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[Display omitted] Random insertion of vinylphosphonic acid (VPA) units into a of PEG-PAA block copolymer improves the chemical stability and properties of hybrid nanoobjects obtained from the complexation of the copolymer with metal ions. Block polymers based on poly(acrylic acid) (PAA) and poly(ethylene glycol) (PEG) are modified by random insertion of 0 to 100 % of phosphonic acid functions in PAA block by a RAFT polymerization process. These polymers are then used to form hybrid polyionic complexes (HPICs) by complexation with gadolinium or europium ions. The properties of the obtained assemblies are evaluated by magnetic relaxivity, fluorescence and light scattering measurements. The insertion of VPA units within the PAA block increases the chemical stability of the hybrid micelles by maintaining their integrity even at low pH. This insertion also minimizes the exchange of ions between HPICs and the surrounding medium thanks to a strengthening of interactions toward lanthanide ions. When such systems are used as MRI contrast agents or luminescent probe, 50/50 AA/VPA composition appears to be a good compromise to achieve optimal relaxivity or luminescent properties while ensuring a good chemical stability. [ABSTRACT FROM AUTHOR]

Many therapeutic formulations incorporate poly(ethylene glycol) (PEG) as a stealth component to minimize early clearance. However, PEG is immunogenic and susceptible to accelerated clearance after multiple administrations. Here, we present two novel reformulations of a polyion complex (PIC), originally composed of poly(ethylene glycol)113-b-poly(glutamic acid)50 (PEG-PLE) and brain-derived neurotrophic factor (BDNF), termed Nano-BDNF (Nano-BDNF PEG-PLE). We replace the PEG based block copolymer with two new polymers, poly(sarcosine)127-b-poly(glutamic acid)50 (PSR-PLE) and poly(methyl-2-oxazolines)38-b-poly(oxazolepropanoic acid)27-b-poly(methyl-2-oxazoline)38 (PMeOx-PPaOx-PMeOx), which are driven to association with BDNF via electrostatic interactions and hydrogen bonding to form a PIC. Formulation using a microfluidic mixer yields small and narrowly disperse nanoparticles which associate following similar principles. Additionally, we demonstrate that encapsulation does not inhibit access by the receptor kinase, which affects BDNF's physiologic benefits. Finally, we investigate the formation of nascent nanoparticles through a series of characterization experiments and isothermal titration experiments which show the effects of pH in the context of particle self-assembly. Our findings indicate that thoughtful reformulation of PEG based, therapeutic PICs with non-PEG alternatives can be accomplished without compromising the self-assembly of the PIC. [ABSTRACT FROM AUTHOR]

A diblock copolymer (P(VBTAC/NaSS)17-b-PAPTAC50; P(VS)17A50) composed of amphoteric random copolymer, poly(vinylbenzyl trimethylammonium chloride-co-sodium p-styrensunfonate) (P(VBTAC/NaSS); P(VS)) and cationic poly(3-(acrylamidopropyl) trimethylammonium chloride) (PAPTAC; A) block, and poly(acrylic acid) (PAAc49) were prepared via a reversible addition−fragmentation chain transfer radical polymerization. Scrips V, S, and A represent VBTAC, NaSS, and PAPTAC blocks, respectively. Water-soluble polyion complex (PIC) vesicles were formed by mixing P(VS)17A50 and PAAc49 in water under basic conditions through electrostatic interactions between the cationic PAPTAC block and PAAc49 with the deprotonated pendant carboxylate anions. The PIC vesicle collapsed under an acidic medium because the pendant carboxylate anions in PAAc49 were protonated to delete the anionic charges. The PIC vesicle comprises an ionic PAPTAC/PAAc membrane coated with amphoteric random copolymer P(VS)17 shells. The PIC vesicle showed upper critical solution temperature (UCST) behavior in aqueous solutions because of the P(VS)17 shells. The pH- and thermo-responsive behavior of the PIC vesicle were studied using 1H NMR, static and dynamic light scattering, and percent transmittance measurements. When the ratio of the oppositely charged polymers in PAPTAC/PAAc was equal, the size and light scattering intensity of the PIC vesicle reached maximum values. The hydrophilic guest molecules can be encapsulated into the PIC vesicle at the base medium and released under acidic conditions. It is expected that the PIC vesicles will be applied as a smart drug delivery system. [ABSTRACT FROM AUTHOR]

[Display omitted] • Carboxylated trithiocarbonate mediates RAFT polymerization of a bisphosphonic acrylate. • Two RAFT methodologies lead to phosphonated double hydrophilic block copolymers. • DHBCs interact with lanthanide ions (Gd, Eu) to form polyionic complexes. • Bisphosphonated polyionic complexes enhance the stability of MRI contrast agents. The synthesis of double hydrophilic block copolymers (DHBCs) with one block containing bisphosphonic acid groups was performed by aqueous RAFT polymerization with two approaches, either starting from a PEO-based macro-chain transfer agent (macro-CTA) or by chain extension of a RAFT-capped bisphosphonic acrylate homopolymer with oligo(ethylene glycol) methyl ether acrylate (OEGA). By complexation with gadolinium and europium ions, these polymers are prone to form hybrid polyionic complexes (HPICs) as evidenced by mono- and multi-angle DLS, TEM and luminescence measurements. The obtained HPICs showed better chemical stability at low pH values compared to previously reported counterparts based on carboxylic and monophosphonic acid groups (i.e., PEO- b -PAA and PEO- b -PVPA respectively). Due to their high relaxivity values, the proposed HPICs show potential as contrast agents for magnetic resonance imaging (MRI). [ABSTRACT FROM AUTHOR]

Diblock copolymers consisting of a hydrophilic poly(2-(methacryloyloxy)ethyl phosphorylcholine) (PMPC) block and either a cationic or anionic block were prepared from (3-(methacrylamido)propyl)trimethylammonium chloride (MAPTAC) or sodium 2-(acrylamido)-2- methylpropanesulfonate (AMPS). Polymers were synthesized via reversible addition-fragmentation chain transfer (RAFT) radical polymerization using a PMPC macro-chain transfer agent. The degree of polymerization for PMPC, cationic PMAPTAC, and anionic PAMPS blocks was 20, 190, and 196, respectively. Combining two solutions of oppositely charged diblock copolymers, PMPC-b-PMAPTAC and PMPC-b-PAMPS, led to the spontaneous formation of polyion complex vesicles (PICsomes). The PICsomes were characterized using 1H NMR, static abd dynamic light scattering, transmittance electron microscopy (TEM), and atomic force microscopy. Maximum hydrodynamic radius (Rh) for the PICsome was observed at a neutral charge balance of the cationic and anionic diblock copolymers. The Rh value and aggregation number (Nagg) of PICsomes in 0.1 M NaCl was 78.0 nm and 7770, respectively. A spherical hollow vesicle structure was observed in TEM images. The hydrodynamic size of the PICsomes increased with concentration of the diblock copolymer solutions before mixing. Thus, the size of the PICsomes can be controlled by selecting an appropriate preparation method. [ABSTRACT FROM AUTHOR]

Nonconventional stimuli-responsive luminescent polymers without aromatic units have garnered considerable attention. In this study, luminescent ampholytic block copolymer (BCP) and random copolymer (RCP) consisting of nonconjugated vinyl amine (VAm) and N -acryloyl-L-threonine (AThrOH) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and subsequent deprotection. The ampholytic BCP and RCP display concentration-enhanced emissions, which are apparently higher than those of the VAm homopolymer and polyion complex, and wavelength-dependent emissions, thus validating clusterization-triggered emission (CTE). The intrinsic photoluminescence properties of the primary amine-containing ampholytic copolymers and corresponding polyion complexes were investigated in aqueous solution in response to the change in pH. Two noncovalent interactions, which involve electrostatic interactions between cationic VAm and anionic AThrOH units and hydrogen bonds (e.g., the amino group in VAm/hydroxyl and amide groups in AThrOH), contribute to the achievement of unique self-assembled structures and stimuli-responsive and fluorescent properties of VAm-containing BCP and RCP, which were verified by dynamic light scattering, circular dichroism, and fluorescence measurements. The ability of the copolymers to form clusterized states of the VAm unit can be governed by the comonomer sequence and external stimuli (e.g., pH change, the addition of salt and urea), leading to the manipulation of the assembled structures with CTE features. [Display omitted] • Luminescent ampholytic block and random copolymers without aromatic units were developed. • Copolymers consisting of vinyl amine (VAm) and N -acryloyl-L-threonine were synthesized by RAFT polymerization. • The ampholytic copolymers exhibited concentration-enhanced emissions and wavelength-dependent emissions. • Unique assembled structures and VAm-based clusterization-triggered emission (CTE) were confirmed. • The comonomer sequence and external stimuli led to the manipulation of the assembled structures with CTE features. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Recently, colloidal carrier systems have been receiving much attention in the field of drug targeting because of their high loading capacity for drugs as well as their unique disposition characteristics in the body. This paper highlights the utility of polymeric micelles formed through the multimolecular assembly of block copolymers as novel core–shell typed colloidal carriers for drug and gene targeting. The process of micellization in aqueous milieu is described in detail based on differences in the driving force of core segregation, including hydrophobic interaction, electrostatic interaction, metal complexation, and hydrogen bonding of constituent block copolymers. The segregated core embedded in the hydrophilic palisade is shown to function as a reservoir for genes, enzymes, and a variety of drugs with diverse characteristics. Functionalization of the outer surface of the polymeric micelle to modify its physicochemical and biological properties is reviewed from the standpoint of designing micellar carrier systems for receptor-mediated drug delivery. Further, the distribution of polymeric micelles is described to demonstrate their long-circulating characteristics and significant tumor accumulation, emphasizing their promising utility in tumor-targeting therapy. As an important perspective on carrier systems based on polymeric micelles, their feasibility as non-viral gene vectors is also summarized in this review article. [Copyright &y& Elsevier]

Abstract: This review describes the design of polymeric micelles from block copolymers and their performances as nano-scale drug delivery systems, with emphasis on our recent work. The basic drug delivery system platform developed by our group consists of polymeric micelles comprising a core–shell structure with a versatile drug-loading hydrophobic core and biocompatible hydrophilic shell, and are several tens to one hundred nanometer in size. These characteristics are preferable to bypass both renal clearance and entrapment by the reticuloendothelial system, thus allowing subsequent accumulation within tumor tissues by the enhanced permeability and retention effect. Furthermore, polymeric micelles may be designed for enhanced biological performance by modification of the block copolymers to contain chemistries that can sense a specific biological environment. These “smart” micelles allow for target site-triggered drug release by reversible stabilization of the micelle structure and controlled intracellular trafficking (efficient endosomal release). Smart micelles designed with responsive features have demonstrated the utility in many cases compared to controls lacking such functionality. Additionally, the ability to control the size of polymeric micelles in the range of several tens to hundreds of nanometer significantly affects their longevity in the blood stream and efficiency of tumor tissue accumulation and penetration. In hypovascular tumor tissues, smaller polymeric micelles are more effective for tissue accumulation/penetration, bringing about stronger anti-tumor activity. All together, fine-tuning the structure of block copolymers enables preparation of polymeric micelles with versatile functions for treatment of many diseases including intractable cancer. [Copyright &y& Elsevier]

Abstract: The current study synthesized macromolecular magnetic resonance imaging (MRI) contrast agents constituted of the poly(ethylene glycol)-b-poly(l-lysine) block copolymer (PEG-P(Lys)). A chelate group, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), was attached to the primary amino group of the block copolymer in desired contents. Gd-DOTA-based macromolecular contrast agents were prepared from PEG-P(Lys) having DOTA (PEG-P(Lys-DOTA) and Gd(III) ions. All of the PEG-P(Lys) block copolymers having gadolinium ions (PEG-P(Lys-DOTA-Gd)) showed higher T 1 relaxivity (per gadolinium), r 1 =5.6–7.3mM−1 s−1, than that of a low-molecular-weight gadolinium-chelate, diethylenetriaminepentaacetic acid-gadolinium(III) (Gd-DTPA) at 9.4T. The study prepared the polyion complex (PIC) micelles from the amino groups of the lysine units and an oppositely charged polyanion, poly(methacrylic acid) or dextran sulfate, in an aqueous medium. In contrast, the fully DOTA-attached PEG-P(Lys-DOTA-Gd) formed a PIC with a polycation. Compared with partially DOTA-attached cationic PEG-P(Lys-DOTA-Gd), this PIC micelle yielded a forty percent decrease of r 1. This r 1 decrease was considered to result from a change in the accessibility of water molecules to gadolinium ions in the micelles'' inner core. The r 1 was decreased upon formation of the PIC micelle, and this change proved that our concept worked in vitro. Blood-circulation characteristics of PIC micelles were controlled by means of changing the molecular weight of the counter anion. The PIC micelles accumulated in tumor tissues, and MRI study showed T1W image of axial slice of tumor area was significantly enhanced at 24h after the injection. [Copyright &y& Elsevier]

Abstract: We describe the preparation and characterisation of inorganic–organic hybrid block copolymer silver nanoparticles via the preparation of spherical multi-responsive polymeric micelles of poly(N-methyl-2-vinyl pyridinium iodide)-block-poly(ethylene oxide), P2MVP38-b-PEO211 and poly(acrylic acid)-block-poly(isopropyl acrylamide), PAA55-b-PNIPAAm88 in the presence of AgNO3. Hence, the P2MVP and PAA segments were employed to fix Ag+ ions within the micellar core (25°C) or shell (60°C), while the PEO segments ensured spontaneous reduction of Ag+ ions into metallic Ag, as well as colloidal stabilisation. Spherical and elongated composite core–shell(–corona) nanoparticles (CNPs) were formed containing several small, spherical silver nanoparticles within the micellar core or shell. As the co-assembly of the oppositely charged copolymers into micelles is electrostatically driven, the CNPs can be destabilised by, for example, addition of simple salts, i.e., the CNPs are stimuli responsive. CNP size and morphology control can be achieved via the preparation protocol. For example, heating to 60°C, i.e., above the PNIPAAm LCST, results in core–shell–corona CNPs with the Ag-NPs situated in the aggregate shell. [Copyright &y& Elsevier]

Abstract: In this review we present an overview of the developments of (self-)assembly of linear block copolymers containing one or more polyelectrolyte blocks in aqueous solution. Different micellar structures and phase behaviour are described. The role of inter- and intramolecular complex coacervation is emphasised. Recent developments in applications of assembly of polyelectrolyte-containing copolymers are presented. [Copyright &y& Elsevier]

Block copolymers composed of a cationic segment and a hydrophilic segment spontaneously associate with polyanionic DNA to form block copolymer micelles. The distinct feature of the associate is that the core of the polyion complex between DNA and the polycation is coated by a layer of the hydrophilic polymer. The characteristic core-shell structure endows the associate with a high colloidal stability and reduced interaction with blood components. These desirable properties are the major advantages of the micellar DNA delivery system for in vivo application. In this article, the synthesis of block copolymers as well as graft copolymers utilized as DNA delivery systems are described. Particular emphasis is devoted to the association behavior and the physicochemical properties of polyion complex micelles entrapping DNA and related substances in relation to the biological aspects of the associates. Biodistribution and the factors that affect the intracellular fate of the micelles is also addressed based on recent studies in this field. [Copyright &y& Elsevier]

RNA nanotechnology has promise for developing mRNA carriers with enhanced physicochemical and functional properties. However, the potential synergy for mRNA delivery of RNA nanotechnology in cooperation with established carrier systems remains unknown. This study proposes a combinational system of RNA nanotechnology and mRNA polyplexes, by focusing on mRNA steric structure inside the polyplexes. Firstly, several mRNA strands are bundled through hybridization with RNA oligonucleotide crosslinkers to obtain tight mRNA structure, and then the bundled mRNA is mixed with poly(ethylene glycol) (PEG)-polycation block copolymers to prepare PEG-coated polyplex micelles (PMs). mRNA bundling results in highly condensed mRNA packaging inside PM core with dense PEG chains on the surface, thereby, improving PM stability against polyion exchange reaction and ribonuclease (RNase) attack. Importantly, such stabilization effects are attributed to bundled structure of mRNA rather than the increase in total mRNA amount encapsulated in the PMs, as encapsulation of long mRNA strands without bundling fails to improve PM stability. Consequently, PMs loading bundled mRNA exhibit enhanced stability in mouse blood circulation, and induce efficient protein expression in cultured cells and mouse brain. Image 1 [ABSTRACT FROM AUTHOR]

DNA folding is a core phenomenon in genome packaging within a nucleus. Such a phenomenon is induced by polyelectrolyte complexation between anionic DNA and cationic proteins of histones. In this regard, complexes formed between DNA and cationic polyelectrolytes have been investigated as models to gain insight into genome packaging. Upon complexation, DNA undergoes folding to reduce its occupied volume, which often results in multi-complex associated aggregates. However, when cationic copolymers comprising a polycation block and a neutral hydrophilic polymer block are used instead, DNA undergoes folding as a single molecule within a spontaneously formed polyplex micelle (PM), thereby allowing the observation of the higher-order structures that DNA forms. The DNA complex forms polymorphic structures, including globular, rod-shaped, and ring-shaped (toroidal) structures. This review focuses on the polymorphism of DNA, particularly, to elucidate when, how, and why DNA organizes into these structures with cationic copolymers. The interactions between DNA and the copolymers, and the specific nature of DNA in rigidity; i.e., rigid but foldable, play significant roles in the observed polymorphism. Moreover, PMs serve as potential gene vectors for systemic application. The significance of the controlled DNA folding for such an application is addressed briefly in the last part. [ABSTRACT FROM AUTHOR]