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Extracting, stabilizing, or delivering biomacromolecules such as proteins and peptides in organic phases have potential applications in biocatalysis, protein extraction, and food antioxidation. However, most current delivery/stabilization platforms face various limitations such as protein/peptide molecular size, platform stability/reusability, and/or potential damage to the cargos. A potential solution to these problems is micellar self-assemblies from amphiphilic invertible polymers, which have recently been demonstrated to be powerful as molecular hosts to deliver both small molecular drugs and functional polypeptides in the aqueous phase. To better understand the function of biomacromolecules and predict the usefulness of the formed invertible micellar assemblies (IMAs) as biomacromolecular hosts in organic phases, it is critical to characterize the spatial distribution, structure, and dynamics of biomacromolecules in the IMA including those upon release. However, the background signals of the IMAs limit the application of most peptide characterization approaches. In this work, we overcome the technical barriers by using site-directed spin labeling electron paramagnetic resonance to probe the spatial arrangement and release of a model, the hemagglutinin (HA) peptide, in the IMAs formed from two different amphiphilic invertible polymers. By site-specifically probing three residues along the peptide chain, for the first time, we depict the possible spatial distribution of HA within the IMAs. By triggering the disassembly of the IMAs with a thermodynamically good solvent (in this study, acetone), we detailed the stability of IMAs in toluene and the peptide release conditions once the polarity of the medium changes. Our findings are important for the application of peptides/proteins at the polar-nonpolar interface or using this interface to extract or deliver biomacromolecules. Our work also demonstrates the power of SDSL-EPR on probing peptide or micelle dynamics, which can be generalized to understand proteins or other biomacromolecules in micellar polymer assemblies in varied applications.

Strategically designed amphiphilic invertible polymers (AIPs) are capable of (i) self-assembling into invertible micellar assemblies (IMAs) in response to changes in polarity of environment, polymer concentration, and structure, (ii) accommodating (solubilizing) substances that are otherwise insoluble in water, and (iii) inverting their molecular conformation in response to changes in the polarity of the local environment. The unique ability of AIPs to invert the molecular conformation depending on the polarity of the environment can be a decisive factor in establishing the novel stimuli-responsive mechanism of solubilized drug release that is induced just in response to a change in the polarity of the environment. The IMA capability to solubilize lipophilic drugs and deliver and release the cargo molecules by conformational inversion of polymer macromolecules in response to a change of the polarity of the environment was demonstrated by loading IMA with a phytochemical drug, curcumin. It was demonstrated that four sets of micellar vehicles based on different AIPs were capable of delivering the curcumin from water to an organic medium (1-octanol) by means of unique mechanism: AIP conformational inversion in response to changing polarity from polar to nonpolar. The IMAs are shown to be nontoxic against human cells up to a concentration of 10 mg/L. On the other hand, the curcumin-loaded IMAs are cytotoxic to breast carcinoma cells at this concentration, which confirms the potential of IMA-based vehicles in controlled delivery of poorly water-soluble drug candidates and release by means of this novel stimuli-responsive mechanism.

'Host-guest' interactions between self-assembled micellar nanostructures from amphiphilic invertible polymers (AIPs) and two peptides, swine-origin Influenza A surface protein Hemagglutinin and research antibody peptide V5, are investigated by changing the polymer concentration and polymer/peptide ratio in the aqueous solution. Formation of mixed micellar assemblies from AIP and each peptide is revealed using detailed 1H NMR spectroscopic study. Peptide molecule localization in the micellar assemblies depends on the specific interactions between amino acid functional groups of the peptide and polymer fragments. The resulting mixed micellar structures can be considered as a promising material toward delivery and stimuli-responsive sustained release of peptides. [ABSTRACT FROM AUTHOR]

Systematic review of experimental and clinical data on the use of curcumin in the treatment of osteosarcoma is presented. The current status of curcumin’s therapeutic potential against bone cancer is analyzed in regard to using polymeric micelles (including recently developed invertible, responsive, micelles) as a platform for curcumin delivery to treat osteosarcoma. The potential of micellar assemblies from responsive macromolecules in a controlled delivery of curcumin to osteosarcoma cells, and the release using a new inversion mechanism is revealed. [ABSTRACT FROM AUTHOR]

Amphiphilicinvertible polymers (AIPs) are a new class of macromoleculesthat self-assemble into micellar structures and rapidly change structurein response to changes in solvent polarity. Using small-angle neutronscattering (SANS) data, we obtained a quantitative description ofthe invertible micellar assemblies (IMAs). The detailed compositionand size of the assemblies (including the effect of temperature) weremeasured in aqueous and toluene polymer solutions. The results showthat the invertible macromolecules self-assemble into cylindricalcore–shell micellar structures. The composition of the IMAsin aqueous and toluene solutions was used to reveal the inversionmechanism by changing the polarity of the medium. Our experimentsdemonstrate that AIP unimers self-assemble into IMAs in aqueous solution,predominantly through interactions between the hydrophobic moietiesof macromolecules. The hydrophobic effect (or solvophobic interaction)is the major driving force for self-assembly. When the polarity ofthe environment is changed from polar to nonpolar, poly(ethylene glycol)(PEG) and aliphatic dicarboxylic acid fragments of AIP macromoleculestend to replace each other in the core and the shell of the IMAs.However, neither the interior nor the exterior of the IMAs consistsof fragments of a single component of the macromolecule. In aqueoussolution, with the temperature increasing from 15 to 35 °C, theIMAs’ mixed core from aliphatic dicarboxylic acid and PEG moietiesand PEG-based shell change the structure. As a result of the progressivedehydration of the macromolecules, the hydration level (water content)in the micellar core decreases at 25 °C, followed by dehydratedPEG fragments entering the interior of the IMAs when the temperatureincreases to 35 °C. [ABSTRACT FROM AUTHOR]