Formation Of Polyion Complex Micelles Research Articles

Poly(Ethylene Glycol) Crosslinked Multi-Armed Poly(l-Lysine) with Encapsulating Capacity and Antimicrobial Activity for the Potential Treatment of Infection-Involved Multifactorial Diseases.

With the development of modern medical technology, common diseases usually can be treated by traditional medicines and their formulation, while diseases with multiple etiologies still remain a great challenge in clinic. Nanoformulation was widely explored to address this problem. However, due to limited drug loading space of nanocarriers, co-delivery strategy usually fails to achieve sufficient loading of multiple drugs simultaneously. In this research, we explored the potential of poly(ethylene glycol) (PEG) crosslinked alternating copolymers MPLL-alt-PEG as both an anionic drug carrier and antimicrobial agent. The high cationic charge density of multi-armed poly(l-lysine) (MPLL) segments in MPLL-alt-PEG could endow the electrostatic encapsulation of anionic model drugs through the formation of polyion complex micelles with a MPLL/drug complex core and crosslinked PEG outer shell, enabling pH-sensitive drug release. Meanwhile, the MPLL-alt-PEG copolymer exhibits a broad spectrum of antimicrobial activities against various clinically relevant microorganisms with low hemolytic activity. Studies on antibacterial mechanism revealed that MPLL-alt-PEG attacked bacteria through the membrane disruption mechanism which is similar to that of typical antimicrobial peptides. Taken together, the present study shed light on the possibility of endowing a polymeric carrier with therapeutic effect and thus offered a promising strategy for achieving a comprehensive treatment of bacterial infection-involved multifactorial diseases.

Polyion complex micelle formation from double-hydrophilic block copolymers composed of charged and non-charged segments in aqueous media

Polymeric micelles are representative self-assembly structures of block copolymers and have widely been investigated from both fundamental and applied aspects. In 1995, we discovered polyion complex (PIC) micelles formed from a pair of oppositely charged block copolymers with poly(ethylene glycol) segments through electrostatic interactions in aqueous media, which expanded the concept of polymeric micelle formation in selective solvents. Hereafter, extensive studies have been carried out on PIC micelles, for example, fundamental characterizations as a novel class of self-assembly systems and applications as nanocarrier systems for the delivery of charged molecules with therapeutic efficacies, including nucleic acids and proteins. This review mainly focuses on physicochemical studies on the formation of PIC micelles, particularly the critical molecular factors that have a role to determine the self-assembly scheme of charged block copolymers for micelle structures. This review focuses on the physicochemical characterization of polyion complex (PIC) micelles, particularly addressing the critical molecular factors to determine the self-assembly scheme of double-hydrophilic block copolymers composed of charged and non-charged segments into micelle structures. The process of PIC micelle formation provides new insights on the block copolymer self-assembly in thermodynamically equilibrium condition in aqueous medium, such as chain length recognition and transition from uPIC, which is the PIC of smallest neutralizing unit, to PIC micelle structures.

Thermosensitive polyion complex micelles prepared by self-assembly of two oppositely charged diblock copolymers

Polyion complex (PIC) micelles were spontaneously formed in aqueous solutions through electrostatic interaction between two oppositely charged block copolymers, poly(N-isopropylacrylamide)-b-poly(L-glutamic acid) and poly(N-isopropylacrylamide)-b-poly(L-lysine). Their controlled synthesis was achieved via the ring opening polymerization of N-carboxyanhydrides (NCA), γ-benzyloxycarbonyl-L-lysine (Lys(Z)-NCA) or γ-benzyl-L-glutamate (BLG-NCA) with amino-terminated poly(N-isopropylacrylamide) macroinitiator and the subsequent deprotection reaction. The formation of PIC micelles was confirmed by dynamic light scattering and transmission electron microscopy. Turbidimetric characterization suggested that the formed PIC micelles had a concentration-dependent thermosensitivity and their phase transition behaviors could be easily adjusted either by the block length of coplymers or the concentration of micelles.

Formation of polyion complex micelles with tunable isoelectric points based on zwitterionic block copolymers

Zwitterionic block copolymers can form polyion complex (PIC) micelles without any additional ionic compounds because their backbones contain both cationic and anionic residues. For the generation of polyion complex (PIC) micelles with tunable isoelectric points (pI), the zwitterionic block copolymers, poly(ethylene oxide)45-b-[poly(2-succinyloxyethyl methacrylate)x-r-poly(2-(dimethylamino)ethyl methacrylate)y] (PEO45-b-(PSEMAx-r-PDMAy)) zwitterionic block copolymers were synthesized via atom transfer radical polymerization (ATRP) of 2-hydroxyethyl methacrylate (HEMA) and 2-(dimethylamino)ethyl methacrylate (DMA), and subsequent succinylation of the hydroxy groups on HEMA. The electrostatic interaction between oppositely charged 2-succinyloxyethyl methacrylate (SEMA) and DMA residues led to spontaneous micelle formation of the zwitterionic block copolymers in an aqueous solution. The pH-dependent protonation/deprotonation behavior of the SEMA and DMA residues induced a change in the net charge of the micelle. Since the pIs of PIC micelles are closely related to the SEMA to DMA ratio (x/y) of the zwitterionic block, PIC micelles with certain pI values, which can be predicted by simple calculations based on the average pKa values of DMA and SEMA, can be easily tailored to achieve our objectives. Open image in new window

Synthesis of double hydrophilic block copolymers and induced assembly with oligochitosan for the preparation of polyion complex micelles

This paper reports on the polyion complex micelles (PIC micelles) formed between neutral-ionizable double hydrophilic block copolymers (DHBC), poly(ethylene oxide)-block-poly(acrylic acid) (PEO-b-PAA), and oligochitosan, a natural polyamine. The controlled synthesis of PEO-b-PAA polymers was achieved by atom transfer radical polymerization (ATRP) of tert-butyl acrylate with ω-bromide-functionalized PEO macroinitiators (Mw = 2000 and 5000 g mol−1) and the subsequent deprotection reaction under acidic conditions. A series of copolymers with a narrow molecular weight distribution (Mw/Mn ≤ 1.2) and varied PAA block lengths was synthesized. Capillary electrophoresis (CE) was shown to unambiguously prove the blocky structure of the copolymers. It also showed that about 60% of the sodium counter ions were condensed onto the polyacrylate block in the pure diblock copolymer solution, which is consistent with the formation of polyion complex micelles triggered by counter-ion release in the presence of oligochitosan. The formation of oligochitosan/PAA–PEOcore–corona micelles has been investigated by dynamic light scattering (DLS), small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM). A minimum length of the PAA block is necessary to ensure micelle formation. The range of pH, where PIC micelles form, critically depends on the PAA block length, which also determines the size of the micelles. Micelles can be dissociated at ionic strength above 0.4 mol L−1. Since these PIC micelles have been used as recyclable structuring agents for the formation of ordered mesoporous materials, the reversibilty of the assembling process was studied upon pH and ionic strength cyclic variations. A hysteresis of stability was observed at low pH, probably due to hydrogen bonding.

From well‐defined diblock copolymers prepared by a versatile atom transfer radical polymerization method to supramolecular assemblies

AbstractThe synthesis of well‐defined diblock copolymers by atom transfer radical polymerization (ATRP) was explored in detail for the development of new colloidal carriers. The ATRP technique allowed the preparation of diblock copolymers of poly(ethylene glycol) (PEG) (number‐average molecular weight: 2000) and ionic or nonionizable hydrophobic segments. Using monofunctionalized PEG macroinitiator, ionizable and hydrophobic monomers were polymerized to obtain the diblock copolymers. This polymerization method provided good control over molecular weights and molecular weight distributions, with monomer conversions as high as 98%. Moreover, the copolymerization of hydrophobic and ionizable monomers using the PEG macroinitiator made it possible to modulate the physicochemical properties of the resulting polymers in solution. Depending on the length and nature of the hydrophobic segment, the nonionic copolymers could self‐assemble in water into nanoparticles or polymeric micelles. For example, the copolymers having a short hydrophobic block (5 < degree of polymerization < 9) formed polymeric micelles in aqueous solution, with an apparent critical association concentration between 2 and 20 mg/L. The interchain association of PEG‐based polymethacrylic acid derivatives was found to be pH‐dependent and occurred at low pH. The amphiphilic and nonionic copolymers could be suitable for the solubilization and delivery of water‐insoluble drugs, whereas the ionic diblock copolymers offer promising characteristics for the delivery of electrostatically charged compounds (e.g., DNA) through the formation of polyion complex micelles. Thus, ATRP represents a promising technique for the design of new multiblock copolymers in drug delivery. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 3861–3874, 2001

Formation of Stable and Monodispersive Polyion Complex Micelles in Aqueous Medium from Poly(L-lysine) And Poly(Ethylene Glycol)-Poly(Aspartic Acid) Block Copolymer

In this study, the formation of polyion complex micelles from a pair of poly(L-lysine) homopolymers (P(Lys)) and poly(ethylene glycol)-poly(aspartic acid) block copolymers (PEG-P(Asp)) with varying chain length was demonstrated in aqueous medium. There exists the lower critical chain length in the charged segments of both P(Lys) and PEG-P(Asp) to form stable polyion complex micelles in nanometric scale. The scaled average characteristic line width (ΓTK2) was independent on the detection angles for all combinations, suggesting that the formed polyion complex micelles may have a spherical shape. Furthermore, the transitional diffusion coefficient (DT) had no concentration dependence, indicating the micelle system was free from secondary aggregates (the cluster of micelles). It is of interest that the micellar size was almost constant (ca. 50 nm) regardless of the change in the chain length of the charged segments. Size distribution was extremely narrow, and the values of variance μ2/Γ 2) were always less than 0.1. Laser-Doppler electrophoresis measurements revealed that the polyion complex micelles were electrically neutral, suggesting that the PEG corona surrounding the polyion complex core may contribute to their stable dispersion in an aqueous medium through steric repulsion of the tethered hydrophilic chain, in this case, PEG. This system was considerably stable against the change in ionic strength, and it maintained a constant diameter in the region below 0.4 M NaCl. However, they dissociated under high ionic strength condition as 0.6 M NaCl. The system may have potential utility to include charged peptides and nucleotides in the core, delivering these biologically useful substances into a target site in the body.

Spontaneous Formation of Polyion Complex Micelles with Narrow Distribution from Antisense Oligonucleotide and Cationic Block Copolymer in Physiological Saline

Spontaneous Formation of Polyion Complex Micelles with Narrow Distribution from Antisense Oligonucleotide and Cationic Block Copolymer in Physiological Saline

Formation of Polyion Complex Micelles in an Aqueous Milieu from a Pair of Oppositely-Charged Block Copolymers with Poly(ethylene glycol) Segments

Stable and monodispersive polyion complex micelles were prepared in an aqueous milieu through electrostatic interaction between a pair of oppositely-charged block copolymers with poly(ethylene glycol) segments : poly(ethylene glycol)-poly(L-lysine) block copolymer (PEG-P(Lys)) and poly(ethylene glycol)-poly(α,β-aspartic acid) block copolymer (PEG-P(Asp)). It was confirmed from photon correlation spectroscopy (dynamic light scattering) that the scaled average characteristic line width (Γ/K 2 ) was independent of the magnitude of the scattering vector (K 2 ), and the diffusion coefficient (D T ) kept constant regardless of the concentration, indicating that the polyion complex micelles were spherical particles without any secondary aggregates. Further, polydispersity indexes (μ2/Γ 2 ) were always less than 0.1 in the range of the measured concentration (1-10 mg/mL). The hydrodynamic radius at infinite dilution of polyion complex micelles was then determined to be 15.2 nm by using the Stokes-Einstein equation. The unimodal size distribution with d w /d n of 1.07 was confirmed from the correlation function profile by the histogram analysis. The size of polyion complex micelles was unchanged even after a 1-month storing, suggesting that the polyion complex micelles are in thermodynamic equilibrium. Viscosity measurement as well as laser-Doppler electrophoresis provided evidence of the stoichiometry of the polyion complex micelles formation. These polyion complex micelles have potential utility as vehicles for charged compounds, i.e., proteins and nucleic acids, in the field of drug delivery.