Poly(ethylene glycol) Corona Chain Length Controls End-Group-Dependent Cell Interactions of Dendron Micelles (original) (raw)
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Dendritic PEG outer shells enhance serum stability of polymeric micelles
Nanomedicine : nanotechnology, biology, and medicine, 2018
A higher surface density of poly(ethylene glycol) (PEG) on polymeric micelles enhances their stability in serum, leading to improved plasma circulation. To obtain fundamental, mechanistic understanding of the PEG effect associated with polymeric architecture/configuration, we have synthesized PEGylated dendron-based copolymers (PDCs) and linear block copolymers (LBCs) with similar molecular weights. These copolymers formed dendron (hyperbranched) and linear micelles, respectively, which were compared in terms of their stabilities in serum, micelle-serum protein interactions, and in vivo biodistributions. Overall, the dendron micelles exhibited a better serum stability (longer half-life) and thus a slower release profile than the linear micelles. Fluorescence quenching assays and molecular dynamics (MD) simulations revealed that the high serum stability of the dendron micelles can be attributed to reduced micelle-serum protein interactions, owing to their dendritic, dense PEG outer s...
Hydrophobic dendrons based on different branching patterns, viz. 3,5-di-and 3,4,5-trisub-stituted phenyl rings, consist of the same backbone but exhibit different sizes, shapes, and hydrophobic densities. These dendrons are attached to poly(ethylene glycol) and the core properties of the copolymer micelles are investigated in tetrahydrofuran (THF)/water mixtures by neutron scattering. Two polymers with intermediate hydrophobicity are studied further with variations in the solvent composition and the temperature. The aggregation numbers for 3,4,5-based dendron copolymers are lower, with more THF molecules of solvation compared with the 3,5-based dendron copolymer, the difference being greater at higher generations due to different molecular shapes. The micellar core size increases in small steps with dendron size so that dye encapsulation is tuned.
A dendrimer–hydrophobic interaction synergy improves the stability of polyion complex micelles
Polymer Chemistry, 2017
Polyion complex (PIC) micelles incorporating PEG-dendritic copolymers display an unprecedented stability towards ionic strength that is amplified via hydrophobic interactions. The tridimensional orientation of peripheral hydrophobic linkers between charged groups and the globular/rigid dendritic scaffold maximizes this stabilization compared to PIC micelles from linear polymers. As a result, micelles stable at concentrations higher than 3 M NaCl are obtained, which represents the highest saline concentration attained with PIC micelles. Advantage of this stabilizing dendritic effect has been taken for the design of a robust, pH-sensitive micelle for the controlled intracellular release of the anticancer drug doxorubicin. This micelle displays a slightly higher toxicity, and distinctive mechanisms of cell uptake and intracellular trafficking relative to the free drug. The preparation of mixed PIC micelles by combining differently functionalized PEG-dendritic block copolymers has allowed to fine-tune their stability, paving the way towards the facile modulation of properties like biodegradability, drug loading, or the response to external stimuli.
PEG-Graft Density Controls Polymeric Nanoparticle Micelle Stability
Chemistry of Materials, 2014
Polymeric nanoparticle micelles typically comprise amphiphilic block copolymers, having a hydrophobic core that is useful for chemotherapeutic encapsulation, and a hydrophilic corona for aqueous stability. Formulations often require the use of excipients to overcome poor particle stability, yet these excipients can be cytotoxic. In order to create a stable polymeric nanoparticle micelle without the use of excipients, we investigate a series of amphiphilic polymers where the hydrophobic core composition and molar mass is maintained and the hydrophilic corona is varied. With the graft copolymer, poly(D,L-lactide-co-2-methyl-2-carboxytrimethylenecarbonate)-g-poly(ethylene glycol) (P(LA-co-TMCC)-g-PEG), we demonstrate how PEG density can be tuned to improve the stability of the resulting self-assembled micelle. Increased PEG density leads to micelles that resist aggregation during lyophilization, allowing resuspension in aqueous media with narrow distribution. Furthermore, high PEG density micelles resist dissociation in serum protein containing media, with almost no dissociation seen in serum after 72 h. By changing the number of PEG chains per polymer backbone from 0.5 to 6, we observe increased stability of the nanoparticle micelles. All formulations are cytocompatible, as measured with MDA-MB-231 cells, and show no evidence for hemolysis, as measured with red blood cells. Importantly, PEG density does not impact drug loading within the nanoparticle micelle core, as demonstrated with the potent chemotherapeutic drug, docetaxel, confirming the role of the hydrophobic core for encapsulation. The surface properties of the polymeric nanoparticle micelles can thus be selectively modulated by variation in PEG density, which in turn influences stability, obviates the need for excipients and provides key insights into the design of drug delivery platforms.
Dendron-mediated self-assembly of highly PEGylated block copolymers: a modular nanocarrier platform
Chemical Communications, 2011
PEGylated dendron coils (PDCs) were investigated as a novel potential nanocarrier platform. PDCs self-assembled into micelles at lower CMCs than linear copolymer counterparts by 1-2 orders of magnitude, due to the unique architecture of dendrons. MD simulations also supported thermodynamically favourable self-assembly mediated by dendrons. Self-assembled molecular nanoconstructs with controllable physical, chemical, and biological properties represent one of the most versatile platforms for drug delivery. 1 Above their critical micelle concentrations (CMCs), linear, branched, and hyperbranched amphiphilic block copolymers can assemble into thermodynamically stable supramolecular structures of different sizes, morphologies, and properties. 2 Among those copolymers, dendron-coils (DC) have attracted a great deal of scientific interest due to their unique structure and properties. A DC is comprised of a dendron, a branch of a dendrimer, and flexible hydrophilic and/or hydrophobic linear polymers, which allows us to engineer its amphiphilicity in a form suitable for self-assembly and molecular delivery. 3 The monodisperse, highly branched molecular architecture of the dendron imparts a precise control over the peripheral functional groups and multivalency, as in dendrimers. 4 Uniquely, DCs have been reported to self-assemble into micelles at CMCs as low as in the order of 10 À8 M, which are expected to be significantly lower than CMCs of linear-block copolymers with similar hydrophilic-lipophilic balances (HLBs). 5 The high HLB is important for a nanocarrier to achieve a large surface coverage by a hydrophilic layer, e.g., poly(ethylene glycol) (PEG), to maximize its in vivo circulation time while minimizing its non-specific interactions with biological components. 6 Although DC-based micelles are ideally suited for nanocarriers, the role of dendrons should be explored by systematic and quantitative studies.
Two classes of amphiphilic macromolecules were evaluated for drug delivery applications: those that exist as unimolecular micelles and those that self-assemble in aqueous solution to form micelles. This study compares the poly(ethylene glycol) (PEG) chain length and density that constitute the corona of both classes. In particular, the effect of PEG branching on micellar size, water-solubility, resolubilization rate, drug loading efficiency and drug release rate were analyzed. Pluronic P85 and Cremophor EL, commonly used in pharmaceutical applications, were used as controls. Indomethacin (IMC) was used as the drug for encapsulation, release and resolubilization experiments. Results indicated that smaller micellar sizes, higher water solubilities and faster resolubilization rates were achieved from higher PEG densities compared to linear PEG analog of similar mass. Further, micellar sizes of both higher density PEG and linear PEG macromolecules were constant over a wide temperature range (2-70°C). In contrast, Cremophor EL formed aggregates at 15°C and Pluronic P85 underwent a size transition at 45°C. IMC loading efficiencies for all amphiphilic macromolecules were comparable to controls. However, faster resolubilization and slower drug release were observed for higher density PEG macromolecules compared to linear PEG analogs and controls.
Towards a structural characterization of charge-driven polymer micelles
The European Physical Journal E, 2009
Light scattering and small-angle neutron scattering experiments were performed on comicelles of several combinations of oppositely charged (block co)polymers in aqueous solutions. Fundamental differences between the internal structure of this novel type of micelle -termed complex coacervate core micelle (C3Ms), polyion complex (PIC) micelle, block ionomer complex (BIC), or interpolyelectrolyte complex (IPEC)-and its traditional counterpart, i.e., a micelle formed via self-assembly of polymeric amphiphiles, give rise to differences in scaling behaviour. Indeed, the observed dependencies of micellar size and aggregation number on corona block length, N corona, are inconsistent with scaling predictions developed for polymeric micelles in the star-like and crew-cut regime. Generic C3M characteristics, such as the relatively high core solvent fraction, the low core-corona interfacial tension, and the high solubility of the coronal chains, are causing the deviations. A recently proposed scaling theory for the cross-over regime, as well as a primitive first-order self-consistent field (SCF) theory for obligatory co-assembly, follow our data more closely.
Macromolecules
Thermosensitive and pegylated polyion complex (PIC) micelles were formed by coassembly of oppositely and permanently charged poly(sodium 2-acrylamido-2-methylpropanesulfonate)-block-poly(N-isopropylacrylamide), PAMPS-b-PNIPAAM, and poly[(3-acrylamidopropyl)-trimethylammonium chloride]-block-poly(ethylene oxide), PAMPTMA-b-PEO, block copolymers under stoichiometric charge neutralization conditions and polyelectrolyte chain length matching. PAMPTMA-b-PEO block copolymers with different block lengths were prepared for the first time by atom transfer radical polymerization (ATRP) using a PEO macroinitiator. PIC micelles were characterized by 1H NMR, static light scattering (SLS), dynamic light scattering (DLS), and transmission electron microscopy (TEM). At room temperature, spherical almost monodisperse PIC micelles, consisting of a mixed PAMPTMA/PAMPS coacervate core and a mixed PEO/PNIPAAM shell, were formed, with size of about 80−110 nm. The PIC micelles completely dissociated to un...