pH-triggered poly(ethylene glycol) nanogels prepared through orthoester linkages as potential drug carriers

<p>The new acid-labile poly(ethylene glycol) (PEG) nanogels were prepared by copolymerization of a new crosslinking agent containing orthoester groups (OEAM) and methoxypolyethylene glycol acrylate (MPEGAC). DOX was loaded into PEG nanogels with a loading content of 18.2%, which was highly desirable for targeted cancer therapy without premature drug release in neutral environment. The cellular uptake and cytotoxicity of DOX-loaded PEG nanogels were measured using SH-SY5Y and HepG2 cells. Tumor penetration and antitumor activity were investigated using SH-SY5Y tumor-like spheroids. All results demonstrate that the pH-sensitive PEG nanogels may be used as potential drug carriers for chemotherapy.</p

Dynamic crosslinked polymeric nano-prodrugs for highly selective synergistic chemotherapy

To achieve highly selective synergistic chemotherapy attractive for clinical translation, the precise polymeric nano-prodrugs (PPD-NPs) were successfully constructed via the facile crosslinking reaction between pH-sensitive poly(ortho ester)s and reduction-sensitive small molecule synergistic prodrug (Pt(IV)-1). PPD-NPs endowed the defined structure and high drug loading of cisplatin and demethylcantharidin (DMC). Moreover, PPD-NPs exhibited steady long-term storage and circulation via the crosslinked structure, suitable negative potentials and low critical micelle concentration (CMC), improved selective tumour accumulation and cellular internalization via dynamic size transition and surficial amino protonation at tumoural extracellular pH, promoted efficient disintegration and drug release at tumoural intracellular pH/glutathione, and enhanced cytotoxicity via the synergistic effect between cisplatin and DMC with the feed ratio of 1:2, achieving significant tumour suppression while decreasing the side effects. Thus, the dynamic crosslinked polymeric nano-prodrugs exhibit tremendous potential for clinically targeted synergistic cancer therapy

pH-triggered dynamic erosive small molecule chlorambucil nano-prodrugs mediate robust oral chemotherapy

Currently, the dynamic erosive small molecule nano-prodrug is of great demand for oral chemotherapy, owing to its precise structure, high drug loading and improved oral bioavailability via overcoming various physiologic barriers in gastrointestinal tract, blood circulation and tumor tissues compared to other oral nanomedicines. Herein, this work highlights the successful development of pH-triggered dynamic erosive small molecule nano-prodrugs based on in vivo significant pH changes, which are synthesized via amide reaction between chlorambucil and star-shaped ortho esters. The precise nano-prodrugs exhibit extraordinarily high drug loading (68.16%), electric neutrality, strong hydrophobicity, and dynamic large-to-small size transition from gastrointestinal pH to tumoral pH. These favorable physicochemical properties can effectively facilitate gastrointestinal absorption, blood circulation stability, tumor accumulation, cellular uptake, and cytotoxicity, therefore achieving high oral relative bioavailability (358.72%) and significant tumor growth inhibition while decreasing side effects. Thus, this work may open a new avenue for robust oral chemotherapy attractive for clinical translation

Endonuclease mimetic activity of laccase with sequence preference following redox potential and interaction of bases

Degradation of lignin, a natural macromolecule, by laccase via substrate radicals has been intensively studied. However, the interactions between laccase and DNA have not been thoroughly elucidated to date. In this report, we demonstrate that laccase has the endonuclease-mimetic activity with the sequence preference. The decay of plasmid and cDNA was observed with atomic force microscopy (AFM), electron paramagnetic resonance (EPR) and DNA sequencing. Concomitantly, Image 1 appeared, which produced the DNA lesion. The sequencing results showed that A and AA were the preferred nucleotides flanking the cleaved sites. The hydrogen bonds between complementary base pairs and the base redox potential were responsible for the long-lived charge transfer state within the A-repetitive sequence governing the sequence preference. This discovery implies alternative strategies of surviving the phosphorus stress and resistance to alien DNA in certain species, in which laccase is abundant. These results enrich our understanding of the mechanisms of DNA damage and are important for the interpretation of disease treatment

The mechanism of trans-δ-viniferin inhibiting the proliferation of lung cancer cells A549 by targeting the mitochondria

Trans-δ-viniferin (TVN), as a natural extract, is a resveratrol dimer with attractive biological activities, particularly its anti-tumor character. However, the mechanism of TVN interfering with cancerous proliferation has not been fully understood. Herein in this study, we found that TVN could trigger cancerous mitochondrial membrane potential (ΔΨm) reduction, with intracellular reactive oxidative species (ROS) level increasing, leading to apoptosis, which makes TVN a promising candidate for lung cancer cells A549 treatment. Therefore, this study provides TVN as an option to meet the demand for higher antitumor availability with lower biotoxicity and other clinical applications