Core Of Micelles Research Articles

Fast In Vitro Release and In Vivo Absorption of an Anti-Schizophrenic Drug Paliperidone from Its Soluplus®/TPGS Mixed Micelles.

The purpose of this study was to develop a drug delivery system for paliperidone (PPD) in order to provide a more effective therapeutic strategy for patients with acute schizophrenia. PPD-loaded Soluplus®/TPGS mixed micelles (PPD-S/T-MM) were prepared using the thin-film hydration method. The critical micelle concentration (CMC) of blank S/T-MM was 4.77 × 10−2 mg/mL. PPD presented much higher solubility in PPD-S/T-MM formulation than that in pure water. The particle size of blank or drug loaded S/T-MM was around 60 nm. The polydispersity index (PDI) was less than 0.1. PPD-S/T-MM presented a nearly spherical shape under transmission electron microscopy. The encapsulation efficiency (EE%) of PPD-S/T-MM was higher than 94%. Based on the analysis of XRD and DSC, it was proved that PPD was incorporated in the core of the mixed micelles as amorphous dispersion or solid solution. PPD-S/T-MM were stable when they were undergoing dilution with water and the change of environmental pH. Although PPD-S/T-MM showed lower rates to release PPD than those from PPD raw material in acidic solution, they provided faster release rates in neutral conditions than those from PPD raw material who only showed modest dissolution in the same neutral condition. This proves that PPD-S/T-MM can release PPD in a more controlled manner. After oral administration of PPD-S/T-MM (dose of PPD, 6 mg/kg) in rats, the plasma concentration of PPD increased rapidly: Tmax was 0.83 ± 0.29 h, and Cmax was 844.33 ± 93.73 ng/mL. Oral administration of PPD suspension resulted in longer Tmax and lower Cmax. The relative oral bioavailability was about 158% for PPD-S/T-MM over PPD suspension. These findings confirm that PPD-S/T-MM can provide faster release in neutral conditions and better oral absorption in rats than those from PPD raw material, which should potentially benefit patients with acute schizophrenia.

Core-Cross-Linking of Polymeric Micelles by Di-para-Substituted S-Aroylthiooximes as Linkers for Controlled H2S Release.

As one of the gasotransmitters, the therapeutic effects of hydrogen sulfide (H2S) were reported widespread in recent years. Considering the short physiological half-life and significant dose-dependent effects of H2S, it is vital to achieve controlled H2S delivery for biomedical applications. Polymeric micelles have been explored to regulate H2S delivery. However, the dilution-induced dissociation of micelles in physiological conditions limits their therapeutic effects. The circulation stability of polymeric micelles could be improved through core-cross-linking, but reduced H2S releasing efficiency is usually unavoidable. To solve these problems, we developed di-para-substituted S-aroylthiooximes (p-diSATOs) as linkers, which integrated cross-linking of micelle core and conjugation of H2S donors through one simple reaction. Compared with SATO-bearing non-cross-linked micelle, the core-cross-linked micelle (CCM) prepared through this method exhibited initial rapid H2S release owing to the electron-withdrawing effect of p-diSATOs, and subsequently, a sustained release could last for a long period of time. Considering the characteristic H2S releasing behavior of CCM, it may accelerate wound healing through initial efficient and subsequent prolonged pro-healing effects. As a proof of concept, we explored the therapeutic potential of CCM using a murine burn wound model, which exhibited pro-healing effect on burn wounds.

CD44-targeting hydrophobic phosphorylated gemcitabine prodrug nanotherapeutics augment lung cancer therapy

Gemcitabine (GEM) is among the most used chemotherapies for advanced malignancies including non-small cell lung cancer. The clinical efficacy of GEM is, however, downplayed by its poor bioavailability, short half-life, drug resistance, and dose-limiting toxicities (e.g. myelosuppression). In spite of many approaches exploited to improve the efficacy and safety of GEM, limited success was achieved. The short A6 peptide (sequence: Ac-KPSSPPEE-NH2) is clinically validated for specific binding to CD44 on metastatic tumors. Here, we designed a robust and CD44-specific GEM nanotherapeutics by encapsulating hydrophobic phosphorylated gemcitabine prodrug (HPG) into the core of A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG), which exhibited reduction-triggered HPG release and specific targetability to CD44 overexpressing tumor cells. Interestingly, A6 greatly enhanced the internalization and inhibitory activity of micellar HPG (mHPG) in CD44 positive A549 cells, and increased its accumulation in A549 cancerous lung, leading to potent repression of orthotopic tumor growth, depleted toxicity, and marked survival benefits compared to free HPG and mHPG (median survival time: 59 days versus 30 and 45 days, respectively). The targeted delivery of gemcitabine prodrug with disulfide-crosslinked biodegradable micelles appears to be a highly appealing strategy to boost gemcitabine therapy for advance tumors. Statement of significanceGemcitabine (GEM) though widely used in clinics for treating advanced tumors is associated with poor bioavailability, short half-life and dose-limiting toxicities. Development of clinically translatable GEM formulations to improve its anti-tumor efficacy and safety is of great interest. Here, we report on CD44-targeting GEM nanotherapeutics obtained by encapsulating hydrophobic phosphorylated GEM prodrug (HPG), a single isomer of NUC-1031, into A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG). A6-mHPG demonstrates stability against degradation, enhanced internalization and inhibition toward CD44+ cells, and increased accumulation in A549 lung tumor xenografts, leading to potent repression of orthotopic tumor growth, depleted toxicity and marked survival benefits. The targeted delivery of GEM prodrug using A6-mHPG is a highly appealing strategy to GEM cancer therapy.

Rylene Dye-Loaded Polymeric Nanoparticles for Photothermal Eradication of Harmful Dinoflagellates, Akashiwo sanguinea and Alexandrium pacificum.

In the era of climate changes, harmful dinoflagellate outbreaks that produce potent algal toxins, odor, and water discoloration in aquatic environments have been increasingly reported. Thus, various treatments have been attempted for the mitigation and management of harmful blooms. Here, we report engineered nanoparticles that consist of two different types of rylene derivatives encapsulated in polymeric micelles. In addition, to avoid dissociation of the aggregate, the core of micelle was stabilized via semi-interpenetrating network (sIPN) formation. On two types of the marine red-tide dinoflagellates, Akashiwo sanguinea and Alexandrium pacificum, the nanoparticle uptake followed by fluorescence labeling and photothermal effect was conducted. Firstly, fluorescence microscopy enabled imaging of the dinoflagellates with the ultraviolet chromophore, Lumogen Violet. Lastly, near-infrared (NIR) laser irradiation was exposed on the Lumogen IR788 nanoparticle-treated Ak. Sanguinea. The irradiation resulted in reduced cell survival due to the photothermal effect in microalgae. The results suggested that the nanoparticle, IR788-sIPN, can be applied for potential red-tide algal elimination.

Resveratrol Stabilization and Loss by Sodium Caseinate, Whey and Soy Protein Isolates: Loading, Antioxidant Activity, Oxidability.

The interaction of protein carrier and polyphenol is variable due to their environmental sensitivity. In this study, the interaction between resveratrol and whey protein isolate (WPI), sodium caseinate (SC) and soy protein isolate (SPI) during storage were systematically investigated from the aspects of polyphenol loading, antioxidant activity and oxidability. It was revealed that resveratrol loaded more in the SPI core and existed both in the core of SC micelles and on the particle surface, while WPI and resveratrol mainly formed in complexes. The loading capacity of the three proteins ranked in order SC > SPI > WPI. ABTS assay showed that the antioxidant activity of the protein carriers in the initial state was SC > SPI > WPI. The results of sulfhydryl, carbonyl and amino acid analysis showed that protein oxidability was SPI > SC > WPI. WPI, with the least oxidation, improved the storage stability of resveratrol, and the impact of SC on resveratrol stability changed from a protective to a pro-degradation effect. Co-oxidation occurred between SPI and resveratrol during storage, which refers to covalent interactions. The data gathered here suggested that the transition between the antioxidant and pro-oxidative properties of the carrier is the primary factor to investigate its protective effect on the delivered polyphenol.

Concentration-dependent β-cyclodextrin-promoted refolding of gold nanoparticles-conjugated bovine serum albumin complexed with gemini surfactants with different spacer groups

This work demonstrates refolding of unfolded bioconjugated bovine serum albumin [(BSA, 10 μM):gold nanoparticles (AuNPs, 0.0124 μM)] using β-cyclodextrin (β-CD). Protein bioconjugates are first unfolded with 0.2 mM of each of gemini surfactants, 12–4–12,2Br and 12–8–12,2Br- that have hydrophobic spacer groups of different lengths. At this concentration of a gemini surfactant, protein bioconjugates remain in compressed form due to strong hydrophobic interactions imparted by highly hydrophobic microdomain within the core of the gemini micelles formed along the chain of a bioconjugate. The compressed protein bioconjugates get relaxed in presence of a low concentration of β-CD which strips off surfactant molecules from bioconjugate-micelles complexes. Relaxed denatured protein bioconjugates then get refolded once remaining surfactant molecules are stripped off at a higher concentration of β-CD. A step-wise refolding process of bioconjugated protein chains exactly opposite to the unfolding is noted. Binding isotherms are constructed using Förster’s resonance energy transfer (FRET) and nanometal surface energy transfer (NSET) parameters calculated based on energy transfer process occurs between Trp residues and AuNPs. α-helix of protein bioconjugates remains in inverse relationship to β-turns during refolding by β-CD. Refolding is found to be more in presence of 12–8–12,2Br- than 12–4–12,2Br-. Secondary/tertiary structural changes of refolded BSA, on being bioconjugated, have been determined through various spectroscopic analysis. An approach towards construing the refolding of denatured AuNPs-bioconjugates as potential materials and impacts of AuNPs on conformations of refolded protein is presented here.

Microfluidic Synthesis of Block Copolymer Micelles: Application as Drug Nanocarriers and as Photothermal Transductors When Loading Pd Nanosheets.

The synthesis of polymeric nanoparticles from a block copolymer based on poly(ethylene glycol) and a polymethacrylate containing the nucleobase analog 2,6-diacylaminopyridine is optimized by microfluidics to obtain homogeneous spherical micelles. Loading and delivery properties are studied using naproxen as a model. The incorporation of a Pd precursor in the polymer organic solution fed into the micromixer allows the preparation of Pd(II) precursor-polymer hybrid systems and the subsequent reduction with CO leads to the in situ synthesis of Pd nanosheets inside of the hydrophobic core of the polymeric micelles. This methodology is highly efficient to yield all polymeric nanoparticles loaded with Pd nanosheets as detected by electron microscopy and energy-dispersive X-ray spectroscopy. The cell viability of these Pd nanosheets-containing polymeric nanoparticles is evaluated using five cell lines, showing a high cytocompatibility at the tested concentrations without detrimental effects in cell membrane and nuclei. Furthermore, the use of these hybrid polymeric nanoparticles as photothermal transductors is evaluated using near infrared as irradiation source as well as its application in photothermal therapy using different cell lines demonstrating a high efficiency in all cell cultures.

Enhanced thermodynamic, pharmacokinetic and theranostic properties of polymeric micelles via hydrophobic core-clustering of superparamagnetic iron oxide nanoparticles

BackgroundSuperparamagnetic iron oxide nanoparticles (SPIO) have been applied for decades to design theranostic polymeric micelles for targeted cancer therapy and diagnostic MR imaging. However, the effects of SPIO on the physicochemical, and biological properties of polymeric micelles have not yet been fully elucidated. Therefore, we investigated potential effect of SPIO on the physical and biological properties of theranostic polymeric micelles using representative cancer drug (doxorubicin; Doxo) and polymer carrier (i.e., poly (ethylene glycol)-co-poly(D,L-lactide), PEG-PLA).MethodsSPIO were synthesized from Fe(acetyl acetonate)3 in an aryl ether. SPIO and Doxo were loaded into the polymeric micelles by a solvent-evaporation method. We observed the effect of SPIO-clustering on drug loading, micelle size, thermodynamic stability, and theranostic property of PEG-PLA polymeric micelles. In addition, cellular uptake behaviors, pharmacokinetic and biodistribution study were performed.ResultsSPIO formed hydrophobic geometric cavity in the micelle core and significantly affected the integrity of micelles in terms of micelle size, Doxo loading, critical micelle concentration (CMC) and in vitro dissociation. In vivo pharmacokinetic studies also showed the enhanced Area Under Curve (AUC) and elongated the half-life of Doxo.ConclusionsClustered SPIO in micelles largely affects not only MR imaging properties but also biological and physical properties of polymeric micelles.

Morphology of Ionic Micelles as Studied by Numerical Solution of the Poisson Equation.

The existing concepts of the ionic micelle structure were specified. It was noted that the composition of dispersed phase particles in a liquid dispersion medium should necessarily include adsorbed counterions rigidly bound to these particles. By numerical solution of the Poisson equation for the two most often used approximations, the Poisson–Boltzmann (PB) model and the Jellium-approximation (JA), the electric potential decay from the Stern potential of dispersed phase particles was defined. A new methodological approach to analyze the reaction of micelle potential decay based on small variability of the CMC value was proposed. It made possible to determine the dimension parameter, which in the presence of weak thermal effects approximately corresponds to the micelle hydrodynamic radius, and to calculate the electrokinetic potential of micelles. The results of theoretical calculations were compared with our previous experimental data on the thickness of the SDS micelle hydrophilic layer obtained by SAXS. A good agreement between the calculated and measured values was obtained, and it was noted that for low concentrations the experimental values are more correctly described by the PB model, but for concentrations greater than 100 mM the JA model is more preferable. It was found that the slipping plane is located near the outer Stern plane and is separated from it only by a few molecular layers of water. The influence stronger than the thermal one can shift the slipping plane closer to the micelle core. Accordingly, the smallest hydrodynamic micelle size is determined by the outer Stern plane. The results of our work allowed us to conclude that the micelle is not something soft and watery, but according to its specified structure, it is a more solid-like particle than was previously assumed. The proposed approach can be extended to investigate other effects of a physicochemical nature, in particular, those observed with the addition of an external electrolyte or nanoparticles.

Universal Scaling for the Exit Dynamics of Block Copolymers from Micelles at Short and Long Time Scales.

The correlation function for the exit of poloxamer copolymers from equilibrated micelles is found to show up to four regimes depending on the chain flexibility: an initial fast reorganization, a logarithmic intermediate regime, followed by an exponential intermediate regime, and a final exponential decay. The logarithmic intermediate regime has been observed experimentally and attributed to the polydispersity of the polymer samples. However, we present dynamic single-chain mean-field theory simulations with chains of variable flexibility which show the same logarithmic relaxation but with strictly monodisperse systems. In agreement with our previous studies, we propose that this logarithmic response arises from a degeneracy of energy states of the hydrophobic block in the micelle core. For this to occur, a sufficiently large number of degenerate conformational states are required, which depend on the polymer flexibility and therefore should not be present for rigid polymers. Experimental results for monodisperse polymeric samples claiming the absence of such a logarithmic response may also lack a sufficient number of hydrophobic blocks for the required number of configurational states for this type of response to be seen. The insight gained from analyzing the simulation results allows us to propose a modified Eyring equation capable of reproducing the observed dynamic behavior. On scaling experimental results from different sources and systems according to this equation, we find a unique master curve showing a universal nature of the intermediate regimes: the logarithmic regime together with the secondary exponential decay. The terminal exponential regime at long times proposed by the standard Halperin and Alexander model is beyond the range of the data analyzed in this article. The universality observed suggests an entropic origin of the short-time dynamic response of this class of systems rather than the polydispersity.

Downsizing to 25-nm Reverse Polymeric Micelle Composed of AB3-type Polydepsipeptide with Comprising siRNA

Abstract Amphiphilic block polydepsipeptides of AB-type and AB3-type (hydrophilic A block: poly(sarcosine), hydrophobic B block: poly(l-lactic acid)) were prepared, and the N-terminals were arranged by guanidium or guanidino-peptide nucleic acid for loading siRNA in a reverse polymeric micelle. The amphiphilic polymers were successfully dispersed and assembled into reverse micelles in triglyceride or diisopropyl adipate. With loading siRNA into the core of the polymeric micelles, the micelle size was reduced down to a diameter of 25 nm in the case of the guanidino-peptide nucleic acid used as the capturing site. This small-size reverse micelle may be available for a transdermal drug delivery system (DDS) for siRNA.

Charged Polypeptide Tail Boosts the Salt Resistance of Enzyme-Containing Complex Coacervate Micelles.

Encapsulation of proteins can have advantages for their protection, stability, and delivery purposes. One of the options to encapsulate proteins is to incorporate them in complex coacervate core micelles (C3Ms). This can easily be achieved by mixing aqueous solutions of the protein and an oppositely charged neutral-hydrophilic diblock copolymer. However, protein-containing C3Ms often suffer from salt-inducible disintegration due to the low charge density of proteins. The aim of this study is to improve the salt stability of protein-containing C3Ms by increasing the net charge of the protein by tagging it with a charged polypeptide. As a model protein, we used CotA laccase and generated variants with 10, 20, 30, and 40 glutamic acids attached at the C-terminus of CotA using genetic engineering. Micelles were obtained by mixing the five CotA variants with poly(N-methyl-2-vinyl-pyridinium)-block-poly(ethylene oxide) (PM2VP128-b-PEO477) at pH 10.8. Hydrodynamic radii of the micelles of approximately 31, 27, and 23 nm for native CotA, CotA-E20, and CotA-E40, respectively, were determined using dynamic light scattering (DLS) and fluorescence correlation spectroscopy (FCS). The encapsulation efficiency was not affected using enzymes with a polyglutamic acid tail but resulted in more micelles with a smaller number of enzyme molecules per micelle. Furthermore, it was shown that the addition of a polyglutamic acid tail to CotA indeed resulted in improved salt stability of enzyme-containing C3Ms. Interestingly, the polyglutamic acid CotA variants showed an enhanced enzyme activity. This study demonstrates that increasing the net charge of enzymes through genetic engineering is a promising strategy to improve the practical applicability of C3Ms as enzyme delivery systems.

Interfacial geometry in particle-forming phases of diblock copolymers

Frank-Kasper phases are complex particle packings known to form in a wide variety of hard and soft materials, including single-component AB diblock copolymer melts. An important open question in the context of this system is why these lower-symmetry packings are selected over the classical, higher-symmetry, body-centered cubic phase. To address this question, we simulated a library of diblock copolymer melts under intermediate-segregation conditions using self-consistent field theory and performed a combination of geometric and thermodynamic analyses. Our findings show that imprinting of the enclosing Voronoi polyhedra onto the micelle core is generally weak, but nonetheless coincides with sharpening of the interface between A and B monomers compared to more spherical cores. The corresponding reduction in enthalpy, which is the dominant contribution to the free energy, drives the bcc-$\ensuremath{\sigma}$ transition, overcoming increases in stretching penalties and giving way to more polyhedral micelle cores. These results offer insight into the stability and formation of Frank-Kasper phases under experimentally realistic conditions.

Specific Interactions in the Model of Mixed Multicomponent Micelles: Predicting Aggregation Behavior and Details of Structure

Modeling of multicomponent micellar aggregates is important for screening and selecting formulations in a variety of engineering applications, including micelle-mediated separation, drug delivery and nanoreactors. Typically, the constituent molecules of such aggregates have complex chemical structure and are engaged in specific and nonspecific interactions with one another and with the hydration water. Description of these interactions in the strongly nonuniform aggregates is very difficult, impeding the development of the theoretical models. In this work we extend to the multicomponent aggregates a molecular-thermodynamic model that describes the hydrogen bonding and other specific interactions in the hydrated corona. The model is formulated for an arbitrary number of nonionic and ionic amphiphiles that self-assemble into polydisperse aggregates in an aqueous solution. For describing the aggregation equilibrium together with the material balance in this solution, a simple method is suggested and tested. We illustrate application of our model by predicting aggregation equilibrium and characteristics of the three-component aggregates in the aqueous mixture of the nonionic surfactant Triton X-114, a micelle-forming alkylimidazolium ionic liquid (1-methyl-3-octylimidazolium chloride), and n-octanol. Our calculations suggest that the tails of the octanol molecules are deeply buried in the cores of the mixed micelles with only one methylene group penetrating the coronae and that the entire hydrocarbon tail of the ionic liquid resides in the core. Taking into account the populations of polydisperse spherical and rodlike aggregates, we model equilibrium partitioning of the components between the aggregates and the surrounding aqueous solution. The model predicts that addition of the ionic liquid to the mixture promotes the partitioning of n-octanol into the Triton-rich micelles.

Temperature-Transferable Coarse-Grained Model for Poly(propylene oxide) to Study Thermo-Responsive Behavior of Triblock Copolymers.

Thermo-responsive behavior of ethylene oxide (EO)-propylene oxide (PO) copolymers makes them suitable for many potential applications. Reproducing the origins of the tunable properties of EO-PO copolymers using coarse-grained (CG) models such as the MARTINI force field is critically important for building a better understanding of their behavior. In the present work, we have investigated the effects of coarse-graining on the water-polymer interaction across a temperature range. We compared the performance of different all-atom force fields to find the most appropriate one for the purpose of PO block parameterization in the MARTINI platform. We parameterized a CG temperature-dependent PO model based on the reproduction of the atomistic free energy of transfer of propylene oxide trimer from octane to water over a range of temperatures (20-60 °C) and compared the atomistic bond and angle distributions. Then, we used the model to study the effects of EO/PO ratio, molecular weight, and concentration on the thermo-responsive behavior of EO-PO copolymers in water. The results show an excellent agreement with experiments in different areas. Our temperature-dependent model reproduces (1) micellar phase above critical micelle temperature (CMT) and unimer phase below CMT for different Pluronics (a class of EO-PO triblock copolymers) spanning many EO/PO ratios and molecular weights; (2) spherical-to-rodlike micellar shape transition for Pluronics with 60 wt % of PO content or more; (3) diffusion coefficients for Pluronics with high PO content (P104 Pluronic with a PO mass of 3500 g mol-1) across a broad range of temperatures; and (4) micelle core size and micelle diameter similar to experimental results. Overall, our model improves the temperature sensitivity of EO-PO copolymers of existing models significantly, particularly for copolymers that are dominated by PO agents.

Preparation, characterization and antioxidant properties of curcumin encapsulated chitosan/lignosulfonate micelles

In this work, chitosan/lignosulfonate composite micelles (CS-LS) were successfully prepared through polyelectrolyte self-assembly. Curcumin was encapsulated in CS-LS to obtain CUR-CS-LS. The results showed that the average diameter of CS-LS and CUR-CS-LS were 239 nm and 286 nm, respectively. The results show that the aromatic rings of lignosulfonate are assembled into the hydrophobic core of micelles through π–π interactions, and chitosan binds outside the hydrophobic core as a hydrophilic shell through electrostatic interactions. Curcumin is encapsulated in the hydrophobic core through hydrophobic interactions. Encapsulation improves the thermal stability and pH stability of curcumin. Compared with free curcumin, the retention efficiency of curcumin in CUR-CS-LS increased by approximately 6.66 and 6.46 times under the same heat treatment and pH conditions, respectively. Encapsulation also increases the antioxidant activity of curcumin in aqueous solution. In addition, the release mechanism of curcumin is diffusion and matrix swelling. These findings explain that CS-LS may be an effective promising delivery system for encapsulating hydrophobic biologically active substances.

Scission energy and topology of micelles controlled by the molecular structure of additives.

We employ coarse-grained (CG) molecular dynamics simulations (MD) to investigate the effects of the molecular structure of additives on the scission energy and morphology of charged micelles. Considering sodium dodecyl sulfate (SDS) as a representative charged surfactant and taking trimethylphenylammonium chloride (TMPAC) and octyltrimethylammonium bromide (OTAB) as oppositely charged additives, we show that the scission energy and topology of micelles vary significantly depending on the molecular structure of the hydrophobic part of the additives. The cyclic aromatic tail of the TMPAC disrupts the core structure of the SDS micelle and hence decreases the micelle scission energy, whereas the linear alkyl tail of the OTAB packs very well with the micelle core and increases the scission energy. Although both the additives have similar head structures, they lead to very different micelle morphologies because of the difference in the shape of their tail structures; ring-like or toroidal shaped micelles are formed in SDS/TMPAC solution whereas bicelle-like structures are formed in SDS/OTAB solution when the additive to surfactant ratio is higher than a certain value.

Covalent core-radiolabeling of polymeric micelles with 125I/211At for theranostic radiotherapy.

Astatine-211 (211At) is one of the most promising α-emitters for targeted alpha therapy, especially of cancer metastases. However, the lack of a stable isotope, frequent in vivo deastatination, and limited radiochemical knowledge makes it challenging to apply. Here, we report a new strategy for radiolabeling the lipophilic core of polymeric micelles (PMs) with covalently bound 211At. The PMs were radiolabeled via either an indirect synthon-based method or directly on the amphipathic block copolymer. The radiochemistry was optimized with iodine-125 (125I) and then adapted for 211At, enabling the use of both elements as a potential theranostic pair. PMs that were core-radiolabeled with both 125I or 211At were prepared and characterized, based on a PEG(5k)-PLGA(10k) co-polymer. The stability of the radiolabeled PMs was evaluated in mouse serum for 21 h, showing radiochemical stability above 85%. After in vivo evaluation of the 211At- labeled PMs, 4-5 % ID/g of the 211At could still be detected in the blood, showing a promising in vivo stability of the PMs. Further, 211At-labeled PMs accumulated in the spleen (20-30 %ID/g) and the liver (2.5- 5.5 %ID/g), along with some detection of 211At in the thyroid (3.5-9 %ID/g). This led to the hypothesis that deastatination takes place in the liver, whereas good stability of the 211At core-radiolabel was observed in the blood.

Effect of tertiary amino groups in the hydrophobic segment of an amphiphilic block copolymer on zinc phthalocyanine encapsulation and photodynamic activity.

Polymer micelles are promising nanocarriers for hydrophobic photosensitizers of photodynamic therapy (PDT). Poly(styrene-co-(2-(N,N-dimethylamino)ethyl acrylate))-block-poly(polyethylene glycol monomethyl ether acrylate) (P(St-co-DMAEA)-b-PPEGA; 1) was prepared via reversible addition and fragmentation chain transfer (RAFT) polymerization as a carrier for a zinc phthalocyanine (ZnPc) photosensitizer to be used in PDT. The DMAEA-unit composition in the P(St-co-DMAEA) segment was adjusted to 0.40 molar ratio, which caused a sharp increase in water-solubility when the pH decreased from 7.4 to 5.0. The polymer 1 micelle size distribution also shifted to lower when the pH decreased, whereas this change was not observed in PSt-co-PPEGA (2), which was previously reported. The UV-vis spectrum of the ZnPc-loaded micelles of polymer 1 exhibited relatively sharp Q bands, comparable to those measured in DMSO, indicating good compatibility of the condensed core with ZnPc. ZnPc-loaded micelles of polymer 1 exerted excellent photocytotoxicity in the MNNG-induced mutant of the rat murine RGM-1 gastric epithelial cell line (RGK-1). In contrast, the ZnPc-loaded micelles of polymer 2 were completely inactive under the same conditions. Fluorescence from the RGK-1 cells treated with ZnPc-loaded micelles of polymer 1 was observed after 4 h of co-incubation, while no fluorescence was observed in cells treated with ZnPc-loaded micelles of polymer 2. These results indicate that the pH-responsive nature and good compatibility with ZnPc exhibited by the polymer 1 micelles are essential characteristics of ZnPc carriers for efficient photodynamic therapy.

Enhanced stability of complex coacervate core micelles following different core-crosslinking strategies.

Complex coacervate core micelles (C3Ms) are formed by mixing aqueous solutions of a charged (bio)macromolecule with an oppositely charged-neutral hydrophilic diblock copolymer. The stability of these structures is dependent on the ionic strength of the solution; above a critical ionic strength, the micelles will completely disintegrate. This instability at high ionic strengths is the main drawback for their application in, e.g., drug delivery systems or protein protection. In addition, the stability of C3Ms composed of weak polyelectrolytes is pH-dependent as well. The aim of this study is to assess the effectiveness of covalent crosslinking of the complex coacervate core to improve the stability of C3Ms. We studied the formation of C3Ms using a quaternized and amine-functionalized cationic-neutral diblock copolymer, poly(2-vinylpyridine)-block-poly(ethylene oxide) (QP2VP-b-PEO), and an anionic homopolymer, poly(acrylic acid) (PAA). Two different core-crosslinking strategies were employed that resulted in crosslinks between both types of polyelectrolyte chains in the core (i.e., between QP2VP and PAA) or in crosslinks between polyelectrolyte chains of the same type only (i.e., QP2VP). For these two strategies we used the crosslinkers 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and dimethyl-3,3'-dithiopropionimidate dihydrochloride (DTBP), respectively. EDC provides permanent crosslinks, while DTBP crosslinks can be broken by a reducing agent. Dynamic light scattering showed that both approaches significantly improved the stability of C3Ms against salt and pH changes. Furthermore, reduction of the disulphide bridges in the DTBP core-crosslinked micelles largely restored the original salt-stability profile. Therefore, this feature provides an excellent starting point for the application of C3Ms in controlled release formulations.