-
Accounts of Chemical Research Jun 2019Electronic transistors have revolutionized the fields of microelectronics, computers, and mobile devices. Their ability to digitize electronic signals allows high... (Review)
Review
Electronic transistors have revolutionized the fields of microelectronics, computers, and mobile devices. Their ability to digitize electronic signals allows high fidelity data transfer as well as formation of logic gates. Inspired by electronic transistors, transistor-like organic materials have been under intensive investigation to amplify biological signals in a broad range of applications such as biosensing, diagnostic imaging, and therapeutic delivery. This Account highlights the inception and implementation of a "proton transistor" nanoparticle that can digitize acidotic pH signals in biological systems. Similar to electronic transistors, the ultra-pH-sensitive (UPS) nanoparticles derive their binary threshold response from phase separation phenomena. Hydrophobic micellization drives nanophase separation from unimers to aggregated polymeric micelles, which is responsible for the all-or-nothing proton distribution between the micelle and unimer states. Depending on the assembly status, conjugated fluorophores are quenched (micelle state) or freely fluoresce (solution unimer state) allowing robust detection of the phase transition behavior across a narrow pH range. Based on this mechanistic insight, we created a UPS nanoparticle library encompassing a broad physiological pH range from 4.0 to 7.4. For biological applications, we engineered a barcode-like nanosensor capable of digitizing multiple pH signals at a single organelle resolution in live cells. The barcode system allowed easy identification of mutant Kirsten rat sarcoma viral oncogene (KRAS), a common mutation involved in tumorigenesis, which leads to rapid cellular proliferation, as the protein driver for accelerated organelle acidification and lysosome catabolism in a broad set of isogenic as well as heterogeneous cancer cell lines. Adoption of the technology to an ON-OFF/Always-ON design allowed the quantification of proton flux across the membranes of endocytic organelles. For medical applications, we demonstrate the ability to achieve binary detection of solid cancers with clear tumor margin delineation by near-infrared fluorescence imaging. Image-guided resection of head/neck and breast tumors resulted in significantly improved long-term survival over white light or tumor debulking surgeries in tumor-bearing mice, catapulting the clinical evaluation of the UPS nanosensor in cancer patients. This Account serves as the first comprehensive summary of the molecular mechanism and biological applications of the digital pH threshold sensors. Building on the concept of cooperative phase transition behavior, we hope this Account will promote the rational design and development of additional transistor-like chemical sensors to digitize analog biological signals.
Topics: Animals; Fluorescence; Fluorescent Dyes; Fluorometry; HeLa Cells; Humans; Hydrogen-Ion Concentration; Micelles; Nanoparticles; Neoplasms; Organelles; Phase Transition; Polymers
PubMed: 31067025
DOI: 10.1021/acs.accounts.9b00080 -
Igaku Butsuri : Nihon Igaku Butsuri... 2017Radiochromic hydrogel dosimeters are a useful tool for the verification of 3D dose distributions using optical CT scanners which are lower cost and with higher spatial...
Radiochromic hydrogel dosimeters are a useful tool for the verification of 3D dose distributions using optical CT scanners which are lower cost and with higher spatial resolution in a limited time than MRI scanners. In this paper, recent development of radiochromic micelle gel and genipin-gelatin gel dosimeters are described. They have the advantage of water equivalency, low or no diffusion property, and lower toxicity. Micelle gels consist of leuco dye, surfactant, radical initiator (halocarbons), and gelling agent. The dose sensitivities are affected by the concentration of each component and the temperature during irradiation. In non-diffusing genipin-gelatin gels, radiation induced bleaching is observed. The dose sensitivity is strongly affected by the concentration of genipin and sulfuric acid and by the blending time with gelatin. Higher dose sensitivity and standardization of the dose evaluation procedure will be the future issue.
Topics: Gels; Hydrogels; Micelles; Radiation Dosimeters; Radiometry; Tomography Scanners, X-Ray Computed
PubMed: 29151471
DOI: 10.11323/jjmp.37.2_95 -
Advances in Colloid and Interface... Oct 2022Although the anionic surfactant sodium dodecyl sulfate, SDS, has been used for more than half a century as a versatile and efficient protein denaturant for protein... (Review)
Review
Although the anionic surfactant sodium dodecyl sulfate, SDS, has been used for more than half a century as a versatile and efficient protein denaturant for protein separation and size estimation, there is still controversy about its mode of interaction with proteins. The term "rod-like" structures for the complexes that form between SDS and protein, originally introduced by Tanford, is not sufficiently descriptive and does not distinguish between the two current vying models, namely protein-decorated micelles a.k.a. the core-shell model (in which denatured protein covers the surface of micelles) versus beads-on-a-string model (where unfolded proteins are surrounded by surfactant micelles). Thanks to a combination of structural, kinetic and computational work particularly within the last 5-10 years, it is now possible to rule decisively in favor of the core-shell model. This is supported unambiguously by a combination of calorimetric and small-angle X-ray scattering (SAXS) techniques and confirmed by increasingly sophisticated molecular dynamics simulations. Depending on the SDS:protein ratio and the protein molecular mass, the formed structures can range from multiple partly unfolded protein molecules surrounding a single shared micelle to a single polypeptide chain decorating multiple micelles. We also have much new insight into how this species forms. It is preceded by the binding of small numbers of SDS molecules which subsequently grow by accretion. Time-resolved SAXS analysis reveals an asymmetric attack by SDS micelles followed by distribution of the increasingly unfolded protein around the micelle. The compactness of the protein chain continues to evolve at higher SDS concentrations according to single-molecule studies, though the protein remains completely denatured on the tertiary structural level. SDS denaturation can be reversed by addition of nonionic surfactants that absorb SDS forming mixed micelles, leaving the protein free to refold. Refolding can occur in parallel tracks if only a fraction of the protein is initially stripped of SDS. SDS unfolding is nearly always reversible unless carried out at low pH, where charge neutralization can lead to superclusters of protein-surfactant complexes. With the general mechanism of SDS denaturation now firmly established, it largely remains to explore how other ionic surfactants (including biosurfactants) may diverge from this path.
Topics: Micelles; Proteins; Scattering, Small Angle; Sodium Dodecyl Sulfate; Surface-Active Agents; X-Ray Diffraction
PubMed: 36027673
DOI: 10.1016/j.cis.2022.102754 -
Journal of Hazardous Materials Apr 20222,3,3,3-tetrafluoro-2-(heptafluoropropoxy) propanoate, a.k.a. "GenX", is a surfactant introduced as a safer alternative to replace perfluorooctanoate (PFOA) in the...
2,3,3,3-tetrafluoro-2-(heptafluoropropoxy) propanoate, a.k.a. "GenX", is a surfactant introduced as a safer alternative to replace perfluorooctanoate (PFOA) in the manufacturing of fluorinated polymers, however, GenX is shown to cause adverse health effects similar to, or even worse than, those of the legacy PFOA. With an overarching goal to understand the behavior of GenX molecules in aqueous media, we report here on GenX micelle formation and structure in aqueous solutions, on the basis of results obtained from a combination of experimental techniques such as surface tension, fluorescence, viscosity, and small-angle neutron scattering (SANS), and molecular dynamics (MD) simulations. To our best knowledge, this is the first report on GenX micelles. The critical micelle concentration (CMC) of GenX ammonium salt in water is 175 mM. GenX forms small micelles with association number 6-8 and 10 Å radius. GenX molecules prefer to align along the micelle surface, and the ether oxygen of GenX has very little interaction with and exposure to water. Information on the surfactant and interfacial properties of GenX is crucial, since such properties are manifestations of interactions between GenX molecules and between GenX and water molecules and, in turn, the amphiphilic character of GenX dictates its fate and transport in the aqueous environment, its interactions with various biomolecules, and its binding to adsorbent materials.
Topics: Micelles; Surface Tension; Surface-Active Agents; Water; Water Pollutants, Chemical
PubMed: 35016121
DOI: 10.1016/j.jhazmat.2021.128137 -
International Journal of Molecular... Feb 2022The use of surfactants in polymerization reactions is particularly important, mainly in emulsion polymerizations. Further, micelles from biocompatible surfactants find... (Review)
Review
The use of surfactants in polymerization reactions is particularly important, mainly in emulsion polymerizations. Further, micelles from biocompatible surfactants find use in pharmaceutical dosage forms. This paper reviews recent developments in the synthesis of novel gemini and bicephalous surfactants, micelle formation, and their applications in polymer and nanoparticle synthesis, oil recovery, catalysis, corrosion, protein binding, and biomedical area, particularly in drug delivery.
Topics: Micelles; Polymerization; Polymers; Surface-Active Agents
PubMed: 35163721
DOI: 10.3390/ijms23031798 -
Molecules (Basel, Switzerland) Nov 2022An amine-terminated polyamidoamine (PAMAM) dendron and two long alkyl groups were designed as a novel drug carrier that possesses an interior for the encapsulation of...
An amine-terminated polyamidoamine (PAMAM) dendron and two long alkyl groups were designed as a novel drug carrier that possesses an interior for the encapsulation of drugs and a biocompatible surface. We synthesized three dendron-bearing lipids, DL-G1, DL-G2, and DL-G3, which included first, second, and third generation polyamidoamine dendrons, respectively. The synthesized dendrimer encapsulating anticancer drug, 5-fluorouracil (5-FU), was prepared by extraction with chloroform from mixtures of the dendrimers and varying amounts of the drug. In vitro cytotoxicity of PAMAM conjugated di-n-dodecylamine micelles (G1, G2, G3) were analyzed on human gastric adenocarcinoma cells (AGS) by water-soluble tetrazolium-1 (WST-1) cell proliferation assay. Upon exposure to 5-FU loaded micelles, the viability of the cells decreased gradually in all generations. Cytotoxicity increased with increasing generation and reached its highest rate of 69.8 ± 3.2% upon 15 µM 5FU-loaded 25 µM PAMAM DL-3 micelle treatment. These results demonstrate that 5FU-loaded PAMAM conjugated di-n-dodecylamine treatment inhibits the proliferation of AGS cells in a generation-dependent manner.
Topics: Humans; Dendrimers; Excipients; Micelles; Lipids; Fluorouracil
PubMed: 36431916
DOI: 10.3390/molecules27227817 -
ACS Macro Letters Apr 2022Bottlebrush polymers are characterized by an expansive parameter space, including graft length and spacing along the backbone, and these features impact various...
Bottlebrush polymers are characterized by an expansive parameter space, including graft length and spacing along the backbone, and these features impact various structural and physical properties such as molecular diffusion and bulk viscosity. In this work, we report a synthetic strategy for making grafted block polymers with poly(propylene oxide) and poly(ethylene oxide) side chains, bottlebrush analogues of poloxamers. Combined anionic and sequential ring-opening metathesis polymerization yielded low dispersity polymers, at full conversion of the macromonomers, with control over graft length, graft end-groups, and overall molecular weight. A set of bottlebrush poloxamers (BBPs), with identical graft lengths and composition, was synthesized over a range of molecular weights. Dynamic light scattering and transmission electron microscopy were used to characterize micelle formation in aqueous buffer. The critical micelle concentration scales exponentially with overall molecular weight for both linear and bottlebrush poloxamers; however, the bottlebrush architecture shifts micelle formation to a much higher concentration at a comparable molecular weight. Consequently, BBPs can exist in solution as unimers at significantly higher molecular weights and concentrations than the linear analogues.
Topics: Micelles; Molecular Weight; Poloxamer; Polymerization; Polymers
PubMed: 35575325
DOI: 10.1021/acsmacrolett.2c00053 -
Macromolecular Bioscience Jan 2017Polymeric micelles (PM) have been extensively used for tumor-targeted delivery of hydrophobic anti-cancer drugs. The lipophilic core of PM is naturally suitable for... (Review)
Review
Polymeric micelles (PM) have been extensively used for tumor-targeted delivery of hydrophobic anti-cancer drugs. The lipophilic core of PM is naturally suitable for loading hydrophobic drugs and the hydrophilic shell endows them with colloidal stability and stealth properties. Decades of research on PM have resulted in tremendous numbers of PM-forming amphiphilic polymers, and approximately a dozen micellar nanomedicines have entered the clinic. The first generation of PM can be considered solubilizers of hydrophobic drugs, with short circulation times resulting from poor micelle stability and unstable drug entrapment. To more optimally exploit the potential of PM for targeted drug delivery, several physical (e.g., π-π stacking, stereocomplexation, hydrogen bonding, host-guest complexation, and coordination interaction) and chemical (e.g., free radical polymerization, click chemistry, disulfide and hydrazone bonding) strategies have been developed to improve micelle stability and drug retention. In this review, the most promising physico-chemical approaches to enhance micelle stability and drug retention are described, and how these strategies have resulted in systems with promising therapeutic efficacy in animal models, paving the way for clinical translation, is summarized.
Topics: Chemical Phenomena; Drug Delivery Systems; Micelles; Neoplasms; Pharmaceutical Preparations; Polymers
PubMed: 27413999
DOI: 10.1002/mabi.201600160 -
Biophysical Journal Jun 2021To understand the transition from inanimate matter to life, we studied a process that directly couples simple metabolism to evolution via natural selection, demonstrated...
To understand the transition from inanimate matter to life, we studied a process that directly couples simple metabolism to evolution via natural selection, demonstrated experimentally by Adamala and Szostak. In this process, dipeptides synthesized inside precursors of cells promote absorption of fatty acid micelles to vesicles, inducing their preferential growth and division at the expense of other vesicles. The process is explained on the basis of coarse-grained molecular dynamics simulations, each extending for tens of microseconds, carried out to model fusion between a micelle and a membrane, both made of fatty acids in the absence and presence of hydrophobic dipeptides. In all systems with dipeptides, but not in their absence, fusion events were observed. They involve the formation of a stalk made by hydrophobic chains from the micelle and the membrane, similar to that postulated for vesicle-vesicle fusion. The emergence of a stalk is facilitated by transient clusters of dipeptides, side chains of which form hydrophobic patches at the membrane surface. Committor probability calculations indicate that the size of a patch is a suitable reaction coordinate and allows for identifying the transition state for fusion. Free-energy barrier to fusion is greatly reduced in the presence of dipeptides to only 4-5 kcal/mol, depending on the hydrophobicity of side chains. The mechanism of mediated fusion, which is expected to apply to other small peptides and hydrophobic molecules, provides a robust means by which a nascent metabolism can confer evolutionary advantage to precursors of cells.
Topics: Dipeptides; Hydrophobic and Hydrophilic Interactions; Lipid Bilayers; Membrane Fusion; Micelles; Molecular Dynamics Simulation
PubMed: 33887225
DOI: 10.1016/j.bpj.2021.04.012 -
Journal of Oleo Science 2021Monoammonium glycyrrhizinate is produced by the neutralization of glycyrrhizic acid from plant licorice with ammonia. In this study, the physicochemical properties of...
Monoammonium glycyrrhizinate is produced by the neutralization of glycyrrhizic acid from plant licorice with ammonia. In this study, the physicochemical properties of aqueous monoammonium glycyrrhizinate were investigated from the viewpoint of surface chemistry. The structure of the amphiphilic molecule is bola type, comprising two glucuronic acid moieties having two carboxylic acids groups and an aglycone part having a carboxylic acid at the opposite end of the molecule from the glucuronic acids. We found that the physicochemical properties of aqueous monoammonium glycyrrhizinate are dependent on the ionization of the carboxylic acid groups. The solubility of monoammonium glycyrrhizinate gradually increased above pH 4 in the buffer solution. The critical micelle concentration (CMC) and surface tension at the CMC (γ) of monoammonium glycyrrhizinate were determined by the surface tension method to be 1.5 mmol L and 50 mN m in pH 5 buffer and 3.7 mmol L and 51 mN m in pH 6 buffer, respectively. The surface tension gradually decreased with increasing concentration of monoammonium glycyrrhizinate in the pH 7 buffer, but the CMC was not defined by the curve. Light scattering measurements also did not reveal a clear CMC in the pH 7 buffer. The ionization of the carboxylic acid groups in the bola-type amphiphilic molecule with increasing pH is disadvantageous for micelle formation. Cryo-transmission electron microscopy showed that monoammonium glycyrrhizinate forms rod-like micelles in pH 5 buffer, and small angle X-ray scattering experiments confirmed that the average micellar structure was rod-like in pH 5 buffer. Thus, it was found that monoammonium glycyrrhizinate can form micelles only in weakly acidic aqueous solutions.
Topics: Buffers; Glycyrrhizic Acid; Hydrogen-Ion Concentration; Micelles; Solubility; Surface Tension
PubMed: 34193668
DOI: 10.5650/jos.ess21046