Thermoresponsive Polymeric Nanoparticles: Nucleation from Cooperative Polymerization Driven by Dative Bonds

Cooperative polymerization, aided by the nucleation–elongation mechanism, has the promise of providing polymers and nanostructures that are otherwise inaccessible. The molecular origin of the cooperative growth of polymers is driven by a secondary interaction, often based on polarization, electrostatics, or sterics-driven secondary structure. Here, we demonstrate that covalent dative interactions can be used to achieve cooperative polymerization. Our results suggest that the initial polymer formation serves as the nucleus for monodisperse nanoparticle assembly. The dynamic nature of the dative interaction in this equilibrium self-assembly has been shown to endow these nanoparticles with thermal responsive characteristics

Hierarchical-Coassembly-Enabled 3D-Printing of Homogeneous and Heterogeneous Covalent Organic Frameworks

Covalent organic frameworks (COFs) are crystalline polymers with permanent porosity. They are usually synthesized as micrometer-sized powders or two-dimensional thin films and membranes for applications in molecular storage, separation, and catalysis. In this work, we report a general method to integrate COFs with imine or β-ketoenamine linkages into three-dimensional (3D)-printing materials. A 3D-printing template, Pluronic F127, was introduced to coassemble with imine polymers in an aqueous environment. By limitation of the degree of imine polycondensation during COF formation, the amorphous imine polymer and F127 form coassembled 3D-printable hydrogels with suitable shear thinning and rapid self-healing properties. After the removal of F127 followed by an amorphous-to-crystalline transformation, three β-ketoenamine- and imine-based COFs were fabricated into 3D monoliths possessing high crystallinity, hierarchical pores with high surface areas, good structural integrity, and robust mechanical stability. Moreover, when multiple COF precursor inks were employed for 3D printing, heterogeneous dual-component COF monoliths were fabricated with high spatial precision. This method not only enables the development of COFs with sophisticated 3D macrostructure but also facilitates the heterogeneous integration of COFs into devices with interconnected interfaces at the molecular level

Biodistribution Analysis of NIR-Labeled Nanogels Using <i>in Vivo</i> FMT Imaging in Triple Negative Human Mammary Carcinoma Models

The purpose of this study is to evaluate the biodistribution properties of random-copolymer-based core-cross-linked nanogels of various sizes and surface poly­(ethylene glycol) composition. Systematic variations of near-IR labeled nanogels, comprising varying particle sizes (28–135 nm), PEG corona quantity (0–50 mol %), and PEG length (PEG <i>M</i>_n 1000, 2000, and 5000), were prepared and injected in mice that had been subcutaneously implanted with MDA-MB-231-luc-D3H2LN human mammary carcinoma. <i>In vivo</i> biodistribution was obtained using fluorescence molecular tomography imaging at 0, 6, 24, 48, and 72 h postinjection. Retention of total body probe and percentages of total injected dose in the tumor, liver, spleen, lungs, heart, intestines, and kidneys were obtained. Smaller nanogels (∼30–40 nm) with a high PEG conjugation (∼43–46 mol %) of <i>M</i>_n 2000 on their coronas achieved the highest tumor specificity with peak maximum 27% ID/g, a statistically significant propensity toward accumulation with 16.5% ID/g increase from 0 to 72 h of imaging, which constitutes a 1.5-fold increase. Nanogels with greater tumor localization also had greater retention of total body probe over 72 h. Nanogels without extensive PEGylation were rapidly excreted, even at similar sizes to PEGylated nanogels exhibiting whole body retention. Of all tissues, the liver had the highest % ID, however, like other tissues, it displayed a monotonic decrease over time, suggesting nanogel clearance by hepatic metabolism. <i>Ex vivo</i> quantification of individual tissues from gross necropsy at 72 h postinjection generally correlated with the FMT analysis, providing confidence in tissue signal segmentation <i>in vivo</i>. The parameters determined to most significantly direct a nanogel to the desired tumor target can lead to improve effectiveness for nanogels as therapeutic delivery vehicles

Discovery of an Orally Active and Liver-Targeted Prodrug of 5‑Fluoro-2′-Deoxyuridine for the Treatment of Hepatocellular Carcinoma

We report a series of novel O-(substituted benzyl) phosphoramidate prodrugs of 5-fluoro-2′-deoxyuridine for the treatment of hepatocellular carcinoma. Through structure optimization, the <i>o</i>-methylbenzyl analog (<b>1t</b>) was identified as an orally bioavailable and liver-targeted lead compound. This lead prodrug is well-tolerated at a dose up to 3 g/kg in Kuming mice via oral administration. An efficacy study demonstrated that it possesses good inhibitory effect (61.67% and 72.50%, respectively) on tumor growth in a mouse xenograft model. A metabolism study in Sprague–Dawley rats suggested that <b>1t</b> can release the desired 5′-monophosphate in the liver with high liver-targeting index