Core-shell Micellar Structure Research Articles

Polymeric Nanocarriers with Controlled Chain Flexibility Boost mRNA Delivery In Vivo through Enhanced Structural Fastening.

Messenger RNA (mRNA) shows high therapeutic potential, though effective delivery systems are still needed for boosting its application. Nanocarriers loading mRNA via polyion complexation with block catiomers into core-shell micellar structures are promising systems for enhancing mRNA delivery. Engineering the interaction between mRNA and catiomers through polymer design can promote the development of mRNA-loaded micelles (mRNA/m) with increased delivery efficiency. Particularly, the polycation chain rigidity may critically affect the mRNA-catiomer interplay to yield potent nanocarriers, yet its effect remains unknown. Herein, the influence of polycation stiffness on the performance of mRNA/m by developing block complementary catiomers having polycation segments with different flexibility, that is, poly(ethylene glycol)-poly(glycidylbutylamine) (PEG-PGBA) and PEG-poly(L-lysine) (PEG-PLL) is studied. PEG-PGBA allows more than 50-fold stronger binding to mRNA than the relatively more rigid PEG-PLL, resulting in mRNA/m with enhanced protection against enzymatic attack and polyanions. mRNA/m from PEG-PGBA significantly enhances mRNA in vivo bioavailability and increased protein translation, indicating the importance of controlling polycation flexibility for forming stable polyion complexes with mRNA toward improved delivery.

Superparamagnetic Iron Oxide Nanoparticles/Doxorubicin-Loaded Starch-Octanoic Micelles for Targeted Tumor Therapy.

The magnetic resonance imaging diagnosis and high-efficiency tumor targeting treatment are of notable importance for cancer therapy. In this study, starch-octanoic acid (ST-OA) micelles were successfully prepared to co-encapsulate the anti-tumor drug doxorubicin (DOX) and superparamagnetic iron oxide nanoparticles (SPIONs), taking advantage of the hydrophobic core of the core-shell micellar structure. Size distribution, morphology and in vitro release behaviors of micelles were investigated. In addition, magnetic properties and the anti-tumor theranostic performance were confirmed by conducting the cellular uptake, in vivo imaging and anti-tumor activity experiments. Therefore, co-encapsulation and specific delivery of the chemotherapeutic drug and contrast agent into tumor cells can realize the diagnosis and treatment of malignant tumor at the same time.

Amphiphilic diblock and triblock copolymers based on poly(2-methyl-2-oxazoline) and poly(D,L-lactide): Synthesis, physicochemical characterizations and self-assembly properties

A range of amphiphilic diblock and triblock copolymers based on poly (2-methyl-2-oxazoline) (PMeOx) and poly (D,L-lactide) (PLA) with various compositions and molecular masses were prepared combining cationic ring-opening polymerization and click chemistry. Their hydrophilic weight ratios (f) covered a wide range of composition (21–77%). In water, these amphiphilic copolymers self-assembled to form, in the case of diblock copolymers, core-shell micellar structures with a dense PLA core and a hydrated PMeOx shell in the whole range of f values. The triblock copolymers formed micellar aggregates of finite sizes made of bridged micelles, the micelles being connected by some of the PLA end-blocks. Moreover, the micelles displayed original core-multishell nanostructures in a specific range of f values (48%), never reported for this kind of triblock copolymers. The amphiphilic copolymers of this study displayed a rich variety of controlled self-assembled morphologies which could be promising candidates for drug delivery applications.

Mild microwave activated, chemo-thermal combinational tumor therapy based on a targeted, thermal-sensitive and magnetic micelle.

The development of combinational anti-tumor therapy is of great value. Here, the thermal-sensitive and hepatic tumor cell targeting peptide-A54 modified polymer, A54-poly(ethylene glycol)-g-poly(acrylamide-co-acrylonitrile) (A54-PEG-g-p(AAm-co-AN)) can self-assemble into an 80nm-sized micelle, which shows a thermal-sensitive behavior with an upper critical solution temperature (UCST) of 43°C. This self-assembled and targeted A54-PEG-g-p(AAm-co-AN) micelle can co-encapsulate anti-tumor drug doxorubicin (DOX) and magnetic nanoparticles (MNPs) taking advantage of the hydrophobic core of the core-shell micellar structure, when the temperature is lower than 43°C. A much higher accumulation of the MNPs@A54-PEG-g-p(AAm-co-AN) to the tumor navigated by the A54 targeting peptide is achieved. Due to the thermal-agent effect of the accumulated MNPs in tumor, the mild microwave (8W) applied afterwards specifically elevates the local tumor temperature by 13°C, compared to 6°C without MNPs accumulation in 30min. The greater temperature rise resulted from the thermal-agent effect of MNPs doesn't only activate the drug release inside tumor cells, but also achieve an augmented hyperthermia. A mild microwave activated, chemo-thermal combinational tumor therapy is thus developed.

Micelles from HOOC-PnBA-b-PAA-C12H15 Diblock Amphiphilic Polyelectrolytes as Protein Nanocarriers.

We investigate the potential of self-assembled nanostructures of the PnBA-b-PAA amphiphilic diblock polyelectrolyte as candidates for protein nanocarriers. Three PnBA-b-PAA copolymers with different molecular weights and PnBA/PAA weight ratios are tested. The system with the most well-defined core-shell micellar structure is chosen for complexation with lysozyme. Its solutions are found to contain well-defined core-shell micelles that are stable upon increase in solution salt content to physiological levels. Upon mixing with lysozyme we find that the protein globules accumulate preferably at the outer parts of the hydrated corona of the micelles. Increasing the protein concentration, intermicellar aggregation is enhanced in a controllable way. At high salt content the number of proteins per micelle is lower compared with the low salt content, which points to an interaction of predominantly electrostatic nature. While light scattering is very sensitive to complexation, small-angle neutron scattering is able to distinguish between the contributions from individual micelles and aggregates. This work demonstrates the use of scattering techniques to characterize protein-polymer interactions in multiple hierarchical levels.

Deoxycholic acid-grafted PEGylated chitosan micelles for the delivery of mitomycin C

Mitomycin C (MTC) was incorporated to a micelle system preparing from a polymer named deoxycholic acid chitosan-grafted poly(ethylene glycol) methyl ether (mPEG-CS-DA). mPEG-CS-DA was synthesized and characterized by 1H nuclear magnetic resonance (1H-NMR) and Fourier transform infrared spectroscopy. mPEG-CS-DA formed a core-shell micellar structure with a critical micelle concentration of 6.57 µg/mL. The mPEG-CS-DA micelles were spherical with a hydrodynamic diameter of about 231 nm. After poly(ethylene glycol)ylation of deoxycholic acid chitosan (CS-DA), the encapsulation efficiency and drug loading efficiency increased from 50.62% to 56.42% and from 20.51% to 24.13%, respectively. The mPEG-CS-DA micelles possessed a higher drug release rate than the CS-DA micelles. For pharmacokinetics, the area under the curve (AUC) of the mPEG-CS-DA micelles was 1.5 times higher than that of MTC injection, and these micelles can enhance the bioavailability of MTC. mPEG-CS-DA micelles reduced the distribution of MTC in almost all normal tissues and had the potential to improve the kidney toxicity caused by MTC injection.

Tailoring the amphiphilicity and self-assembly of thermosensitive polymers: end-capped PEG-PNIPAAM block copolymers.

In this work we report on the synthesis and self-assembly of a thermo-sensitive block copolymer system of n-octadecyl-poly(ethylene glycol)-block-poly(N-isopropylacrylamide), abbreviated as C18-PEGn-b-PNIPAAMm. We present a facile synthetic strategy for obtaining highly tunable thermo-responsive block copolymers starting from commercial PEG-based surfactants (Brij®) or a C18 precursor and conjugating with PNIPAAM via an Atom Transfer Radical Polymerization (ATRP) protocol. The self-assembly and detailed nanostructure were thoroughly investigated in aqueous solutions using both small-angle X-ray and neutron scattering (SAXS/SANS) combined with turbidity measurements. The results show that the system forms rather well defined classical micellar structures at room temperature that first undergo a collapse, followed by inter-micellar aggregation upon increasing the temperature. For the pure C18-PNIPAAM system, however, rather ill-defined micelles were formed, demonstrating the important role of PEG in regulating the nanostructure and the stability. It is found that the PEG content can be used as a convenient parameter to regulate the thermoresponse, i.e., the onset of collapse and aggregation. A detailed theoretical modeling analysis of the SAXS/SANS data shows that the system forms typical core-shell micellar structures. Interestingly, no evidence of back folding, where PEG allows PNIPAAM to form part of the C18 core, can be found upon crossing the lower critical solution temperature (LCST). This might be attributed to the entropic penalty of folding a polymer chain and/or enthalpic incompatibility between the blocks. The results show that by appropriately varying the balance between the hydrophobic and hydrophilic content, i.e. the amphiphilicity, tunable thermoresponsive micellar structures can be effectively designed. By means of SAXS/SANS we are able to follow the response on the nanoscale. These results thus give considerable insight into thermo-responsive micellar systems and provide guidelines as to how these systems can be tailor-made and designed. This is expected to be of considerable interest for potential applications such as in nanomedicine where an accurate and tunable thermoresponse is required.

The influence of selective solvents on the transition behavior of poly(styrene-b-monomethoxydiethylenglycol-acrylate-b-styrene) thick films

Thick poly(styrene-b-monomethoxydiethylenglycol-acrylate-b-styrene) [P(S-b-MDEGA-b-S)] films (thickness 5 μm) are prepared from different solvents on flexible substrates by solution casting and investigated with small-angle X-ray scattering. As the solvents are either PS- or PMDEGA-selective, micelles with different core-shell micellar structures are formed. In PMDEGA-selective solvents, the PS block is the core and PMDEGA is the shell, whereas in PS-selective solvents, the order is reversed. After exposing the films to liquid D2O, the micellar structure inside the films prepared from PMDEGA-selective solvents remains unchanged and only the PMDEGA (shell part) swells. On the contrary, in the films prepared from PS-selective solvents, the micelles revert the core and the shell. This reversal causes more entanglements of the PMDEGA chains between the micelles. Moreover, the thermal collapse transition of the PMDEGA block in liquid D2O is significantly broadened. Irrespective of the solvent used for film preparation, the swollen PMDEGA shell does not show a prominent shrinkage when passing the phase transition, and the transition process occurs via compaction. The collapsed micelles have a tendency to densely pack above the transition temperature.

Self-Assembly Behavior of Thermoresponsive Oligo(ethylene glycol) Methacrylates Random Copolymer.

A well-defined random copolymer containing 2-(2-methoxyethoxy) ethyl methacrylate (MEO2MA, Mn = 188 g/mol) and poly(ethylene glycol) methyl ether methacrylate (PEGMA, Mn = 2080 g/mol) (poly(MEO2MA-co-PEGMA2080)), Mn = 17300 g/mol) was synthesized using the atom transfer radical polymerization (ATRP) process, and its thermoresponsive behaviors in aqueous solution were investigated. In comparison to other temperature-sensitive random copolymers based on oligo(ethylene glycol) methacrylates, this copolymer exhibited an unusual thermally induced two-stage aggregation process. The copolymer chains associate at the first thermal transition followed by a rearrangement process at the second thermal transition to produce a stable core-shell micellar structure. The morphology of the micelle comprises of a methacrylate core stabilized by the longer ethylene glycol segments (Mn = 2080 g/mol) shell.

Syntheses of amphiphilic biodegradable copolymers of poly(ethyl ethylene phosphate) and poly(3-hydroxybutyrate) for drug delivery

Biodegradable and amphiphilic triblock copolymers poly(ethyl ethylene phosphate)-poly(3-hydroxy-butyrate)-poly(ethyl ethylene phosphate) (PEEP-b-PHB-b-PEEP) have been successfully synthesized through ring-opening polymerization. The structures are confirmed by gel permeation chromatography and NMR analyses. Crystallization investigated by X-ray diffraction reveals that the block copolymer with higher content of poly(ethyl ethylene phosphate) (PEEP) is more amorphous, showing decreased crystallizability. The obtained copolymers self-assemble into biodegradable nanoparticles with a core-shell micellar structure in aqueous solution, verified by the probe-based fluorescence measurements and transmission electronic microscopy (TEM) observation. The hydrophobic poly(3-hydroxybutyrate) (PHB) block serves as the core of the micelles and the micelles are stabilized by the hydrophilic PEEP block. The size and size distribution are related to the compositions of the copolymers. Paclitaxel (PTX) has been encapsulated into the micelles as a model drug and a sustained drug release from the micelles is observed. MTT assay also demonstrates that the block copolymers are biocompatible, rendering these copolymers attractive for drug delivery.

Complexes of Polyelectrolyte-Neutral Double Hydrophilic Block Copolymers with Oppositely Charged Surfactant and Polyelectrolyte

Complexes between sodium (sulfamate-carboxylate)isoprene/ethylene oxide double hydrophilic diblock copolymers (SCIEO) and dodecyltrimethylammonium bromide (DTMAB), as well as quaternized poly(2-vinylpyridine) (QP2VP), were studied in aqueous solutions, at pH 7. The complexes are formed due to electrostatic interactions between the anionic groups of the polyelectrolyte block of the copolymers and the cationic groups of the surfactant or the homopolyelectrolyte. The structure of the complexes was investigated as a function of the mixing ratio of the two components in solution and ionic strength by static, dynamic, and electrophoretic light scattering, atomic force microscopy, and fluorescence spectroscopy. The mass and size of the complexes depend on the mixing ratio between the components. A transition from intrachain to an interchain association was observed for block copolymer/ surfactant complexes. SCIEO/QP2VP complexes were found to respond to increasing concentrations of added salt. Spherical and ellipsoid shaped complexes with a core-shell micellar like structure were formed in the systems studied.

Methoxy poly(ethylene glycol)-conjugated linoleic acid polymeric micelles for paclitaxel delivery

A methoxy poly(ethylene glycol) (MePEG)-conjugated linoleic acid (CLA) polymeric conjugate is synthesized with the use of dicyclohexycarbodiimide and 4-dimethylaminopyridine as the coupling agent and the catalyst, respectively. Self-assembled MePEG-CLA conjugate micelles are prepared by dialysis in water. Fluorescence spectroscopy indicates that the MePEG-CLA conjugate exhibits a typical core-shell micellar structure, and the estimated critical micelle concentration is 1.2 × 10−5 mol L−1. Dynamic light scattering and transmission electron microscopy demonstrate that the prepared MePEG-CLA micelles have spherical shape and an average diameter of approximately 100 nm. Paclitaxel is entrapped into MePEG-CLA lyophilized powder. The release of paclitaxel from the loaded micelles is investigated in vitro. A biphasic release pattern with a fast release rate followed by a slow release is observed.

Incorporation of camptothecin into N-phthaloyl chitosan-g-mPEG self-assembly micellar system

The capability of N-phthaloylchitosan-grafted poly (ethylene glycol) methyl ether (mPEG)(PLC-g-mPEG) to enhance the aqueous solubility and stability of the lactone form of camptothecin (CPT) was investigated. PLC-g-mPEG formed a core-shell micellar structure after dialysis of the polymer solutions in dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) against water, with a critical micelle concentration (CMC) of 28 μg/ml. CPT was loaded into the inner core of the micelles by dialysis method. The results showed an increase in the CPT-loading amount with an increasing concentration of CPT. The stability of drug-loaded micelles was studied by gel-permeation chromatography (GPC), and their in vitro release behaviors were analyzed. Release of CPT from the micelles was sustained. When compared to the unprotected CPT, CPT-loaded PLC-g-mPEG micelles were able to prevent the hydrolysis of the lactone group of the drug. The kinetics of the CPT hydrolysis in human serum albumin (HSA) and fetal bovine serum (FBS) were pseudo-first order. The hydrolysis rate constants for CPT and CPT-loaded PLC-g-mPEG micelles in phosphate-buffered saline (PBS) pH 7.4, were 7.4 × 10 −3 min −1 and 9.1 × 10 −3 h −1, parallel to an increase in half-life of CPT from 94 min to 76.15 h, respectively.

Surface Morphologies of Langmuir−Blodgett Monolayers of PEOnPSn Multiarm Star Copolymers

Star polymers composed of equal numbers of poly(ethylene oxide) (PEO) and polystyrene (PS) arms with variable lengths and a large (up to 38 total) number of arms, PEO(n)PS(n), have been examined for their ability to form domain nanostructures at the air-water and air-solid interfaces. All PEO(n)PS(n) star polymers formed stable Langmuir-Blodgett (LB) monolayers transferable to a solid substrate. A range of nanoscale surface morphologies have been observed, ranging from cylindrical to circular domains to bicontinuous structures as the weight fraction of the PEO block varied from 19% to 88% and n from 8 to 19. For the PS-rich stars and at elevated surface pressure, a two-dimensional supramolecular netlike nanostructure was formed. In contrast, in the PEO-rich star polymer with the highest PEO content, we observed peculiar dendritic superstructures caused by intramolecular segregation of nonspherical core-shell micellar structures. On the basis of Langmuir isotherms and observed monolayer morphologies, three different models of possible surface behavior of the star polymers at the interfaces were proposed.

Inner core segment design for drug delivery control of thermo-responsive polymeric micelles

Modification of the thermo-responsive behavior of polymeric micelles for specific drug delivery functions was investigated using combinations of micellar inner cores and outer shell polymer chemistries. Polymeric micelles comprised of AB block copolymers of PIPAAm (poly( N-isopropylacrylamide)) with either PBMA (poly(butyl methacrylate)) or PSt (polystyrene) were employed. PIPAAm–PBMA and PIPAAm–PSt block copolymers formed a core-shell micellar structure after dialysis of the block copolymer solutions in organic solvents against water at 20°C. The hydrophobic drug, adriamycin, (ADR) was loaded into the inner core of the polymeric micelles by dialysis. The polymers showed reversible intermicellar dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST for PIPAAm=32.5°C), observed by DLS (dynamic light scattering) and transmittance measurements. Upon heating above the LCST, PIPAAm–PBMA micelles exhibited an abrupt increase in micropolarity and an abrupt decrease in microrigidity sensed by pyrene and 1,3- bis(1-pyrenyl)propane (PC 3P), respectively. In contrast, PIPAAm–PSt micelles maintained constant values with lower micropolarity and higher microrigidity than those of PIPAAm–PBMA micelles over the temperature range 20 to 40°C. From these results, structural deformations produced by outer shell polymer structural change with temperature cycles through the LCST are proposed for the PBMA core possessing a lower T g (ca. 20°C) than the outer shell PIPAAm LCST. The PSt core with a much higher T g (ca. 100°C) than the outer shell LCST retained its structure, regardless of outer shell changes. PIPAAm–PBMA micelles released ADR only when heated above the LCST, while PIPAAm–PSt micelles did not. Cell cultures treated with PIPAAm–PBMA micelles loaded with ADR showed high in vitro cytotoxicity when heated above the LCST, while PIPAAm–PSt micelles loaded with ADR expressed very low in vitro cytotoxicity irrespective of temperature change through the LCST. The nature of hydrophobic segments comprising the micelle inner core offers an important control point for thermo-responsive drug release and the drug activity of the thermo-responsive polymeric micelle.

Reversibly thermo-responsive alkyl-terminated poly( N-isopropylacrylamide) core-shell micellar structures

Alkyl-terminated PIPAAm was obtained by covalent coupling of alkyl groups of different chain lenghts (C 3, C 6, C 8, C 12 and C 18) to one end of poly( N-isopropylacrylamide) (PIPAAm). At the molecular level, incorporation of the alkyl chains with PIPAAm chains promoted aggregation at temperatures below the LCST (lower critical solution temperature) of pure PIPAAm, reflecting the hydrophobic contribution of the alkyl chains to the LCST. The LCST changes were greatest for stearoyl (C 18)-terminated PIPAAm (PIPAAm-C 18H 35). Interestingly, this polymer above its critical micelle concentration (cmc, 80 mg/L) in aqueous solution had the same LCST as unmodified PIPAAm, owing to formation of a core-shell micellar structure shielding the hydrophobic inner alkyl core from interactions with water. Micelle formation and the micellar structure of the alkyl-terminated PIPAAm aqueous dispersions were analyzed by fluorescence, surface tension and DLS (dynamic light scattering) measurements. Micelle formation is facilitated by both an increase in hydrophobicity of the incorporated group and suppression of PIPAAm hydrophilicity upon heating, closely relating to intramolecular hydrophilic/hydrophobic balance. PIPAAm-C 18H 35 micelles exhibit two heterogeneous microdomains; a hydrophobic inner core highly capable of solubilizing hydrophobic pyrene molecules, plus a hydrated outer shell that stabilizes this micellar structure below its LCST and shows reversible thermoresponsive aggregation/dispersion in heating/cooling thermal cycles through the LCST.