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Advanced Drug Delivery Reviews 2020Over the last three decades, polymeric micelles have emerged as a highly promising drug delivery platform for therapeutic compounds. Particularly, poorly soluble small... (Review)
Review
Over the last three decades, polymeric micelles have emerged as a highly promising drug delivery platform for therapeutic compounds. Particularly, poorly soluble small molecules with high potency and significant toxicity were encapsulated in polymeric micelles. Polymeric micelles have shown improved pharmacokinetic profiles in preclinical animal models and enhanced efficacy with a superior safety profile for therapeutic drugs. Several polymeric micelle formulations have reached the clinical stage and are either in clinical trials or are approved for human use. This furthers interest in this field and underscores the need for additional learning of how to best design and apply these micellar carriers to improve the clinical outcomes of many drugs. In this review, we provide detailed information on polymeric micelles for the solubilization of poorly soluble small molecules in topics such as the design of block copolymers, experimental and theoretical analysis of drug encapsulation in polymeric micelles, pharmacokinetics of drugs in polymeric micelles, regulatory approval pathways of nanomedicines, and current outcomes from micelle formulations in clinical trials. We aim to describe the latest information on advanced analytical approaches for elucidating molecular interactions within the core of polymeric micelles for effective solubilization as well as for analyzing nanomedicine's pharmacokinetic profiles. Taking into account the considerations described within, academic and industrial researchers can continue to elucidate novel interactions in polymeric micelles and capitalize on their potential as drug delivery vehicles to help improve therapeutic outcomes in systemic delivery.
Topics: Animals; Drug Compounding; Drug Delivery Systems; Drug Interactions; Humans; Micelles; Nanoparticles; Pharmaceutical Preparations; Polymers; Solubility
PubMed: 32980449
DOI: 10.1016/j.addr.2020.09.009 -
Macromolecular Rapid Communications Apr 2022Hydrogels belong to the most promising materials in polymer and materials science at the moment. As they feature soft and tissue-like character as well as high... (Review)
Review
Hydrogels belong to the most promising materials in polymer and materials science at the moment. As they feature soft and tissue-like character as well as high water-content, a broad range of applications are addressed with hydrogels, e.g., tissue engineering and wound dressings but also soft robotics, drug delivery, actuators, and catalysis. Ways to tailor hydrogel properties are crosslinking mechanisms, hydrogel shape, and reinforcement, but new features can be introduced by variation of hydrogel composition as well, e.g., via monomer choice, functionalization or compartmentalization. In particular, multicompartment hydrogels drive progress toward complex and highly functional soft materials. In the present review the latest developments in multicompartment hydrogels are highlighted with a focus on three types of compartments; micellar/vesicular, droplets, and multilayers including various subcategories. Furthermore, several morphologies of compartmentalized hydrogels and applications of multicompartment hydrogels will be discussed as well. Finally, an outlook toward future developments of the field will be given. The further development of multicompartment hydrogels is highly relevant for a broad range of applications and will have a significant impact on biomedicine and organic devices.
Topics: Drug Delivery Systems; Hydrogels; Micelles; Polymers; Tissue Engineering
PubMed: 35092101
DOI: 10.1002/marc.202100895 -
Journal of Controlled Release :... Apr 2021Polymeric micelles, i.e. aggregation colloids formed in solution by self-assembling of amphiphilic polymers, represent an innovative tool to overcome several issues... (Review)
Review
Polymeric micelles, i.e. aggregation colloids formed in solution by self-assembling of amphiphilic polymers, represent an innovative tool to overcome several issues related to drug administration, from the low water-solubility to the poor drug permeability across biological barriers. With respect to other nanocarriers, polymeric micelles generally display smaller size, easier preparation and sterilization processes, and good solubilization properties, unfortunately associated with a lower stability in biological fluids and a more complicated characterization. Particularly challenging is the study of their interaction with the biological environment, essential to predict the real in vivo behavior after administration. In this review, after a general presentation on micelles features and properties, different characterization techniques are discussed, from the ones used for the determination of micelles basic characteristics (critical micellar concentration, size, surface charge, morphology) to the more complex approaches used to figure out micelles kinetic stability, drug release and behavior in the presence of biological substrates (fluids, cells and tissues). The techniques presented (such as dynamic light scattering, AFM, cryo-TEM, X-ray scattering, FRET, symmetrical flow field-flow fractionation (AF4) and density ultracentrifugation), each one with their own advantages and limitations, can be combined to achieve a deeper comprehension of polymeric micelles in vivo behavior. The set-up and validation of adequate methods for micelles description represent the essential starting point for their development and clinical success.
Topics: Colloids; Drug Carriers; Drug Delivery Systems; Micelles; Polymers; Solubility
PubMed: 33652113
DOI: 10.1016/j.jconrel.2021.02.031 -
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 -
Journal of Pharmaceutical Sciences Jun 2021Small angle neutron scattering (SANS) studies of a model pharmaceutical formulation reveal how formulation stability depends on the compatibility of individual...
Small angle neutron scattering (SANS) studies of a model pharmaceutical formulation reveal how formulation stability depends on the compatibility of individual components. Solutions of two common protein formulation excipients, polysorbate 80 (PS80), a nonionic surfactant that prevents aggregation, and m-cresol, an antimicrobial agent for multi-dose injectable formulations, are investigated. The addition of m-cresol to PS80 solutions leads to solution turbidity and irreversibly alters PS80 micelle morphology. This slow preservative-induced destabilization of PS80 micelles progresses over days or even weeks, which highlights the essential role that aggregation kinetics plays in preservative-surfactant interactions. The temperature-dependence of PS80 micelle growth kinetics is quantified by SANS in the presence of m-cresol. Aggregation is a two-step process, where initial formation of small aggregates is followed by a period of monotonic power-law growth, providing evidence for the mechanism. Total aggregate mass stays constant after initial aggregate formation, and addition of a pH-regulating citrate buffer dramatically accelerates aggregation kinetics.
Topics: Excipients; Micelles; Polysorbates; Preservatives, Pharmaceutical; Surface-Active Agents
PubMed: 33387597
DOI: 10.1016/j.xphs.2020.12.030 -
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 -
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 -
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 -
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 -
Advanced Healthcare Materials Jul 2022Elastin-like peptides (ELPs) are a versatile platform for tissue engineering and drug delivery. Here, micelle forming ELP chains are genetically fused to three...
Elastin-like peptides (ELPs) are a versatile platform for tissue engineering and drug delivery. Here, micelle forming ELP chains are genetically fused to three therapeutic molecules, keratinocyte growth factor (KGF), stromal cell-derived growth factor 1 (SDF1), and cathelicidin (LL37), to be used in wound healing. Chronic wounds represent a growing problem worldwide. A combinatorial therapy approach targeting different aspects of wound healing would be beneficial, providing a controlled and sustained release of active molecules, while simultaneously protecting these therapeutics from the surrounding harsh wound environment. The results of this study demonstrate that the conjugation of the growth factors KGF and SDF1 and the antimicrobial peptide LL37 to ELPs does not affect the micelle structure and that all three therapeutic moieties retain their bioactivity in vitro. Importantly, when the combination of these micelle ELP nanoparticles are applied to wounds in diabetic mice, over 90 % wound closure is observed, which is significantly higher than when the therapeutics are applied in their naked forms. The application of the nanoparticles designed here is the first report of targeting different aspect of wound healing synergistically.
Topics: Animals; Diabetes Mellitus, Experimental; Elastin; Mice; Micelles; Nanoparticles; Tissue Engineering; Wound Healing
PubMed: 35373501
DOI: 10.1002/adhm.202102795