Polymer-nucleobase composites for chemotherapy drug capture.

Intravenous chemotherapy (e.g., doxorubicin (DOX)) is standard treatment for many cancers but also leads to side effects due to off-target toxicity. To address this challenge, devices for removing off-target chemotherapy agents from the bloodstream have been developed, but the efficacy of such devices relies on the ability of the underlying materials to specifically sequester small-molecule drugs. Anion-exchange materials, genomic DNA, and DNA-functionalized iron oxide particles have all been explored as drug-capture materials, but cost, specificity, batch-to-batch variation, and immunogenicity concerns persist as challenges. Here, we report a new class of fully synthetic drug-capture materials. We copolymerized methacrylic acid and ethylene glycol dimethacrylate in the presence of several nucleobases and derivatives (adenine, cytosine, xanthine, and thymine) to yield a crosslinked resin with nucleobases integrated into the material. These materials demonstrated effective DOX capture: up to 27 mg of DOX per g of material over 20 minutes from a phosphate-buffered saline solution with an initial concentration of 0.05 mg mL-1 of DOX. These materials use only the individual nucleobases for DOX capture and exhibit competitive capture efficacy compared to previous materials that used genomic DNA, making this approach more cost-effective and reducing potential immunological concerns.

Enzyme-Triggered Chemodynamic Therapy via a Peptide-H2 S Donor Conjugate with Complexed Fe2.

Inducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe2+ , CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide-H2 S donor conjugate, complexed with Fe2+ , termed AAN-PTC-Fe2+ . The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H2 S, an inhibitor of catalase, an enzyme that detoxifies H2 O2 . Fe2+ and H2 S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe2+ , the AAN sequence, or the ability to generate H2 S. AAN-PTC-Fe2+ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H2 S-amplified, enzyme-responsive platform for synergistic cancer treatment.

Characterizing Ion-Polymer Interactions in Aqueous Environment with Electric Fields.

Polymers make the basis of highly tunable materials that could be designed and optimized for metal recovery from aqueous environments. While experimental studies show that this approach has potential, it suffers from a limited knowledge of the detailed molecular interaction between polymers and target metal ions. Here, we propose to calculate intrinsic electric fields from polarizable force field molecular dynamics simulations to characterize the driving force behind Eu3+ motion in the presence of poly(ethylenimine methylenephosphonate), a specifically designed metal chelating polymer. Focusing on the metal chelation initiation step (i.e., before binding), we can rationalize the role of each molecule on ion dynamics by projecting these electric fields along the direction of ion motion. We find that the polymer functional groups act indirectly, and the polymer-metal ion interaction is actually mediated by water. This result is consistent with the experimental observation that metal sequestration by these polymers is entropically driven. This study suggests that electric field calculations can help the design of metal chelating polymers, for example, by seeking to optimize polymer-solvent interactions rather than polymer-ion interactions.

Exploring the role of polymer hydrophobicity in polymer-metal binding thermodynamics.

Metal-chelating polymers play a key role in rare-earth element (REE) extraction and separation processes. Often, these processes occur in aqueous solution, but the interactions among water, polymer, and REE are largely under-investigated in these applications. To probe these interactions, we synthesized a series of poly(amino acid acrylamide)s with systematically varied hydrophobicity around a consistent chelating group (carboxylate). We then measured the ΔH of Eu3+ chelation as a function of temperature across the polymer series using isothermal titration calorimetry (ITC) to give the change in heat capacity (ΔCP). We observed an order of magnitude variation in ΔCP (39-471 J mol1 K-1) with changes in the hydrophobicity of the polymer. Atomistic simulations of the polymer-metal-water interactions revealed greater Eu3+ and polymer desolvation when binding to the more hydrophobic polymers. These combined experimental and computational results demonstrate that metal binding in aqueous solution can be modulated not only by directly modifying the chelating groups, but also by altering the molecular environment around the chelating site, thus suggesting a new design principle for developing increasingly effective metal-chelating materials.

Effect of Copolymer Structure on Rare-Earth-Element Chelation Thermodynamics.

Rare-earth elements (REEs) are crucial to modern technology, leading to a high demand for materials capable of REE extraction and purification. Metal-chelating polymers (e.g., polycarboxylic acids, polyamines, and others) are particularly useful in these applications due to their synthetic accessibility and high selectivity. Copolymers with varied mole fractions of acrylic acid and methyl acrylate are synthesized and isothermal titration calorimetry (ITC) to measure the thermodynamics of REE binding for each material is used. Across a series of copolymer compositions, entropically driven binding thermodynamics (∆G, ∆H, and ∆S) that appear to be independent of χAcrylic Acid  are found. ITC stoichiometry data reveal that each copolymer requires between four and five repeat units to bind each REE. These data suggest that alterations in the copolymer structure do not affect the overall binding thermodynamics of REEs to these copolymers.

Biodegradable Poly(Lactic Acid) Nanocomposites for Fused Deposition Modeling 3D Printing.

3D printing by fused deposition modelling (FDM) enables rapid prototyping and fabrication of parts with complex geometries. Unfortunately, most materials suitable for FDM 3D printing are non-degradable, petroleum-based polymers. The current ecological crisis caused by plastic waste has produced great interest in biodegradable materials for many applications, including 3D printing. Poly(lactic acid) (PLA), in particular, has been extensively investigated for FDM applications. However, most biodegradable polymers, including PLA, have insufficient mechanical properties for many applications. One approach to overcoming this challenge is to introduce additives that enhance the mechanical properties of PLA while maintaining FDM 3D printability. This review focuses on PLA-based nanocomposites with cellulose, metal-based nanoparticles, continuous fibers, carbon-based nanoparticles, or other additives. These additives impact both the physical properties and printability of the resulting nanocomposites. We also detail the optimal conditions for using these materials in FDM 3D printing. These approaches demonstrate the promise of developing nanocomposites that are both biodegradable and mechanically robust.

Isothermal titration calorimetry: practical approaches and current applications in soft matter.

Isothermal Titration Calorimetry (ITC) elucidates the thermodynamic profile (ΔH, ΔS, ΔG, Ka, and stoichiometry) of binding and dissociation reactions in solution. While ITC has primarily been used to investigate the thermodynamics of interactions between biological macromolecules and small molecules, it has become increasingly common for measuring binding interactions between synthetic polymers and small molecules, ions, or nanoparticles. This tutorial review describes applications of ITC in studying synthetic macromolecules and provides experimental guidelines for performing ITC experiments. We also highlight specific examples of using ITC to study soft matter, then discuss the limitations and the future of ITC in this field.

Bulk and surface structural changes in high nickel cathodes subjected to fast charging conditions.

A layered oxide cathode, LiNi0.6Mn0.2Co0.2O2, undergoes noticeable crystal expansion by losing significantly higher amounts of Li+ at the end of fast charging cycles. However, the bulk structure of the cycled NMC622 is restored back to its pristine discharged state when intercalated with enough lithium ions during an electrochemical process.

Drug capture materials based on genomic DNA-functionalized magnetic nanoparticles.

Chemotherapy agents are notorious for producing severe side-effects. One approach to mitigating this off-target damage is to deliver the chemotherapy directly to a tumor via transarterial infusion, or similar procedures, and then sequestering any chemotherapeutic in the veins draining the target organ before it enters the systemic circulation. Materials capable of such drug capture are yet to be fully realized. Here, we report the covalent attachment of genomic DNA to iron-oxide nanoparticles. With these magnetic materials, we captured three common chemotherapy agents-doxorubicin, cisplatin, and epirubicin-from biological solutions. We achieved 98% capture of doxorubicin from human serum in 10 min. We further demonstrate that DNA-coated particles can rescue cultured cardiac myoblasts from lethal levels of doxorubicin. Finally, the in vivo efficacy of these materials was demonstrated in a porcine model. The efficacy of these materials demonstrates the viability of genomic DNA-coated materials as substrates for drug capture applications.

Functionalized 3D Architected Materials via Thiol-Michael Addition and Two-Photon Lithography.

Fabrication of functionalized 3D architected materials is achieved by a facile method using functionalized acrylates synthesized via thiol-Michael addition, which are then polymerized using two-photon lithography. A wide variety of functional groups can be attached, from Boc-protected amines to fluoroalkanes. Modification of surface wetting properties and conjugation with fluorescent tags are demonstrated to highlight the potential applications of this technique.

Application of Ionic Liquids in Pot-in-Pot Reactions.

Pot-in-pot reactions are designed such that two reaction media (solvents, catalysts and reagents) are isolated from each other by a polymeric membrane similar to matryoshka dolls (Russian nesting dolls). The first reaction is allowed to progress to completion before triggering the second reaction in which all necessary solvents, reactants, or catalysts are placed except for the starting reagent for the target reaction. With the appropriate trigger, in most cases unidirectional flux, the product of the first reaction is introduced to the second medium allowing a second transformation in the same glass reaction pot--albeit separated by a polymeric membrane. The basis of these reaction systems is the controlled selective flux of one reagent over the other components of the first reaction while maintaining steady-state catalyst concentration in the first "pot". The use of ionic liquids as tools to control chemical potential across the polymeric membranes making the first pot is discussed based on standard diffusion models--Fickian and Payne's models. Besides chemical potential, use of ionic liquids as delivery agent for a small amount of a solvent that slightly swells the polymeric membrane, hence increasing flux, is highlighted. This review highlights the critical role ionic liquids play in site-isolation of multiple catalyzed reactions in a standard pot-in-pot reaction.

Aminobisphosphonate Polymers via RAFT and a Multicomponent Kabachnik-Fields Reaction.

Polyacrylamides containing pendant aminobisphosphonate groups are synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization and a multicomponent postpolymerization functionalization reaction. A Moedritzer-Irani reaction installs the phosphonic acid groups on well-defined, RAFT-generated polymers bearing a pendant amine. An alternate route to the same materials is developed utilizing a three-component Kabachnik-Fields reaction and subsequent dealkylation. Kinetics of the RAFT polymerization of the polymer precursor are studied. Successful functionalization is demonstrated by NMR and FTIR spectroscopy and elemental analysis of the final polymers.

Synthesis of polymeric phosphonates for selective delivery of radionuclides to osteosarcoma.

Discussed in detail is the synthesis and primary structure characterization of two polymers aimed at advancing the treatment of pediatric osteosarcoma. These polymers are designed to systemically deliver radiometals specifically to osteosarcomas using the passive targeting mechanism of enhanced permeability and retention (the EPR effect). The approach begins with the synthesis of a polymer capable of binding radiometals, for which prior data show improved site-specific targeting of solid tumors. Building on this success, a second polymer has been designed for improving the efficacy of currently available radionuclide therapies by incorporating the FDA-approved small-molecule ligand Quadramet directly onto the polymer structure. Time-activity curves of the phosphonate-functionalized polymers show rapid clearance from the central compartment and nontargeted organs, with up to 65% of injected activity being excreted within 3 hours. Both polymer ligands demonstrate good osteosarcoma targeting capability with little to no uptake in organs associated with the dose-limiting bone marrow. Additionally, biodistribution studies in nonosseous tumor models demonstrate the tumor targeting mechanism of the polymer ligands, which appears to be influenced by the high affinity of the phosphonate functionality for the positively charged hydroxyapatite mineral found in bone tumors.

Replacing -CH2CH2- with -CONH- does not significantly change rates of charge transport through Ag(TS)-SAM//Ga2O3/EGaIn junctions.

This paper describes physical-organic studies of charge transport by tunneling through self-assembled monolayers (SAMs), based on systematic variations of the structure of the molecules constituting the SAM. Replacing a -CH(2)CH(2)- group with a -CONH- group changes the dipole moment and polarizability of a portion of the molecule and has, in principle, the potential to change the rate of charge transport through the SAM. In practice, this substitution produces no significant change in the rate of charge transport across junctions of the structure Ag(TS)-S(CH(2))(m)X(CH(2))(n)H//Ga(2)O(3)/EGaIn (TS = template stripped, X = -CH(2)CH(2)- or -CONH-, and EGaIn = eutectic alloy of gallium and indium). Incorporation of the amide group does, however, increase the yields of working (non-shorting) junctions (when compared to n-alkanethiolates of the same length). These results suggest that synthetic schemes that combine a thiol group on one end of a molecule with a group, R, to be tested, on the other (e.g., HS~CONH~R) using an amide-based coupling provide practical routes to molecules useful in studies of molecular electronics.

Solvent Effects in Alternating ADMET Polymerization.

Alternating AB copolymers were synthesized by exploiting the selectivity of the metathesis reaction between α,ω-dienes and α,ω-diacrylates. Unlike standard acyclic diene metathesis (ADMET) polymerizations, the copolymerization of dienes and diacrylates does not require high vacuum conditions. This work utilizes this unique characteristic to explore the effect of various solvents on ADMET polymerization. We found significant variation in the efficacy of the solvents we screened, with CH2Cl2 yielding the highest molecular weight polymer. Additionally, the performance of Grubbs second generation catalyst was compared with Hoveyda-Grubbs second generation catalyst in different solvents, revealing a stark difference in the molecular weight of the resulting polymers in CH2Cl2 but a relatively minor difference in the final molecular weight from polymerizations in acetic acid.

Odd-even effects in charge transport across self-assembled monolayers.

This paper compares charge transport across self-assembled monolayers (SAMs) of n-alkanethiols containing odd and even numbers of methylenes. Ultraflat template-stripped silver (Ag(TS)) surfaces support the SAMs, while top electrodes of eutectic gallium-indium (EGaIn) contact the SAMs to form metal/SAM//oxide/EGaIn junctions. The EGaIn spontaneously reacts with ambient oxygen to form a thin (∼1 nm) oxide layer. This oxide layer enables EGaIn to maintain a stable, conical shape (convenient for forming microcontacts to SAMs) while retaining the ability to deform and flow upon contacting a hard surface. Conical electrodes of EGaIn conform (at least partially) to SAMs and generate high yields of working junctions. Ga(2)O(3)/EGaIn top electrodes enable the collection of statistically significant numbers of data in convenient periods of time. The observed difference in charge transport between n-alkanethiols with odd and even numbers of methylenes--the "odd-even effect"--is statistically discernible using these junctions and demonstrates that this technique is sensitive to small differences in the structure and properties of the SAM. Alkanethiols with an even number of methylenes exhibit the expected exponential decrease in current density, J, with increasing chain length, as do alkanethiols with an odd number of methylenes. This trend disappears, however, when the two data sets are analyzed together: alkanethiols with an even number of methylenes typically show higher J than homologous alkanethiols with an odd number of methylenes. The precision of the present measurements and the statistical power of the present analysis are only sufficient to identify, with statistical confidence, the difference between an odd and even number of methylenes with respect to J, but not with respect to the tunneling decay constant, ß, or the pre-exponential factor, J(0). This paper includes a discussion of the possible origins of the odd-even effect but does not endorse a single explanation.

Sequential reactions with Grubbs catalyst and AD-mix-alpha/beta using PDMS thimbles.

Incompatible Grubbs catalyst and an osmium dihydroxylation catalyst were site-isolated from each other using polydimethylsiloxane thimbles. The Grubbs catalyst was added to the interior of the thimbles, and AD-mix-alpha/beta was added to the exterior. Organic substrates readily fluxed through the walls of the thimbles and reacted with each catalyst. A series of cascade reactions were developed including those with intermediates possessing low boiling points or that were foul smelling.

A materials approach to site-isolation of Grubbs catalysts from incompatible solvents and m-chloroperoxybenzoic acid.

The development of a method for site-isolation of Grubbs second-generation catalyst from MCPBA is described. In these reactions, Grubbs catalyst was dissolved in a solvent consisting of a mixture (1:1 v/v) of 1-butyl-3-methylimidazolium hexafluorophosphate and methylene chloride and completely encapsulated within a thimble fabricated from polydimethylsiloxane (PDMS). A series of molecules that react by cross metathesis or ring-closing metathesis were added to the interior of the thimble and allowed to react. In the last step, m-chloroperoxybenzoic acid (MCPBA) dissolved in MeOH/H(2)O (1:1 v/v) was added to the exterior of the PDMS thimble. Small organic molecules diffused through the PDMS to react with MCPBA to form epoxides, but the Grubbs catalyst remained encapsulated. This result is important because Grubbs catalyst catalytically decomposes MCPBA at ratios of MCPBA to Grubbs of 3000 to 1. The yields for this two-step cascade sequence ranged from 67 to 83 %. The concept behind this sequence is that small organic molecules have high flux through PDMS but large molecules--such as Grubbs catalyst--and ionic reagents--such as MCPBA--have much lower flux through PDMS. Small molecules can thus react both outside and inside PDMS thimbles, whereas incompatible catalysts and reagents remain site-isolated from each other. This method does not require alteration of structures of the catalysts or reagents, so it may be applied to a wide range of homogeneous catalysts and reagents. To demonstrate further that the catalyst was encapsulated, the Grubbs catalyst was successfully recycled within the cascade sequence.