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1. pH and redox triggered doxorubicin release from covalently linked carbon dots conjugates

   https://doi.org/10.1039/D0NR08381J  

   Hettiarachchi, Sajini D.; Kirbas Cilingir, Emel; Maklouf, Heidi; Seven, Elif S.; Paudyal, Suraj; Vanni, Steven; Graham, Regina M.; Leblanc, Roger M. (March 2021, Nanoscale)

   null (Ed.)

   Tumor microenvironment responsive drug delivery systems are potential approaches to reduce the acute toxicity caused by high-dose cancer chemotherapy. Notwithstanding the conventional nano-drug delivery systems, the redox and pH stimuli drug delivery systems are currently gaining attention. Therefore, the current study was designed to compare three different covalent carbon dots (C-dots) systems based on doxorubicin (dox) release profiles and cancer cell viability efficacy under acidic and physiological conditions. The C-dots nanosystems that were examined in this study are directly conjugated (C-dots-dox), pH triggered (C-dots-HBA-dox), and the redox stimuli (C-dots-S–S-dox) conjugates. The drug loading content (DLC%) of the C-dots-S–S-dox, C-dots-HBA-dox, and C-dots-dox was 34.2 ± 0.4, 60.0 ± 0.3, and 70.0 ± 0.2%, respectively, that examined by UV-vis spectral analysis. The dox release paradigms were emphasized that all three conjugates were promisingly released the dox from C-dots faster in acidic pH than in physiological pH. The displayed highest dox released percentage in the acidic medium was 74.6 ± 0.8% obtained by the pH stimuli, C-dots-HBA-dox conjugate. When introducing the redox inducer, dithiothreitol (DTT), preferentially, the redox stimuli C-dot-S–S-dox conjugate demonstrated a faster dox release at acidic pH than in the pH 7.4. The SJGBM2 cell viability experiments revealed that the pH stimuli, C-dots-HBA-dox conjugate, displayed a significant cell viability drop in the artificially acidified pH 6.4 medium. However, in the physiological pH, the redox stimuli, C-dots-S–S-dox conjugate, was promising over the pH stimuli C-dots-HBA-dox, exhibiting cell viability of 60%, though its’ efficacy dropped slightly in the artificially acidified pH 6.4 medium. Moreover, the current study illustrates the stimuli conjugates’ remarkable efficacy on sustain drug release than direct amide linkage. 

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2. Two-Dimensional and Three-Dimensional Ultrathin Multilayer Hydrogels through Layer-by-Layer Assembly

   https://doi.org/10.1021/acs.langmuir.2c00630  

   Kozlovskaya, Veronika; Dolmat, Maksim; Kharlampieva, Eugenia (January 2022, Langmuir)

   Stimuli-responsive multilayer hydrogels have opened new opportunities to design hierarchically organized networks with properties controlled at the nanoscale. These multilayer materials integrate structural, morphological, and compositional versatility provided by alternating layer-bylayer polymer deposition with the capability for dramatic and reversible changes in volumes upon environmental triggers, a characteristic of chemically crosslinked responsive networks. Despite their intriguing potential, there has been limited knowledge about the structure−property relationships of multilayer hydrogels, partly because of the challenges in regulating network structural organization and the limited set of the instrumental pool to resolve structure and properties at nanometer spatial resolution. This Feature Article highlights our recent studies on advancing assembly technologies, fundamentals, and applications of multilayer hydrogels. The fundamental relationships among synthetic strategies, chemical compositions, and hydrogel architectures are discussed, and their impacts on stimuli-induced volume changes, morphology, and mechanical responses are presented. We present an overview of our studies on thin multilayer hydrogel coatings, focusing on controlling and quantifying the degree of layer intermixing, which are crucial issues in the design of hydrogels with predictable properties. We also uncover the behavior of stratified “multicompartment” hydrogels in response to changes in pH and temperature. We summarize the mechanical responses of free-standing multilayer hydrogels, including planar thin coatings and films with closed geometries such as hollow microcapsules and nonhollow hydrogel microparticles with spherical and nonspherical shapes. Finally, we will showcase potential applications of pH- and temperature-sensitive multilayer hydrogels in sensing and drug delivery. The knowledge about multilayer hydrogels can advance the rational design of polymer networks with predictable and well-tunable properties, contributing to modern polymer science and broadening hydrogel applications. 

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3. Self-strengthening stimuli-responsive nanocomposite hydrogels

   https://doi.org/10.1039/D2NR05408F  

   Howard, Elizabeth; Li, Minghao; Kozma, Michael; Zhao, Jiayu; Bae, Jinhye (December 2022, Nanoscale)

   Stimuli-responsive hydrogels with self-strengthening properties are promising for the use of autonomous growth and adaptation systems to the surrounding environments by mimicking biological materials. However, conventional stimuli-responsive hydrogels require structural destruction to initiate mechanochemical reactions to grow new polymeric networks and strengthen themselves. Here we report continuous self-strengthening of a nanocomposite hydrogel composed of poly( N -isopropylacrylamide) (PNIPAM) and nanoclay (NC) by using external stimuli such as heat and ionic strength. The internal structures of the NC-PNIPAM hydrogel are rearranged through the swelling–deswelling cycles or immersing in a salt solution, thus its mechanical properties are significantly improved. The effects of concentration of NC in hydrogels, number of swelling–deswelling cycles, and presence of salt in the surrounding environment on the mechanical properties of hydrogels are characterized by nanoindentation and tensile tests. The self-strengthening mechanical performance of the hydrogels is demonstrated by the loading ability. This work may offer promise for applications such as artificial muscles and soft robotics. 

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4. Free-Standing Thin Hydrogels: Effects of Composition and pH-Dependent Hydration on Mechanical Properties

   https://doi.org/10.1021/acsapm.1c00511  

   M. Dolmat, V. Kozlovskaya (January 2021, ACS applied polymer materials)

   We developed an approach to obtain nanothin freefloating poly(methacrylic acid) (PMAA) hydrogel films through the dissolution of a sacrificial SiO2 layer. The hydrogel films were produced by chemical crosslinking of PMAA in PMAA/poly(Nvinylpyrrolidone) (PVPON) hydrogen-bonded precursors assembled through spin-assisted (SA) multilayer assembly. Surfaceanchored precursor films and hydrogels were released from silicon templates into an aqueous solution via etching the thick sacrificial SiO2 layer from the templates. We studied the impact of the release method on the surface morphology, thickness, and elasticity of the released (PMAA/PVPON)60 and (PMAA)60 films using atomic force microscopy (AFM) and demonstrated that these properties were affected neither by the film release nor by their following transfer onto Si wafers. We found that 16 h crosslinked (PMAA)60 hydrogels and their more swollen 8 h crosslinked counterparts (76% hydration at pH = 5) produced free-floating films with good mechanical integrity and strength. The elastic moduli of a 16 h crosslinked (PMAA)60 film decreased from 1.9 ± 0.1 GPa in the dry state to 77 ± 13 MPa at pH = 5 and then to 14 ± 3 MPa at pH = 6.5. We also showed that incorporating Zr(IV) into twice thinner (PMAA)30 hydrogels (∼60 nm dry thickness) improved film mechanical robustness and allowed their successful release and transfer onto Si wafers. In contrast, Zr-free (PMAA)30 were less tolerant to the release/transfer procedure due to mechanical fragility. The temporary coordination links between Zr(IV) and the hydrogel could be removed from the network by an EDTA chelator. The lift-off approach developed here is simple, versatile, and applicable to a wide range of polymer films. The free-floating hydrogels obtained by this method can be used as transferrable platforms to develop lab-on-a-chip systems, nanocomposite pressure sensing platforms, rapid optical biosensors, and responsive platforms for regulating cell adhesion and more effective cell sheet recoveries. 

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5. Encapsulation and Ultrasound-Triggered Release of G-Quadruplex DNA in Multilayer Hydrogel Microcapsules

   https://doi.org/10.3390/polym10121342  

   Alford, Aaron; Tucker, Brenna; Kozlovskaya, Veronika; Chen, Jun; Gupta, Nirzari; Caviedes, Racquel; Gearhart, Jenna; Graves, David; Kharlampieva, Eugenia (December 2018, Polymers)

   Nucleic acid therapeutics have the potential to be the most effective disease treatment strategy due to their intrinsic precision and selectivity for coding highly specific biological processes. However, freely administered nucleic acids of any type are quickly destroyed or rendered inert by a host of defense mechanisms in the body. In this work, we address the challenge of using nucleic acids as drugs by preparing stimuli responsive poly(methacrylic acid)/poly(N-vinylpyrrolidone) (PMAA/PVPON)n multilayer hydrogel capsules loaded with ~7 kDa G-quadruplex DNA. The capsules are shown to release their DNA cargo on demand in response to both enzymatic and ultrasound (US)-triggered degradation. The unique structure adopted by the G-quadruplex is essential to its biological function and we show that the controlled release from the microcapsules preserves the basket conformation of the oligonucleotide used in our studies. We also show that the (PMAA/PVPON) multilayer hydrogel capsules can encapsulate and release ~450 kDa double stranded DNA. The encapsulation and release approaches for both oligonucleotides in multilayer hydrogel microcapsules developed here can be applied to create methodologies for new therapeutic strategies involving the controlled delivery of sensitive biomolecules. Our study provides a promising methodology for the design of effective carriers for DNA vaccines and medicines for a wide range of immunotherapies, cancer therapy and/or tissue regeneration therapies in the future. 

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