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Docosahexaenoic acid (DHA; 22-carbon-6) is renowned for its diverse biological activities and essential role in human wellness. However, owing to its highly unsaturated structure, dietary DHA is susceptible to oxidation and degradation in the gastrointestinal tract. Proteins are considered ideal carriers for protecting sensitive bioactive compounds like DHA from environmental factors. In this study, we prepared self-assembled micelles of ovalbumin (Ova), myosin (Myo), 7S soy globulin (Ssg), and β-lactoglobulin (β-la) to encapsulate DHA, resulting in O(DHA), M(DHA), S(DHA), and β(DHA) micelles via the chymotrypsin hydrolysis. We evaluated the encapsulation effectiveness of these micelles by assessing their encapsulation efficiency, storage stability, and bioaccessibility of DHA. The results indicated that O(DHA), M(DHA), S(DHA), and β(DHA) formed uniform, monodisperse nanospheres, with an outer shell composed of hydrolyzed micelle material and an inner core of encapsulated DHA. The secondary structures of Ova, Myo, Ssg, and β-la micelles were altered during the micelle formation process. The encapsulation rates for DHA in Ova, Myo, and β-la micelles were all above 70%, with Ssg micelles achieving over 90%. The zeta potential values of O(DHA), M(DHA), S(DHA), and β(DHA) remained between 20 and 30 mV over 4 weeks of storage. The particle diameters of O(DHA), S(DHA), and β(DHA) remained relatively stable throughout the storage period, while the diameter of M(DHA) showed significant changes. Additionally, the bioaccessibilities of O(DHA), M(DHA), and β(DHA) were all above 50%, with S(DHA) reaching 71.36 ± 4.27%. The encapsulation of DHA in Ova, Myo, Ssg, and β-la micelles enhanced the retention of DHA in gastrointestinal fluid. Ova, Myo, Ssg, and β-la micelles significantly improved the efficiency of DHA transport across a Caco-2 cell monolayer. Micelles containing DHA were more effective than free DHA in reducing total cholesterol (TC) and alanine aminotransferase (ALT) levels, increasing the number of autophagosomes, and upregulating the mRNA expression levels of PPARα and CPT1A in HepG2 cells, thereby reducing lipid accumulation. These findings support the use of Ova, Myo, Ssg, and β-la micelles as effective carriers for DHA. [ABSTRACT FROM AUTHOR]

Background/Objectives: Glioblastoma is the most common and lethal primary brain tumor. Patients often suffer from tumor- and treatment induced vasogenic edema, with devastating neurological consequences. Intracranial edema is effectively treated with dexamethasone. However, systemic dexamethasone requires large doses to surpass the blood brain barrier in therapeutic quantities, which is associated with significant side effects. The aim of this study was to investigate a biodegradable, dextran-hydroxyethyl methacrylate (dex-HEMA) based hydrogel, containing polymeric micelles loaded with dexamethasone and liposomes encapsulating dexamethasone phosphate for localized and prolonged delivery. Methods: Poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide (mPEG-b-p(HPMA-Bz)) micelles were loaded with dexamethasone and characterized. The dexamethasone micelles, together with dexamethasone phosphate liposomes, were dispersed in an aqueous dex-HEMA solution followed by radical polymerization using a photoinitiator in combination with light. The kinetics and mechanisms of drug release from this hydrogel were determined. Results: The diameter of the nanoparticles was larger than the mesh size of the hydrogel, rendering them immobilized in the polymer network. The micelles immediately released free dexamethasone from the hydrogel for two weeks. The dexamethasone phosphate loaded in the liposomes was not released until the gel degraded and intact liposomes were released, starting after 15 days. The different modes of release result in a biphasic and sequential release profile of dexamethasone followed by dexamethasone phosphate liposomes. Conclusions: The results show that this hydrogel system loaded with both dexamethasone polymeric micelles and dexamethasone phosphate loaded liposomes has potential as a local delivery platform for the sequential release of dexamethasone and dexamethasone phosphate, for the intracranial treatment of glioblastoma associated edema. [ABSTRACT FROM AUTHOR]

Carbamazepine is a pharmacological medication commonly prescribed to treat epilepsy. Dose adjustments, poor bioavailability, and prolonged side effects present significant challenges associated with its use. Poloxamer micelles have demonstrated exceptional properties as nanocarriers for drug delivery. This research aimed to develop Poloxamer nanomicelles containing carbamazepine and assess their potential to cross the blood–brain barrier. Poloxamer 407 and P-85 micelles, anchored with TAT as a ligand and containing carbamazepine, were prepared. The morphology, entrapment efficiency, drug release, stability, and toxicity of nanomicelles were examined, along with animal studies conducted to evaluate their anticonvulsant effects. The distribution of carbamazepine-Poloxamer in the brain and plasma was assessed. The results indicated the successful formation of spherical nanomicelles with an average size of less than 100 nm, and carbamazepine was effectively incorporated into the micelles. Formulations composed of mixtures of Poloxamer exhibited a high encapsulation efficiency of approximately 92.1% and remained stable for three months. A sustained release of carbamazepine was observed for up to 72 h. The anticonvulsant effect of carbamazepine-loaded nanomicelles in mice was found to be significantly greater than that of those treated with carbamazepine solution, with the effect increasing by approximately tenfold. Compared to free carbamazepine, the carbamazepine-loaded nanomicelles exhibited a 5.5-fold increase in the brain targeting index, with no toxicity observed in mice treated with these nanomicelles. These findings suggest that Poloxamer micelles represent a promising nanoscale, controlled-release delivery system that is free from toxicity and can enhance the penetration of carbamazepine into the brain while improving its anticonvulsant activity. [ABSTRACT FROM AUTHOR]

In this account article, we give an overview of our contribution to the development of stable micellar carriers obtained by self-assembly and photo-polymerization of diacetylenic amphiphiles. The stabilized micelles can be loaded with active substances and used for diagnostic and therapeutic applications, or loaded with a metal catalyst to promote some synthetic transformations in fully aqueous medium. Table of content 1 Introduction 2 Polydiacetylene Micelles Applied to Nanomedicine 2.1 From Amphiphilic Units to Micelles 2.2 In vivo Behavior of Micelles 2.3 Passive Targeting of Tumors with Micelles 2.4 Drug Delivery with Micelles 2.5 Towards Improved Delivery of Micelles to Tumors Using Sonoporation 2.6 Active Targeting with Micelles 2.7 Behavior of Micelles at the Cellular Level and Potential Cytotoxicity 2.8 Micelles for siRNA Transfection 3 Polydiacetylene Micelles Applied to Catalysis 3.1 Copper Nanoparticles in Micelles 3.2 Copper Salts in Micelles 4 Conclusion [ABSTRACT FROM AUTHOR]

To address the limitations of conventional nanotechnology-based drug delivery systems, this work developed enzyme and reduction dual-responsive polymeric micelles. These micelles were synthesized with copolymers composed of TPGS3350-PVGLIG-DOX (TPD) and FA-SS-DOX (FSD), which endow them with tumor-targeted drug delivery capabilities. TPGS3350 contributes to extending the circulation of micelles in body, augmenting their accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect. Upon localized the tumor site, matrix metalloproteinase 2 (MMP2) cleaves the PVGLIG peptide moiety within the micelles, thereby releasing TPGS3350 and exposing the targeting ligand of folate. This approach enables the subsequent internalization of the micelles by tumor cells through folate receptor-mediated endocytosis. After internalization, the high intracellular concentration of glutathione (GSH) triggers the reduction of the disulfide bond within the FA-SS-DOX, leading to the release of the anticancer-drug doxorubicin (DOX), which promotes apoptosis in the tumor cells and enhances the efficacy of chemotherapy. [ABSTRACT FROM AUTHOR]

The aim. Study of the characteristics of 20 % solutions of poloxamer 338 (P338) in water and mixed solvents water - propylene glycol (PG) at various temperatures using rotational viscometry and the spin probe method. Materials and methods. 20 % m/m solutions of P338 in water and water - PG mixtures were the objects of re- search. The solutions were studied by rotational viscometry at 25 °C, 32 °C i 37 °C; the flow behaviour, low-yield stress (τ0), hysteresis area (SN) and dynamic or apparent viscosity (η) were determined. Spin probes based on fatty acids, which differ in molecular structure, solubility, and radical localisation, were added to the solutions. Electron paramagnetic resonance (EPR) spectra was obtained to determine their type and parameters. Results. Depending on the content, PG affects the rheological properties of 20 % P338 solution. The ability of this solution to undergo thermally induced sol-gel transitions, resulting in the formation of gels with plastic flow behaviour at temperatures of 32 °C and 37 °C, is maintained at PG content of up to 20 %. At 37 °C and a 30 % PG content, an atypical thixotropic gel is formed. The rheological characteristics of gels containing 10-20 % PG at 32 °C and 37 °C are higher than those of gels without PG. The increase in the PG concentration from 0 to 40 % generally has little effect on the rotational correlation times (T) and values of the order parameter (S) of the spin probes. In the case of the ammonium salt of 5-doxylstearic acid (5-DSA NH4 salt), the anisotropic EPR spectra at a PG concentration of 40 % undergoes a transformation, becoming a triplet. This coincides with the loss of the ability of 20 % P338 solutions to thermally induced sol↔gel transitions. An increase in the concentration of PG (in contrast to ethanol) does not lead to the solvation of P338 micelle cores by the dispersion medium. The transformation of the EPR spectrum of the 5-DSA NH4 salt into a triplet is probably the result of the interaction between PG and the hydrophilic shell of micelles through the formation of hydrogen bonds. Conclusions. The rheological properties of 20 % P338 solution are affected by the PG, depending on its content. The P338 solutions can undergo a thermally induced sol↔gel transition, provided that the PG content does not exceed 30 %. A correlation has been identified between alterations in the rheological properties of 20 % P338 solution and the corresponding change in the types of EPR spectra observedfor the 5-DSA NH4 salt, namely a transition from anisotropic spectra to triplet. As the PG content in the P338 solution increases up to 40 %, the solvation of micelle cores by the dispersion medium does not occur. It may be posited that the alteration in the structure of P338 micelles is a consequence of the interaction between PG and their hydrophilic shell [ABSTRACT FROM AUTHOR]

Micelles of different types and properties are basically formed by the assembly of surfactants. The conditions for the formation of micelles, their shapes, sizes and morphologies are also different, and are discussed for surfactants, block copolymers and ionic liquids in the present article. Theories by Debye and others, Markov chain model, ladder model of micelle growth are employed to understand in detail the thermodynamics of micelles and mixed micelles formation. Apart from these, other concepts like effect of additives on micelle formation, application of polymeric, multicompartment micelles in drug delivery, fundamentals of formation of single and double critical micelle concentration and computer simulation methods for amphiphile aggregation are reviewed in the present study. [ABSTRACT FROM AUTHOR]

Hydrogels are one of the most commonly used materials in our daily lives, which possess crosslinked three-dimensional network structures and are capable of absorbing large amounts of fluid. Due to their outstanding properties, such as flexibility, tunability, and biocompatibility, hydrogels have been widely employed in biomedical research and clinics, especially in on-demand drug release. However, traditional hydrogels face various limitations, e.g., the delivery of hydrophobic drugs due to their highly hydrophilic interior environment. Therefore, micelle-containing hydrogels have been designed and developed, which possess both hydrophilic and hydrophobic microenvironments and enable the storage of diverse cargos. Based on the functionalities of micelles, these hydrogels can be classified into micelle-doped and chemically/physically crosslinked types, which were reported to be responsive to varied stimuli, including temperature, pH, irradiation, electrical signal, magnetic field, etc. Here, we summarize the research advances of micelle-containing hydrogels and provide perspectives on their applications in the biomedical field based on the recent studies from our own lab and others. [ABSTRACT FROM AUTHOR]

[Display omitted] Oleosins are proteins with a unique central hydrophobic hairpin designed to stabilize lipid droplets (oleosomes) in plant seeds. For efficient droplet stabilization, the hydrophobic hairpin with a strong affinity for the apolar droplet core is flanked by hydrophilic arms on each side. This gives oleosins a unique surfactant-like shape making them a very interesting protein. In this study, we tested if isolated oleosins retain their ability to stabilize oil-in-water emulsions, and investigated the underlying stabilization mechanism. Due to their surfactant-like shape, oleosins when dispersed in aqueous buffers associated to micelle-like nanoparticles with a size of ∼33 nm. These micelles, in turn, clustered into larger aggregates of up to 20 µm. Micelle aggregation was more extensive when oleosins lacked charge. During emulsification, oleosin micelles and micelle aggregates dissociated and mostly individual oleosins adsorbed on the oil droplet interface. Oleosins prevented the coalescence of the oil droplets and if sufficiently charged, droplet flocculation as well. [ABSTRACT FROM AUTHOR]

At present, the drugs used to treat dry eye are mainly ocular topical drugs, with only 5 % of the drugs are absorbed, which on the market have adverse reactions, such as eye pain, eye burns, conjunctival hyperemia and poor patient compliance. In order to reduce irritation and improve bioavailability, a new type of ocular drug delivery system, mixed micelles modified with cationic hyaluronic acid was studied by rotary evaporation method. Vitamin E tocopheryl polyethylene glycol succinate and polyoxyethylene hydrogenated castor oil, two non-ionic surfactants are used for the preparation of cyclosporin micelles. Finally, the micelles were modified with cationic hyaluronic acid to form the final formulation named cationic hyaluronic acid modified cyclosporin A nanomicelle, which was designed with particle size of 17.21 nm, polydispersity index of 0.221, zeta potential of -23.4 mV and osmotic pressure of 299 mOsmol/kg. The release rate of cyclosporin A nanomicelle in vitro reached 88 %, and the preparation showed reduced surface tension (34.46 mN/m) and contact angle (22.8°), which indicated that cyclosporin A nanomicelle had better wetting and spreading properties. Transmission electron microscope showed that the preparation was spherical, homogeneous and no aggregates. After modification with cationic hyaluronic acid, the corneal permeability and apparent permeability increased by about 1.4 times and 1.3 times respectively, indicating that cyclosporin A nanomicelle can improve corneal penetration and improve bioavailability. Draize test of rabbit eye surface showed that cyclosporin A nanomicelle has no ocular irritation. In conclusion, Cationic hyaluronic acid modified cyclosporin A nanomicelle might be a promising ocular drug delivery system for the treatment of dry eye. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a worldwide public health issue with an increasing number of patients annually. However, there is no curative drug for IBD, and the present medication for IBD generally focuses on suppressing hyperactive immune responses, which can only delay disease progression but inevitably induce off-target side effects, including infections and cancers. Herein, late-model orally administered nanotherapeutic micelles (HADLA) were developed based on a conjugate of hyaluronic acid (HA) and dehydrolithocholic acid (DLA), which was simple to achieve and obtained satisfactory therapeutic efficacy in a murine colitis model with a full safety profile. HADLA is capable of targeting inflammatory colon tissues, restoring intestinal barrier function and reducing intestinal epithelial cell death. Moreover, it modulates the adaptive immune system by inhibiting the activation of pathogenic T helper 17 (Th17) cells, and it exhibits more remarkable effects in preventing colitis than DLA alone. Finally, HADLA exhibits a remarkable ability to modulate dysregulated gut microbiomes by increasing beneficial probiotics and decreasing pathogenic bacteria, such as Turicibacter. Compared with the current systemic or subcutaneous administration of biologics, this study opens new avenues in the oral delivery of immune-modulating nanomedicine and introduces DLA as a new medication for IBD treatment. [Display omitted] • Oral delivery of new nanotherapeutic micelles HADLA targets inflammatory colon. • The two carriers, hyaluronic acid and bile acid, are combined together to form HADLA. • HADLA has a unique property of acid-base structural transformation. • HADLA balances the dual behaviors of bile acids for IBD treatment. • HADLA obtains satisfactory therapeutic efficacy in IBD through multiple mechanisms. [ABSTRACT FROM AUTHOR]

Hydrophobic hydration, whereby water spontaneously structures around hydrophobic and amphiphilic molecules, plays a key role in the process of surfactant micelle formation and micellar oil solubilization. Using vibrational Raman multivariate curve resolution spectroscopy, we characterized changes in the hydrophobic hydration occurring within nonionic alkylphenol ethoxylate surfactant Tergitol NP‐12 micelles as a function of oil solubilization. We report trends in the changes of hydrophobic hydration depending on the chain length of the oil as well as the presence of a halogen atom in the oil chemical structure. Changes in hydrophobic hydration directly correlate to changes in the physical properties of the micellar solution, including cloud point and micelle hydrodynamic diameter. We compare hydrophobic hydration of Tergitol NP‐12 to nonionic linear alkyl ethoxylate surfactant Makon TD‐12 and ionic sodium dodecyl sulfate and observe similar trends; the molecular structure of the oil has the largest impact on the hydrophobic hydration. We believe these studies contribute to a fundamental understanding of the importance of hydrophobic hydration in surfactant and oil aggregates, especially as it relates to micellar oil solubilization, and provide insight into how the molecular solubilizate can impact micellar structure, size, and stability. [ABSTRACT FROM AUTHOR]

The persistent transformation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (MFs) and the excessive proliferation of MF-HSCs in the liver contribute to the pathogenesis of liver fibrosis, cirrhosis, and liver cancer. Glycolysis inhibition of MF-HSCs can reverse their MF phenotype and suppress their abnormal expansion. Here, we have developed vitamin A-derivative (VA) decorated PEG-PCL polymeric micelles to encapsulate the labile and hydrophobic camptothecin (CPT) and direct its active attack on HSCs, selectively inhibiting of HIF-1α and cellular glycolysis, ultimately repressing hepatic fibrogenesis. The obtained micelles exhibited a good stability, biocompatibility, pH sensitivity, and exceptional HSC-targetability, allowing an efficient accumulation of their carried CPT in acutely and chronically injured livers. On their intracellular release of CPT specifically in MF-HSCs, these CPT micelles nicely inhibited the HIF-1α and a series of glycolytic players in MF-HSCs and prominently suppressed their proliferation and MF phenotypic characteristics. Accordingly, on in vitro administration to the mice challenged by CCl 4 or subjected to bile duct ligation, these VA-decorated CPT micelles ameliorated the pathological symptoms of the livers, as evidenced by the significant reduction in serum levels of ALT and AST, infiltration of inflammatory cells, and collagen accumulation, the drastic down-regulation of multiple fibrotic genes, and the good recovery of attenuated hepatocyte CYP2E1 and lipogenesis regulator PPARγ. Overall, the CPT carried by VA-decorated PEG-PCL polymeric micelles can selectively inhibit the glycolysis and expansion of HSCs and thus suppress fibrogenesis, providing an original and effective approach for anti-fibrotic therapy. Our work introduces an innovative antifibrotic drug system that is developed upon the active targeting of CPT and aims for the fate reversal of HSCs. Through HSC-targeted delivery achieved by PEG-PCL polymeric micelles decorated with vitamin A-derivatives, CPT significantly suppressed the expressions of HIF-1α and glycolytic enzymes in MF-HSCs, as well as their pathologic expansion in mouse livers. It effectively ameliorated chronic liver fibrosis in mice induced by CCl 4 injection or BDL and restored the damaged liver structure and function. These compelling findings demonstrate the therapeutic potential of glycolytic HSC-targeting in combating fibrosis and related disorders and thus provide new promise for future clinical management of such prevalent and life-threatening conditions. [Display omitted] [ABSTRACT FROM AUTHOR]

Lipid oxidation is a major cause of quality deterioration in food products. In these foods, lipids are often present in a bulk or in emulsified forms. In both systems, the rate, extent and pathway of oxidation are highly dependent on the presence of colloidal structures and interfaces because these are the locations where oxidation normally occurs. In bulk oils, reverse micelles (association colloids) are present and are believed to play a crucial role on lipid oxidation. Conversely, in emulsions, surfactant micelles are present that also play a major role in lipid oxidation pathways. After a brief description of lipid oxidation and antioxidants mechanisms, this review discusses the current understanding of the influence of micellar structures on lipid oxidation. In particular, is discussed the major impact of the presence of micelles in emulsions, or reverse micelles (association colloids) in bulk oil on the oxidative stability of both systems. Indeed, both micelles in emulsions and associate colloids in bulk oils are discussed in this review as nanoscale structures that can serve as reservoirs of antioxidants and pro-oxidants and are involved in their transport within the concerned system. Their role as nanoreactors where lipid oxidation reactions occur is also commented. [ABSTRACT FROM AUTHOR]

The aggregation structure of Triton X (TX) amphiphilic molecules in aqueous solution plays an important role in determining the various properties and applications of surfactant solutions. In this paper, the properties of micelles formed by TX-5, TX-114, and TX-100 molecules with different poly(ethylene oxide) (PEO) chain lengths in TX series of nonionic surfactants were studied via molecular dynamics (MD) simulation. The structural characteristics of three micelles were analyzed at the molecular level, including the shape and size of micelles, the solvent accessible surface area, the radial distribution function, the micelle configuration, and the hydration numbers. With the increase of PEO chain length, the micelle size and solvent accessible surface area also increase. The distribution probability of the polar head oxygen atoms on the surface of the TX-100 micelle is higher than that in the TX-5 or TX-114 micelle. In particular, the tail quaternary carbon atoms in the hydrophobic region are mainly located at the micelle exterior. For TX-5, TX-114, and TX-100 micelles, the interactions between micelles and water molecules are also quite different. These structures and comparisons at the molecular level contribute to the further understanding of the aggregation and applications of TX series surfactants. [ABSTRACT FROM AUTHOR]

Ovarian cancer has a high mortality rate due to difficult detection at an early stage. It is necessary to develop a novel anticancer treatment that demonstrates improved efficacy while reducing toxicity. Here, using the freeze-drying method, micelles encapsulating paclitaxel (PTX) and sorafenib (SRF) with various polymers were prepared, and the optimal polymer (mPEG-b-PCL) was selected by measuring drug loading (%), encapsulation efficiency (%), particle size, polydispersity index, and zeta potential. The final formulation was selected based on a molar ratio (PTX:SRF = 1:2.3) with synergistic effects on two ovarian cancer cell lines (SKOV3-red-fluc, HeyA8). In the in vitro release assay, PTX/SRF micelles showed a slower release than PTX and SRF single micelles. In pharmacokinetic evaluation, PTX/SRF micelles showed improved bioavailability compared to PTX/SRF solution. In in vivo toxicity assays, no significant differences were observed in body weight between the micellar formulation and the control group. The anticancer effect of PTX/SRF combination therapy was improved compared to the use of a single drug. In the xenografted BALB/c mouse model, the tumor growth inhibition rate of PTX/SRF micelles was 90.44%. Accordingly, PTX/SRF micelles showed improved anticancer effects compared to single-drug therapy in ovarian cancer (SKOV3-red-fluc). [ABSTRACT FROM AUTHOR]

The use of pH-responsive polymeric micelles is a promising approach to afford the targeted, pH-mediated delivery of hydrophobic drugs within the low-pH tumour milieu and intracellular organelles of cancer cells. However, even for a common pH-responsive polymeric micelle system—e.g., those utilising poly(ethylene glycol)-b-poly(2-vinylpyridine) (PEG-b-PVP) diblock copolymers—there is a lack of available data describing the compatibility of hydrophobic drugs, as well as the relationships between copolymer microstructure and drug compatibility. Furthermore, synthesis of the constituent pH-responsive copolymers generally requires complex temperature control or degassing procedures that limit their accessibility. Herein we report the facile synthesis of a series of diblock copolymers via visible-light-mediated photocontrolled reversible addition-fragmentation chain-transfer polymerisation, with a constant PEG block length (90 repeat units (RUs)) and varying PVP block lengths (46–235 RUs). All copolymers exhibited narrow dispersity values (Đ ≤ 1.23) and formed polymeric micelles with low polydispersity index (PDI) values (typically <0.20) at physiological pH (7.4), within a suitable size range for passive tumour targeting (<130 nm). The encapsulation and release of three hydrophobic drugs (cyclin-dependent kinase inhibitor (CDKI)-73, gossypol, and doxorubicin) were investigated in vitro at pH 7.4–4.5 to simulate drug release within the tumour milieu and cancer cell endosome. Marked differences in drug encapsulation and release were observed when the PVP block length was increased from 86 to 235 RUs. With a PVP block length of 235 RUs, the micelles exhibited differing encapsulation and release properties for each drug. Minimal release was observed for doxorubicin (10%, pH 4.5) and CDKI-73 exhibited moderate release (77%, pH 4.5), whereas gossypol exhibited the best combination of encapsulation efficiency (83%) and release (91% pH 4.5) overall. These data demonstrate the drug selectivity of the PVP core, where both the block molecular weight and hydrophobicity of the core (and accordingly the hydrophobicity of the drug) have a significant effect on drug encapsulation and release. These systems remain a promising means of achieving targeted, pH-responsive drug delivery—albeit for select, compatible hydrophobic drugs—which warrants their further investigation to develop and evaluate clinically relevant micelle systems. [ABSTRACT FROM AUTHOR]

Various formulations of polymeric micelles, tiny spherical structures made of polymeric materials, are currently being investigated in preclinical and clinical settings for their potential as nanomedicines. They target specific tissues and prolong circulation in the body, making them promising cancer treatment options. This review focuses on the different types of polymeric materials available to synthesize micelles, as well as the different ways that micelles can be tailored to be responsive to different stimuli. The selection of stimuli-sensitive polymers used in micelle preparation is based on the specific conditions found in the tumor microenvironment. Additionally, clinical trends in using micelles to treat cancer are presented, including what happens to micelles after they are administered. Finally, various cancer drug delivery applications involving micelles are discussed along with their regulatory aspects and future outlooks. As part of this discussion, we will examine current research and development in this field. The challenges and barriers they may have to overcome before they can be widely adopted in clinics will also be discussed. [ABSTRACT FROM AUTHOR]

A lattice theory for block copolymer solutions near the boundary between the micellization and liquid–liquid phase separation regions proposes a new kinetic process of micellization where small concentrated-phase droplets are first formed and then transformed into micelles in the early stage of micellization. Moreover, the thermodynamically stable concentrated phase formed from metastable micelles by a unique ripening process in the late stage of phase separation, where the growing concentrated-phase droplet size is proportional to the square root of the time. [ABSTRACT FROM AUTHOR]

Recently, the incidence of cancer keeps increasing, seriously endangers human health, and has evolved into the main culprit of human death. Conventional chemotherapeutic drugs, such as paclitaxel and doxorubicin (DOX), have some disadvantages, including low therapeutic effect, poor water solubility, high toxic side effects, short blood circulation time in the body, and so on. To improve the anti-tumor effect of the drug in vivo and reduce its side effects on the body, researchers have designed and developed a variety of responsive nanocarriers. In this work, we synthesized D-α-tocopherol polyethylene glycol 3350 succinate (TPGS3350)-Gly-Pro-Leu-Gly-Val-Arg (GPLGVR)-DOX (TPD) prodrugs in response to extracellular enzymes of matrix metalloproteinase (MMP-9) in the tumor microenvironment and FA-Asp-Glu-Val-Asp (DEVD)-DOX (FPD) prodrugs responsive to intracellular enzymes of caspase-3. Then, intracellular and extracellular enzyme-responsive TPD&FPD micelles with DOX (TPD&FPD&D) were successfully prepared through dialysis method. The outer layer of TPGS3350 can prolong the blood circulation time of micelles in vivo, followed by accumulation of micelles at tumor tissue through enhanced permeability and retention (EPR) effect. The peptide of GPLGVR can be cleaved by MMP-9 enzymes to remove the outer layer of TPGS3350, exposing the targeting molecule of folate, and then the micelles are engulfed by tumor cells through folate receptor-mediated endocytosis. After entering the tumor cells, the free DOX loaded in the micelles is released, which induces tumor cell apoptosis to activate caspase-3 in the cells, cutting the peptide DEVD to accelerate the intracellular release of the DOX, which further enhances cytotoxicity to improve antitumor effect. [ABSTRACT FROM AUTHOR]

Mixed micelles (MMs), as a new targeted drug delivery system with high adjustability, has been widely studied in biomedicines. In order to study whether mixtures containing two different molecules have an excellent targeted anti-tumor effect, MMs based on D-a-tocopherol polyethylene glycol 1000 succinate (TPGS) and triblock copolymer P84 were prepared, and the characterization, cell endo-cytosis, and exocytosis of P84/TPGS MMs were observed. Paclitaxel (PTX), a classical anti-tumor drug, was selected as a model compound to explore its anti-tumor effect in vivo. The results showed that P84/ TPGS MMs had better stability, suitably distributed particle size, good cell endocytosis, and tumor sphere permeability, which could improve the permeability of PTX in the tumor site and effectively inhibit the growth of the H22 tumor in mice. In conclusion, P84/TPGS MMs is a potential micelle carrier system of cancer targeting, needing further investigation. [ABSTRACT FROM AUTHOR]

Polymeric micelles have long been considered as promising nanocarrier for hydrophobic drugs and imaging probes, due to their nanoscale particle size, biocompatibility and ability to loading reasonable amount of cargoes. Herein, a facile method for dextran micelles preparation was developed and their performance as carriers of superparamagnetic iron oxide (SPIO) nanocrystals was evaluated. Amphiphilic dextran (Dex- g -OA) was synthesized via the Schiff base reactions between oxidized dextran and oleylamine, and self-assembled in situ into nano-size micelles in the reaction systems. The self-assembling behaviors of the amphiphilic dextran were identified using fluorescence resonance energy transfer technique by detection the energy transfer signal between the fluorophore pairs, Cy5 and Cy5.5. Hydrophobic SPIO nanoparticles (Fe3O4 NPs) were successfully loaded into the dextran micelles via the in situ self-assembly process, leading to a series of Fe3O4 NPs-loaded micelle nanocomposites (Fe3O4@Dex- g -OA) with good biocompatibility, superparamagnetism and strongly enhanced T 2 relaxivity. At the magnetic field of 0.5 T, the Fe3O4@Dex- g -OA nanocomposite with particle size of 116.2 ± 53.7 nm presented a higher T 2 relaxivity of 327.9 mM Fe − 1 ·s−1. The prepared magnetic nanocomposites hold the promise to be used as contrast agents in magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

The development of stimuli-responsive polymeric micelles for targeted drug delivery has attracted much research interest in improving therapeutic outcomes. This study designs copolymers responsive to ultraviolet (UV) light and glutathione (GSH). A disulfide linkage is positioned between a hydrophilic poly(ethylene glycol) monomethyl ether (mPEG) and a hydrophobic o-nitrobenzyl methacrylate (ONBMA) to yield amphiphilic copolymers termed mPEG-SS-pONBMA. Three copolymers with different ONBMA lengths are synthesized and formulated into micelles. An increase in particle size and a decrease in critical micelle concentration go together with increasing ONBMA lengths. The ONB cleavage from mPEG-SS-pONBMA-formed micelles results in the transformation of hydrophobic cores into hydrophilic ones, accelerating drug release from the micelles. Obvious changes in morphology and molecular weight of micelles upon combinational treatments account for the dual-stimuli responsive property. Enhancement of a cell-killing effect is clearly observed in doxorubicin (DOX)-loaded micelles containing disulfide bonds compared with those containing dicarbon bonds upon UV light irradiation. Collectedly, the dual-stimuli-responsive mPEG-SS-pONBMA micelle is a better drug delivery carrier than the single-stimuli-responsive mPEG-CC-pONBMA micelle. After HT1080 cells were treated with the DOX-loaded micelles, the high expression levels of RIP-1 and MLKL indicate that the mechanism involved in cell death is mainly via the DOX-induced necroptosis pathway. [ABSTRACT FROM AUTHOR]

novel kind of redox-responsive amphiphilic polyurethane triblock copolymer, PEG-PU(SS)-PEG, was designed and synthesized, in which PEG was the hydrophilic polyethylene glycol at both ends of the copolymer chain, and the middle hydrophobic polyurethane block PU(SS) was prepared from bis(2-hydroxyethyl) disulfide and hexamethylene diisocyanate (HDI) via step-growth polymerization. PEG-PU(SS)-PEG could self-assemble into stable micelles with the average diameter of about 100 nm through nano-precipitation method in aqueous solution, in which the hydrophilic corona and the hydrophobic cores were composed of PEG and PU(SS) blocks, respectively. Hydrophobic anti-cancer drugs, such as curcumin, could be loaded into the hydrophobic micellar cores to construct redox-responsive drug nanocarriers with the drug loading content and the drug loading efficiency as high as 22.2% and 71.3%, respectively. Due to the existence of the disulfide linkages in the hydrophobic PU(SS) blocks, in the presence of glutathione (GSH), the copolymer chains could be triggered to depolymerize, resulting in the disintegration of the nano-micelles and release of loaded curcumin. After being co-incubated with GSH for 6 h, the cumulative release amount of curcumin could reach about 90%. Therefore, PEG-PU(SS)-PEG was a potential candidate for the fabrication of drug nanocarriers. [ABSTRACT FROM AUTHOR]

Natural amphiphilic polymer micelles have garnered considerable research attention as nanocarriers for delivering drugs. The objective of this study was to explore the possibility of applying biocompatible dual-modified starch micelles as drug delivery vehicles. To this end, a dual-modified corn starch polymer (SCD) was synthesized with zwitterionic sulfobetaine and deoxycholic acid; spherical micelles with an average particle size of ~200 nm were prepared through the self-assembly of SCD. The effects of dual modification on the degree of substitution, molecular structure, and functional properties of SCD were investigated. Further, doxorubicin was successfully incorporated into the micelles, and an in vitro drug release study was performed to confirm that the drug-loaded micelles displayed pH-sensitive properties with controlled and sustained release. The dissolve-diffuse-erosion-degradation release process was described according to the dynamic models of drug release for SCD micelles. The results can be used as reference information for further studies in the biotechnology and pharmaceutical domains. [Display omitted] • Dual-modified starch micelles encapsulate doxorubicin. • Delivery of doxorubicin from the system is pH-dependent. • The micelles drug release process follows Korsmeyer-Peppas and first-order models. • Drug release mechanism is a dissolve-diffuse-erosion-degradation process. [ABSTRACT FROM AUTHOR]

Although curcumin in the form of nanoparticles has been demonstrated as a potential anti-tumor compound, the impact of curcumin and nanocurcumin in vitro on normal cells and in vivo in animal models is largely unknown. This study evaluated the toxicity of curcumin-loaded micelles in vitro and in vivo on several tumor cell lines, primary stromal cells, and zebrafish embryos. Breast tumor cell line (MCF7) and stromal cells (human umbilical cord vein endothelial cells, human fibroblasts, and human umbilical cord-derived mesenchymal stem cells) were used in this study. A zebrafish embryotoxicity (FET) assay was conducted following the Organisation for Economic Co-operation and Development (OECD) Test 236. Compared to free curcumin, curcumin PM showed higher cytotoxicity to MCF7 cells in both monolayer culture and multicellular tumor spheroids. The curcumin-loaded micelles efficiently penetrated the MCF7 spheroids and induced apoptosis. The nanocurcumin reduced the viability and disturbed the function of stromal cells by suppressing cell migration and tube formation. The micelles demonstrated toxicity to the development of zebrafish embryos. Curcumin-loaded micelles demonstrated toxicity to both tumor and normal primary stromal cells and zebrafish embryos, indicating that the use of nanocurcumin in cancer treatment should be carefully investigated and controlled. [ABSTRACT FROM AUTHOR]

The crystallinity of polymers strongly affects their properties. For block copolymers, whereby two crystallisable blocks are covalently tethered to one another, the molecular weight of the individual blocks and their relative weight fraction are important structural parameters that control their crystallisation. In the case of block copolymer micelles, these parameters can influence the crystallinity of the core, which has implications for drug encapsulation and release. Therefore, in this study, we aimed to determine how the microstructure of poly(ethylene glycol-b-caprolactone) (PEG-b-PCL) copolymers contributes to the crystallinity of their hydrophobic PCL micelle cores. Using a library of PEG-b-PCL copolymers with PEG number-average molecular weight (Mn) values of 2, 5, and 10 kDa and weight fractions of PCL (fPCL) ranging from 0.11 to 0.67, the thermal behaviour and morphology were studied in blends, bulk, and micelles using differential scanning calorimetry (DSC), wide-angle X-ray diffraction (WXRD), and Synchrotron wide-angle X-ray scattering (WAXS). Compared to PEG and PCL homopolymers, the block copolymers displayed reduced crystallinity in the bulk phase and the individual blocks had a large influence on the crystallisation of one another. The fPCL was determined to be the dominant contributor to the extent and order of crystallisation of the two blocks. When fPCL < 0.35, the initial crystallisation of PEG led to an amorphous PCL phase. At fPCL values between 0.35 and 0.65, PEG crystallisation was followed by PCL crystallisation, whereas this behaviour was reversed when fPCL > 0.65. For lyophilised PEG-b-PCL micelles, the crystallinity of the core increased with increasing fPCL, although the core was predominately amorphous for micelles with fPCL < 0.35. These findings contribute to understanding the relationships between copolymer microstructure and micelle core crystallinity that are important for the design and performance of micellar drug delivery systems, and the broader application of polymer micelles. [ABSTRACT FROM AUTHOR]

The hollow sphere structure has attracted various attention in the catalytic field due to its high specific surface. The good dispersion and morphology of hollow spheres are important to provide high active sites. It is a big challenge to control the morphology and distribution of the active materials during synthesis. Serious deformation and uneven distribution of the spheres were usually obtained due to inappropriate templates. A facile one‐step hydrothermal method using micelles of triblock copolymer surfactant P123 was adopted to in‐situ grow Ni3S2/MoS2 porous hollow spheres on Ni foam with uniform distribution. The as‐produced Ni3S2/MoS2 porous hollow spheres have been demonstrated to have excellent oxygen evolution reaction catalytic performance as integrated electrodes. Low overpotentials of 314 mV and 337 mV have been achieved at current densities of 50 mA cm−2 and 100 mA cm−2 with a Tafel slope of 57 mV dec−1 and an excellent long‐term stability, which is better than other Ni‐base material. [ABSTRACT FROM AUTHOR]

[Display omitted] • Studied pyrene fluorescence in aq. surface active ionic liquid-sodium alginate. • Observed unusual behavior for 1-decyl-3-methylimidazolium chloride system. • Pyrene incorporated into 1-hexadecyl-3-methylimidazolium chloride micelle core. • Pyrene accumulated close to 1-decyl-3-methylimidazolium chloride micelle surface. • Quantified micellar aggregation numbers in presence of sodium alginate. Pyrene fluorescence in aqueous solutions of two surface active ionic liquids, namely, 1-decyl-3-methylimidazolium chloride, and 1-hexadecyl-3-methylimidazolium chloride was investigated in presence of a biopolymer sodium alginate. The principal objective of this study was to explore the influence of the length of the hydrocarbon tails of these surface active ionic liquids on the possible location of the probe (pyrene) molecules in presence of the additive. While an abrupt decrease in the values of the ratio of the intensity of the first vibronic band to that of the third band of pyrene emission spectrum with concentration was observed for 1-hexadecyl-3-methylimidazolium chloride in presence of sodium alginate like the polymer-free case reported earlier, there was a peculiar reversal for 1-decyl-3-methylimidazolium chloride + sodium alginate. The former system manifested a usual sigmoidal profile, but in contrast, the later revealed an inverse sigmoidal dependence. The results indicated preferential incorporation of the pyrene probe into the hydrophobic microenvironment of the 1-hexadecyl-3-methylimidazolium chloride micelles. On the other hand, the solubilized pyrene molecules could have been accommodated in a layer within the 1-decyl-3-methylimidazolium chloride micelles closer to the micellar surface. Fluorescence measurements also helped ascertain the aggregation numbers of the micelles in presence of sodium alginate. [ABSTRACT FROM AUTHOR]

AimTo structurally modify our existing cholic acid (CA)-based telodendrimer (TD; PEG5K-CA8) for effective micellar nanoencapsulation and delivery of the US FDA-approved members of taxane family.Materials & methodsGeneration of hybrid TDs was achieved by replacing four of the eight CAs with biocompatible organic moieties using solution-phase peptide synthesis. Drug loading was done using the standard evaporation method.ResultsHybrid TDs can generate micelles with narrow size distributions, low critical micelle concentration values (1-6 μM), better hematocompatibility and lack of in vitro cytotoxicity.ConclusionAlong with PEG5K-CA8, CA-based hybrid nanoplatform is the first of its kind that can stably encapsulate all three FDA-approved taxanes with nearly 100% efficiency up to 20% (w/w) loading.

Drug nanocrystals, one of most common drug delivery systems, enable the delivery of poorly water-soluble drugs with high drug loading and enhanced dissolution. The rapid clearance and uncontrolled drug release of drug nanocrystals limit their delivery efficiency and clinical application. Herein, an amphiphilic co-polymer, poly oligo(ethylene glycol) methacrylate-b-poly(styrene–co-4-formylphenyl methacrylate) (POEGMA-b-P (St-co-FPMA), PPP), characterized by a hydrophilic part with bottlebrush-like oligo(ethylene glycol) methacrylate (OEGMA) side chains, was synthesized as stabilizers to fabricate a high-drug-loading nanocrystal micelle (053-PPP NC micelle) using the chronic myeloid leukemia (CML) drug candidate N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053 or 053) as a model drug. The 053-PPP NC micelle was characterized and subjected to in vitro and in vivo studies. It featured a worm-like shape of small size, high drug loading (~50%), high colloidal stability, and controlled release in vitro. The presence of the 053-PPP NC micelle resulted in a long-circulation property and a much higher AUC. The 053-PPP NC micelle induced higher accumulation in the tumor tissues under multiple continuous administration. For in vivo efficacy, the 053-PPP NC micelle with a longer dosing interval (96 h), beneficial for improving patient adherence, demonstrated superiority to the 053-F127 NC. The proposed stabilizer PPP and the 053-PPP NC micelle with high drug loading enables drug delivery with long circulation and controlled release of drugs. It is also promising for the development of more efficient nanocrystal-based intravenous injection formulations for poorly water-soluble drugs. It might also offer new possibilities for potential clinical application of the CML candidate drug 053. [ABSTRACT FROM AUTHOR]

Atherosclerosis progression is driven by an imbalance of cholesterol and unresolved local inflammation in the arteries. The administration of recombinant apolipoprotein A-I (ApoA-I)-based high-density lipoprotein (HDL) nanoparticles has been used to reduce the size of atheroma and rescue inflammatory response in clinical studies. Because of the difficulty in producing large quantities of recombinant ApoA-I, here, we describe the preparation of phospholipid-based, ApoA-I-free micelles that structurally and functionally resemble HDL nanoparticles. Micelles were prepared using various phosphatidylcholine (PC) lipids combined with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000] (DSPE-PEG2k) to form nanoparticles of 15–30 nm in diameter. The impacts of PC composition and PEGylation on the anti-inflammatory activity, cholesterol efflux capacity, and cholesterol crystal dissolution potential of micelles were investigated in vitro. The effects of micelle composition on pharmacokinetics and cholesterol mobilization ability were evaluated in vivo in Sprague Dawley rats. The study shows that the composition of HDL-mimicking micelles impacts their overall atheroprotective properties and supports further investigation of micelles as a therapeutic for the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Diabetes mellitus affects almost half a billion patients worldwide and results from either destruction of β‐cells responsible for insulin secretion or increased tissue resistance to insulin stimulation and the reduction of glycemic control. Novel drug delivery systems can improve treatment efficacy in diabetic patients. The low aqueous solubility of most oral antidiabetic drugs decreases drug bioavailability; therefore, there is a demand for the use of novel methods to overcome this issue. The application of bile acids mixed micelles and bilosomes can provide an enhancement in drug efficacy. Bile acids are amphiphilic steroidal molecules that contain a saturated tetracyclic hydrocarbon cyclopentanoperhydrophenanthrene ring, and consist of three 6‐membered rings and a 5‐membered ring, a short aliphatic side chain, and a tough steroid nucleus. This review offers a comprehensive and informative data focusing on the great potential of bile acid, their salts, and their derivatives for the development of new antidiabetic drug delivery system. Significance statement: Diabetes mellitus affects many people all over the world. The low aqueous solubility of most oral antidiabetic drugs that decreases their bioavailability and painful injection with some complications of insulin are the main cause of suffering in the patients from conventional therapeutic methods. In recent years, novel drug delivery systems (NDDSs) are developed to solve these problems. One of the main NDDS was bile acid‐based bilosomes and micelles. Bile acids play as drug‐solubilizing and permeation‐modifying agents. This study evaluated bilosomes and micelles as novel carriers of insulin and relevant therapeutics of diabetes. [ABSTRACT FROM AUTHOR]

The importance of micelles as templates for nanomaterials is growing day by day. This resulted in an increasing interest for micelles in different sizes and shapes. Addition of n-amines to micellar solutions was found to bring change in the shape of the micelles from sphere to rod in aqueous ionic micellar solutions. The change in shape is qualitatively obtained from sudden change in the slope of pH versus amine concentration plots because the degree or protonation of n-alkylamines depends on the shape of micelles. In the present investigation, pH is measured at different temperatures to elucidate the influence of addition of n-amines on sphere-to-rod transition in aqueous micellar solutions. The surfactants employed in the present investigation are cetyltrimethyl ammonium bromide (CTAB), cetylpyridinium chloride (CPC), and sodium dodecyl sulphate (SDS). As the amine concentration is increased, the pH increases linearly at certain amine concentration and the slope of the resulting straight line changes on further addition of amine. It is noticed that increasing temperature requires more amine for structural transition of aqueous ionic micelles. It is also observed that the effectiveness of added amines leading to shape transition from sphere to rod is in the order of C8NH2>C7NH2> C6NH2. [ABSTRACT FROM AUTHOR]

Layer‐by‐layer multilayered film has been creating great opportunities in developing controlled drug and other bioactive molecular delivery system. In this work, coumarin bearing micelles of poly(acrylic acid‐coumarin methacrylate) is first synthesized in a one‐step copolymerization and the reversible photo‐crosslinkable multilayers containing coumarin groups are then fabricated via layering the micelles with polyethyleneimine (PEI). The film growth behavior of polyetheleneimine/poly(acrylic acid‐coumarin methacrylate) (PEI/P(AA‐r‐CMA)) multilayer is found to rely on deposit solution pH. Increasing PEI solution pH and decreasing P(AA‐r‐CMA) pH can greatly accelerate film growing process. This is explained by PEI diffusivity and destabilization of P(AA‐r‐CMA) micelle at solution/multilayer interface. Nile red (NR) is loaded into the film as a model drug via simple post diffusion driven by hydrophobic interactions. Furthermore, photo‐crosslink and decrosslink of PEI/P(AA‐r‐CMA) film is achieved by irradiating the films with light of 365 and 254 nm wavelength, respectively, which therefore ensures the possibility of fine control over drug delivery procedure. [ABSTRACT FROM AUTHOR]

In this paper, three polymers of Angiopep‐2 conjugated polyethylene glycol (PEG)‐β‐cyclodextrin (Ang‐2‐PEG‐βCD), cyclic RGD (cRGD)‐PEG‐βCD, Ad‐PCL‐FITC and corresponding double‐targeted polymer micelles (D‐T micelles) were successfully prepared by host–guest self‐assembly. Transmission electron microscope images showed that uniformly dispersed spherical supermolecular micelles could be formed. The colloidal stability of D‐T micelles in 5% glucose and 10% FBS solution were good within 24 h, which was fine in distilled water at room temperature within 2 weeks. The results of fluorescence microscope and flow cytometry demonstrating the prepared double‐targeted micells showed high intracellular delivery efficiency in both brain microvascular endothelial cells (bEnd.3 cell) and glioma cells (C6 cell). As expected, based on the specific recognition between the peptides and the receptors, the D‐T micelles exhibited better anti‐tumor efficacy than free chemotherapy drug and non‐targeted micelles both in vitro and in vivo, indicating the great potential of D‐T micelles developed here as promising vehicle for glioma targeted drug delivery. [ABSTRACT FROM AUTHOR]

Atherosclerosis, a leading cause of mortality in developed countries, is characterized by the buildup of oxidized low-density lipoprotein (oxLDL) within the vascular intima, unregulated oxLDL uptake by macrophages, and ensuing formation of arterial plaque. Amphiphilic polymers (AMPs) comprised of a branched hydrophobic domain and a hydrophilic poly(ethylene glycol) (PEG) tail have shown promising anti-atherogenic effects through direct inhibition of oxLDL uptake by macrophages. In this study, five AMPs with controlled variations were evaluated for their micellar and structural stability in the presence of serum and lipase, respectively, to develop underlying structure-atheroprotective activity relations. In parallel, molecular dynamics simulations were performed to explore the AMP conformational preferences within an aqueous environment. Notably, AMPs with ether linkages between the hydrophobic arms and sugar backbones demonstrated enhanced degradation stability and storage stability, and also elicited enhanced anti-atherogenic bioactivity. Additionally, AMPs with increased hydrophobicity elicited increased atheroprotective bioactivity in the presence of serum. These studies provide key insights for designing more serum-stable polymeric micelles as prospective cardiovascular nanotherapies.

Doxorubicin (DOX) is a chemotherapy drug that possesses many side effects. This study aimed to synthesize PBMA‐b‐POEGMA [poly (butyl methacrylate)‐b‐poly (oligo ethylene glycol methacrylate)] diblock copolymer as a nanocarrier for loading of DOX, promoting anticancer efficacy of the drug, and decreasing its side effects. Hence, PBMA‐b‐POEGMA diblock copolymer was first synthesized by the RAFT method and then DOX encapsulated into the micellar nanocarrier. Self‐assembly behavior of copolymers and physicochemical/biological properties of nanocarriers were assessed. DLS and TEM images showed nanocarriers possessed spherical‐uniform structure with the mean size and polydispersity of 27 ± 1.34 nm and 0.13 ± 0.21 for blank‐micelles as well as, 45 ± 2.32 nm and 0.18 ± 0.18 for DOX‐loaded micelles, respectively. Synthesized micelles also provided high drug encapsulation efficiency (>80%) with a drug loading content of 4.53%. Moreover, the maximum released amount of drug was reported at 69%, with the Korsmeyer‐Peppas model, as a more suitable model to describe the release behavior of DOX from nanocarriers. Biologically, block copolymers were biocompatible against COS‐7 and 4T1 cell lines, in addition, free‐DOX showed higher cytotoxicity than DOX‐loaded micelles. Furthermore, 0.5 μg/mL concentration of drug‐loaded micelle led to growth inhibition of more than 60% of cancerous cells, during 48 h, so that higher level of cellular uptake of drug and apoptosis in 4T1 cells was induced by drug‐loaded micelles. [ABSTRACT FROM AUTHOR]

BACKGROUND Rebaudioside A (RA) and its monoglucosyl derivative, as like rebaudioside D (RD) are the most popular stevia glycosides but possess poor solubility in water, which limited their application as edible surfactants, the applications as in micellar solubilization and drug delivery. Meanwhile, effect of the monoglucosyl attached to RA moiety remains unclear. RESULTS: Monoglucosyl rebaudioside A (RAG1) was synthesized via hydrolyzing the transglycosylation product of RA with 95% of RA converted. RAG1 content in raw reaction mixture was as high as 69.5% of total glycosides, and harvested with a content of 88.2% by simple filtration. The RAG1 exhibited an aqueous solubility of 87 folds of RA or 391 folds of RD at 25 °C. The surface activity of RAG1 solution was higher than RA and invincible to RD. The RAG1 micelles promoted aqueous solubility of idebenone (IDE) up to 500 folds higher at 25 °C. The cumulative release rate of IDE encapsulated in RAG1 micelles was 777.5% or 456.7% higher of that of free IDE in simulated gastric/intestinal fluids in 14 h, respectively. The RAG1‐IDE remained the same in 98 days at 25 °C. CONCLUSION: The α‐linked glucosyl to RA induced higher hydrophilicity and surface activity than that resulted by β‐linked glucosyl, making RAG1 not only dramatically raise the aqueous solubility of RA, but also endow IDE folds higher in bioaccessibility, yet making the capsule stable at storage. The results would provide a new edible delivery nanocarrier for encapsulation of hydrophobic bioactive components. © 2021 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The cancer drug delivery process involves a series of biological barriers, which require the nanomedicine to exhibit different, even opposite properties for high therapeutic efficacy. The prevailing design philosophy, i.e., integrating these properties within one nanomedicine via on‐demand property transitions such as PEGylation/dePEGylation, complicates nanomedicines' composition and thus impedes clinical translation. Here, polyzwitterionic micelles of poly(tertiary amine‐oxide)‐block‐poly(ε‐caprolactone) (PTAO‐PCL) amphiphiles that enable all the required functions are presented. The zwitterionic nature and unique cell membrane affinity confer the PTAO micelles long blood circulation, efficient tumor accumulation and penetration, and fast cellular internalization. The mitochondrial targeting capability allows drug delivery into the mitochondria to induce mitochondrial dysfunction and overcome tumor multidrug resistance. As a result, the PTAO/drug micelles exhibit potent anticancer efficacy. This simple yet multipotent carrier system holds great promise as a generic platform for potential clinical translation. [ABSTRACT FROM AUTHOR]

[Display omitted] The addition of gallium ions to a solution of a double-hydrophilic block copolymer, i.e. poly(ethylene oxide)- block -poly(acrylic acid), leads to the spontaneous formation of highly monodisperse micelles with a Hybrid PolyIon Complexes (HPICs) core. By combining several techniques, a precise description of the HPIC architecture was achieved. In particular and for the first time, NMR and anomalous small angle X-ray scattering (ASAXS) enable tracking of the inorganic ions in solution and highlighting the co-localization of the gallium and the poly(acrylic acid) blocks in a rigid structure at the core of the micelle. Such a core has a radius of ca 4.3 nm while the complete nano-object with its poly(ethylene oxide) shell has a total radius of ca 11 nm. The aggregation number was also estimated using the ASAXS results. This comprehensive structural characterization of the Ga HPICs corroborates the assumptions made for HPICs based on other inorganic ions and demonstrates the universality of the HPIC structure leading, for example, to new families of contrast agents in medical imaging. [ABSTRACT FROM AUTHOR]

Background: Fungal ocular infections can cause serious consequences, despite their low incidence. It has been reported that Posaconazole (PSC) is used in the treatment of fungal infections in different ocular tissues by diluting the oral suspension, and successful results were obtained despite low ocular permeation. Therefore, we optimized PSC-loaded ocular micelles and demonstrated that the permeation/penetration of PSC in ocular tissues was enhanced. Methods: The micellar-based in situ gels based on the QbD approach to increase the ocular bioavailability of PSC were developed. Different ratios of Poloxamer 407 and Poloxamer 188 were chosen as CMAs. Tsol/gel, gelling capacity and rheological behavior were chosen as CQA parameters. The data were evaluated by Minitab 18, and the formulations were optimized with the QbD approach. The in vitro release study, ocular toxicity, and anti-fungal activity of the optimized formulation were performed. Results: Optimized in situ gel shows viscoelastic property and becomes gel form at physiological temperatures even when diluted with the tear film. In addition, it has been shown that the formulation had high anti-fungal activity and did not have any ocular toxicity. Conclusions: In our previous studies, PSC-loaded ocular micelles were developed and optimized for the first time in the literature. With this study, the in situ gels of PSC for ocular application were developed and optimized for the first time. The optimized micellar-based in situ gel is a promising drug delivery system that may increase the ocular permeation and bioavailability of PSC. [ABSTRACT FROM AUTHOR]

In the study we synthesized thermo-responsive amphiphilic P(vinyl pyrrolidone-co-Methyl methacrylate) (P(VP-co-MMA)) polymers at varying ratios (100/0, 95/5, 94/6, and 92.5/7.5), which were used further for the synthesis of thermo-responsive micelles. The 1H-NMR results revealed the successful copolymerization of VP with MMA without any chemical deterioration. Further, it was observed that the variations in monomers molar ratio showed no prominent effect on the critical micelle concentration of any copolymeric solution. Although micellar self-assembly was observed in all the monomers molar ratio, the degree of self-assembly was directly proportional to the content of MMA monomer. Moreover, the formation of micelles is favored from all the prepared copolymers due to the high hydrophilic monomeric content in the copolymers. In addition, as-synthesized micelles were spherical and had almost similar diameter, that is, 70–90 nm. Moreover, the loading % of Nile red was also similar in all the self-assembled micelles. It was observed that the lower critical solution temperature (LCST) of the polymer decreases with an increase in MMA content, and at 95/5 molar ratio the LCST of P(VP-co-MMA) was around 40 °C, which is suitable for in vivo drug delivery system. Moreover, high payload release, that is, 44%, was measured from P(VP-co-MMA) (95/5) at 45 °C, as compared to 33% payload release at 37 °C, suggesting that micelles formed from P(VP-co-MMA) (95/5) could be suitable for in vivo drug delivery. [ABSTRACT FROM AUTHOR]

In this study, amphiphilic block copolymer mPEG-cholic acid was synthesized in conjunction with TPGS as stabilizer to prepare multifunctional micelles. The formed polymeric micelles (PCTm) were used for the delivery of paclitaxel (PTX) and bufalin (BF). PEG group could enhance solubility and extend circulation time, while cholic acid groups achieved the liver targeted function. Combinations of these approaches could realize a synergistic therapeutic effect in the treatment of advanced hepatocellular carcinoma. CLSM in vitro results demonstrated that drug capsulation into PCTm could enhance cellular uptake. FCM results confirmed the uptake amount of C6/PCTm was 7.5-fold higher than that of free C6 after incubation for 2 h. Competitive inhibition test proved the Na+-taurocholate co-transporting polypeptide (NTCP) involved in the uptake mechanism of PCTm. Meanwhile, in vivo imaging assays demonstrated that the fluorescence intensity of Cy5.5/PCTm was higher than that of free Cy5.5 on liver and tumor with extended circulation time to 48 h. In addition, in vivo studies confirmed that the combined therapy exhibited the strongest tumor inhibition rate of 82.29% with lower systemic toxicity. Hence, these results indicated that PCTm could provide a promising strategy for targeting hepatocellular carcinoma and achieve the goal of synergism and attenuation. [ABSTRACT FROM AUTHOR]

Hyaluronic acid (HA), an important component of the extracellular matrix, has high water solubility and biocompatibility, and good application prospects in biomedicine. Especially in tumour treatment, prodrug polymer micelles prepared from HA and chemotherapeutics can increase water solubility, prolong drug release time, improve organ distribution and therapeutic effects, and show good tumour targeting and biocompatibility. Therefore, this study introduces strategies for using HA to prepare prodrug polymer micelles and discusses recent research on HA prodrug micelles for antitumor applications. [ABSTRACT FROM AUTHOR]

BACKGROUND: The small molecule drug Kartogenin is an activator of the Smad4/Smad5 pathway. It has a strong ability to promote bone differentiation and can promote the directional differentiation of bone marrow mesenchymal stem cells into osteoblasts, but its drug effect is relatively limited. OBJECTIVE: We designed and developed Kartogenin/Pluronic F127 micelles to observe its effect on the directional osteogenic differentiation of bone marrow mesenchymal stem cells. METHODS: Kartogenin was dissolved in dimethyl sulfoxide and mixed with Pluronic F127 solution. The organic solvent was removed by vacuum rotary evaporator to form a dry drug lipid membrane. PBS was added to prepare Kartogenin/Pluronic F127 micelles. The bone marrow mesenchymal stem cells of rats in the logarithmic growth phase were divided into four groups, which were treated with conventional cell culture medium (blank group), cell culture medium containing Pluronic F127 micelle solution (Pluronic F127 group), cell culture medium containing Kartogenin (drug group), and cell culture medium containing Kartogenin/Pluronic F127 micelle solution (experimental group). Among them, the drug concentration in the drug group and the experimental group was 1 μmol/L, and the micelle concentration in Pluronic F127 group was the same as that in the experimental group. Cell proliferation, apoptosis and expression of osteogenic related proteins were detected. RESULTS AND CONCLUSION: (1) Transmission electron microscope revealed that Kartogenin/Pluronic F127 micelles had irregular spherical shape and uniform particle size distribution. The particle size ranged from 32.6 nm to 118.9 nm, most of which were concentrated at 77.3 nm. (2) MTT assay showed that with the extension of culture time, the cell survival rate of the four groups decreased, but remained above 90%, and there was no significant difference in the cell survival rate among the four groups (P > 0.05). (3) Flow cytometry after 24 hours of treatment showed that there was no significant difference in the cell apoptosis rate among the four groups (P > 0.05). (4) After 24 hours of treatment, western blot assay showed that the expression levels of osteopontin, alkaline phosphatase, bone morphogenetic protein-2 and matrix metalloproteinase-2 in drug group and experimental group were higher than those in Pluronic F127 micelle group and blank group (P < 0.05). The expression levels of alkaline phosphatase, bone morphogenetic protein-2 and matrix metalloproteinase-2 in experimental group were higher than those in drug group (P < 0.05). (5) The results showed that Kartogenin/Pluronic F127 micelles could promote the osteogenic differentiation of bone marrow mesenchymal stem cells. [ABSTRACT FROM AUTHOR]

Purpose: Mitochondria are closely correlated with the proliferation and metastasis of tumor for providing suitable micro-environment and energy supply. Herein, we construct a glucose transporter 1 (GLUT1) targeting and hypoxia activating polyprodrug-based micelle (Glu-PEG-Azo-IR808-S-S-PTX) for mitochondria-specific drug delivery and tumor chemo-thermal therapy. Results: The micelle was characterized by hypoxia-sensitive PEG outer layer detachment, high photothermal conversion efficiency, and glutathione (GSH)-sensitive paclitaxel (PTX) release. It showed GLUT1 specifically cellular uptake and hypoxia-sensitive mitochondria targeting on A549 cell. In vivo fluorescence imaging confirmed the micelle also could selectively accumulate in tumor and its mitochondria on A549 tumor-bearing nude mice. Consequently, it not only exhibited higher cytotoxicity, apoptosis rate, and metastasis inhibition rate on A549 cells, but also better tumor growth and metastasis inhibition rate on tumor-bearing nude mice and lower whole-body toxicity. The mechanism might be caused by destroying mitochondria and down-regulating ATP production. Conclusion: This study provided a GLUT1 targeting, hypoxia, and reductive responsive nanomedicine that hold the potential to be exploited for tumor therapy. [ABSTRACT FROM AUTHOR]

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