Redox- and pH-Responsive Water-Soluble Flexible Organic Frameworks Realize Synergistic Tumor Photodynamic and Chemotherapeutic Therapy.

Water-soluble 3D polymers with inherent nanoscale pores have been shown to be ideal platforms for the inclusion and delivery of drugs and hold a great promise as biocompatible materials for diagnostic and therapeutic purposes. Herein, a low cytotoxic water-soluble flexible organic framework FOF-S6 with a hydrodynamic diameter of about 127.5 nm is synthesized through the formation of a hydrazone bond from a semirigid tetraaldehyde and a flexible biacylhydrazines which contains a disulfide bond (1:2). FOF-S6 has the ability to dissociate and release inclusion complexes in response to weakly acidic media and glutathione (GSH) overexpressed in tumor cells. More importantly, a facile strategy is developed to contain and deliver aggregation-induced emission photosensitizers (AIE PS, TBD-DQA-540) and chemotherapeutic drugs (Doxorubicin hydrochloride, DOX). DOX-PS@FOF-S6 is synthesized by a one-pot method, which can realize efficient photo-chemotherapy under the guidance of fluorescence imaging, thereby improving the multidrug resistance of tumor cells and the instability of photosensitizers, so as to improve the tumor treatment efficacy.

Study of Cytotoxicity and Internalization of Redox-Responsive Iron Oxide Nanoparticles on PC-3 and 4T1 Cancer Cell Lines.

Redox-responsive and magnetic nanomaterials are widely used in tumor treatment separately, and while the application of their combined functionalities is perspective, exactly how such synergistic effects can be implemented is still unclear. This report investigates the internalization dynamics of magnetic redox-responsive nanoparticles (MNP-SS) and their cytotoxicity toward PC-3 and 4T1 cell lines. It is shown that MNP-SS synthesized by covalent grafting of polyethylene glycol (PEG) on the magnetic nanoparticle (MNP) surface via SS-bonds lose their colloidal stability and aggregate fully in a solution containing DTT, and partially in conditioned media, whereas the PEGylated MNP (MNP-PEG) without S-S linker control remains stable under the same conditions. Internalized MNP-SS lose the PEG shell more quickly, causing enhanced magnetic core dissolution and thus increased toxicity. This was confirmed by fluorescence microscopy using MNP-SS dual-labeled by Cy3 via labile disulfide, and Cy5 via a rigid linker. The dyes demonstrated a significant difference in fluorescence dynamics and intensity. Additionally, MNP-SS demonstrate quicker cellular uptake compared to MNP-PEG, as confirmed by TEM analysis. The combination of disulfide bonds, leading to faster dissolution of the iron oxide core, and the high-oxidative potential Fe3+ ions can synergically enhance oxidative stress in comparison with more stable coating without SS-bonds in the case of MNP-PEG. It decreases the cancer cell viability, especially for the 4T1, which is known for being sensitive to ferroptosis-triggering factors. In this work, we have shown the effect of redox-responsive grafting of the MNP surface as a key factor affecting MNP-internalization rate and dissolution with the release of iron ions inside cancer cells. This kind of synergistic effect is described for the first time and can be used not only in combination with drug delivery, but also in treatment of tumors responsive to ferroptosis.

Reversible Hydrogel Photopatterning: Spatial and Temporal Control over Gel Mechanical Properties Using Visible Light Photoredox Catalysis.

There is a growing interest in being able to control the mechanical properties of hydrogels for applications in materials, medicine, and biology. Primarily, changes in the hydrogel's physical properties, i.e., stiffness, toughness, etc., are achieved by modulating the network cross-linking chemistry. Common cross-linking strategies rely on (i) irreversible network bond degradation and reformation in response to an external stimulus, (ii) using dynamic covalent chemistry, or (iii) isomerization of integrated functional groups (e.g., azobenzene or spiropyran). Many of these strategies are executed using ultraviolet or visible light since the incident photons serve as an external stimulus that affords spatial and temporal control over the mechanical adaptation process. Here, we describe a different type of hydrogel cross-linking strategy that uses a redox-responsive cross-linker, incorporated in poly(hydroxyethyl acrylate)-based hydrogels at three different weight percent loadings, which consists of two viologen subunits tethered by hexaethylene glycol and capped with styrene groups at each terminus. These dicationic viologen subunits (V2+) can be reduced to their monoradical cations (V•+) through a photoinduced electron transfer (PET) process using a visible light-absorbing photocatalyst (tris(bipyridine)ruthenium(II) dichloride) embedded in the hydrogel, resulting in the intramolecular stacking of viologen radical cations, through radical-radical pairing interactions, while losing two positive charges and the corresponding counteranions from the hydrogel. It is shown how this concerted process ultimately leads to collapse of the hydrogel network and significantly (p < 0.05) increases (by nearly a factor of 2) the soft material's stiffness, tensile strength, and percent elongation at break, all of which is easily reversed via oxidation of the viologen subunits and swelling in water. Application of this reversible PET process was demonstrated by photopatterning the same hydrogel multiple times, where the pattern was "erased" each time by turning off the blue light (∼450 nm) source and allowing for oxidation and reswelling in between patterning steps. The areas of the hydrogel that were masked exhibited lower (by 1-2 kPa) shear storage moduli (G') than the areas that were irradiated for 1.5 h. Moreover, because the viologen subunits in the functional cross-linker are electrochromic, it is possible to visualize the regions of the hydrogel that undergo changes in mechanical properties. This visualization process was illustrated by photopatterning a larger hydrogel (∼9.5 cm on its longest side) with a photomask in the design of an array of stars.