enhance macrophage polarization, promoting infiltration of CD8
T cells and creating a more favorable tumor microenvironment for immunotherapy.
To enhance the efficacy of virotherapy and promote macrophage polarization towards the M1-type in the liver, ION-AAV2 were prepared through the coupling of ION-carboxyl and AAV2-amine using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)/N-hydroxysulfosuccinimide (Sulfo-NHS). Efficacy after systemic delivery of ION-AAV2 in an orthotopic HCC model was evaluated.
After 28 days, the tumor weight in mice treated with ION-AAV2 was significantly reduced by 0.56-fold compared to the control group. The ION-AAV2 treatment led to an approximate 1.80-fold increase in the level of tumor associated M1-type macrophages, while the number of M2-type macrophages was reduced by 0.88-fold. Moreover, a proinflammatory response increased the population of tumor-infiltrating CD8
T cells in the ION-AAV2 group. This transformation converted cold tumors into hot tumors.
Our findings suggest that the conjugation of ION with AAV2 could be utilized in virotherapy while simultaneously exploiting macrophage-modulating cancer immunotherapies to effectively suppress HCC growth.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
A highly efficient and versatile method has been developed for the photothermal aza‐Michael addition, producing
β
‐amino sulfones with excellent yields. The protocol uses mild and simple ...conditions under the batch and continuous flow process and is suitable for synthesis, without the need for transition metal catalysts, ligands, strong acids, or bases. This sustainable approach offers a significant breakthrough in organic synthesis with potential applications in medicinal chemistry and materials science.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The peripheral benzodiazepine receptor (TSPO/PBR) is highly conserved among different species but with perplexing biochemical functions. Multiple ligands of TSPO show commendable regulatory ...activities in lots of biological functions, such as neuro‐protection, cholesterol transport, and so on. These researches support that TSPO may be a potential target for disease treatment and drug development. Previous studies have shown that its ligands benzodiazepines show a satisfactory effect on melanogenic promotion. However, the potential application of TSPO in drug development for pigmentary disorder needs further investigation. In this study, we confirmed the melanogenesis induction of TSPO ligand, Ro5‐4864 in mouse melanoma cell lines, human skin tissue, and zebrafish embryos by inducing melanin synthesis and melanosome transport. Molecular genetics and pharmacological studies showed that TSPO deficiency did not affect melanin production in B16F10 cells and zebrafish embryos, nor did it affect the melanin promotion effect of Ro5‐4864. Whether or not TSPO exists, the expression of lots of melanogenesis‐related proteins, such as TYR, TRP‐1, DCT, Mlph, and Rab27 was upregulated with the Ro5‐4864 administration. These results indicated that Ro5‐4864 induces melanogenesis in a TSPO‐independent manner, which is inconsistent with previous research. This research is a reminder that we need to be very careful during target validation in drug development.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Pulsatile release: When a high‐frequency magnetic field is applied, heat will be generated by coupling to the iron oxide nanoparticles encapsulated in the shells of PLGA hollow microspheres. As the ...temperature approaches the Tg of PLGA, the polymer chains become more mobile, subsequently increasing the free volume of PLGA matrix and significantly enhancing the diffusion of drug molecules.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Although advantageous for siRNA packing and protection, chitosan (CS)-based complexes may lead to difficulties in siRNA release once they arrive at the site of action, due to their ...electrostatic interactions. To assist the intracellular release of siRNA and thus enhance its effectiveness in gene silencing, we incorporated a negatively charged poly(γ-glutamic acid) (γ-PGA) into CS/siRNA complexes. The inclusion of γ-PGA did not alter the complex-formation ability between CS and siRNA; additionally, their cellular uptake was significantly enhanced. The results obtained in our molecular dynamic simulations indicate that the binding between CS and siRNA remained stable in the cytosol environment. In contrast, the compact structure of the ternary CS/siRNA/γ-PGA complexes was unpacked; such a structural unpackage may facilitate the intracellular release of siRNA. In the gene silencing study, we found that the inclusion of γ-PGA into complexes could significantly expedite the onset of gene knockdown, enhance their inhibition efficiency and prolong the duration of gene silencing. These findings may be attributed to the fact that there were significantly more CS/siRNA/γ-PGA complexes internalized into the cells in company with their more rapid intracellular unpackage and release of siRNA when compared with their binary counterparts in the absence of γ-PGA. The aforementioned results suggest that CS/siRNA/γ-PGA complexes can be an efficient vector for siRNA transfection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The blocking of programmed death-ligand 1 (PD-L1) in tumor cells represents a powerful strategy in cancer immunotherapy. Using viral vectors to deliver the cargo for inactivating the PD-L1 gene could ...be associated with host cell genotoxicity and concomitant immune attack. To develop an alternative safe gene delivery method, we designed a unique combination for miRNA34a delivery using a transgene carrier in the form of iron oxide magnetic nanoparticles (IONPs) via magnetofection to downregulate PD-L1 expression in cancer cells. We synthesized IONPs of multiple shapes (IONRs (iron oxide nanorods), IONSs (iron oxide nanospheres), and ITOHs (iron oxide truncated octahedrons)), surface-functionalized with polyethyleneimine (PEI) using the ligand exchange method, as gene delivery systems. Under the guidance of an external magnetic field, PEI@IONPs loaded with plasmid DNA (DNA/PEI@IONPs) encoding GFP showed high transfection efficiency at different weight ratios and time points in A549 and MDA-MB-231 cells. Additionally, the DNA/PEI@IONPs with miRNA34a inserts under a static magnetic field resulted in significant knockdown of the PD-L1 gene, as demonstrated via immunoblotting of the PD-L1 protein. Among the three shapes of IONPs, IONRs showed the highest PD-L1 knockdown efficiency. The genetic expression of miRNA34a was also studied using qPCR and it showed high expression of miRNA in cells treated with PEI@IONRs. Flow cytometry and a live/dead assay confirmed apoptosis after transfection with miRNA34a. To conclude, in this paper, a promising transgene carrier with low cost, negligible cytotoxicity, and high transfection efficiency has been successfully established for miRNA gene delivery in the context of cancer immunotherapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
