The impact of PEGylation patterns on the in vivo biodistribution of mixed shell micelles (original) (raw)
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Tuning PEGylation of mixed micelles to overcome intracellular and systemic siRNA delivery barriers
Biomaterials, 2015
A series of endosomolytic mixed micelles was synthesized from two diblock polymers, poly[ethylene glycol-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (PEG-b-pDPB) and poly[dimethylaminoethyl methacrylate-b-(dimethylaminoethyl methacrylate-co-propylacrylic acid-co-butyl methacrylate)] (pD-b-pDPB), and used to determine the impact of both surface PEG density and PEG molecular weight on overcoming both intracellular and systemic siRNA delivery barriers. As expected, the percent PEG composition and PEG molecular weight in the corona had an inverse relationship with mixed micelle zeta potential and rate of cellular internalization. Although mixed micelles were internalized more slowly, they generally produced similar gene silencing bioactivity (~80% or greater) in MDA-MB-231 breast cancer cells as the micelles containing no PEG (100D/no PEG). The mechanistic explanation for the potent bioactivity of the promising 50 mol% PEG-b-DPB/50 mol% pD-b-pDPB (50D) mixed micelle formulation, despite its relatively low rate of cellular internalization, was further investigated as a function of PEG molecular weight (5 k, 10 k, or 20 k PEG). Results indicated that, although larger molecular weight PEG decreased cellular internalization, it improved cytoplasmic bioavailability due to increased intracellular unpackaging (quantitatively measured via FRET) and endosomal release. When delivered intravenously in vivo, 50D mixed micelles with a larger molecular weight PEG in the corona also demonstrated significantly improved blood circulation half-life (17.8 min for 20 k PEG micelles vs. 4.6 min for 5 kDa PEG micelles) and a 4fold decrease in lung accumulation. These studies provide new mechanistic insights into the functional effects of mixed micelle-based approaches to nanocarrier surface PEGylation. Furthermore, the ideal mixed micelle formulation identified (50D/20 k PEG) demonstrated desirable intracellular and systemic pharmacokinetics and thus has strong potential for in vivo therapeutic use.
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.
Nanoscale, 2014
When nanoparticles (NPs) enter a physiological environment, medium components compete for binding to the NP surface leading to formation of a rich protein shell known as the "protein corona". Unfortunately, opsonins are also adsorbed. These proteins are immediately recognized by the phagocyte system with rapid clearance of the NPs from the bloodstream. Polyethyleneglycol (PEG) coating of NPs (PEGylation) is the most efficient antiopsonization strategy. Linear chains of PEG, grafted onto the NP surface, are able to create steric hindrance, resulting in a significant inhibition of protein adsorption and less recognition by macrophages. However, excessive PEGylation can lead to a strong inhibition of cellular uptake and less efficient binding with protein targets, reducing the potential of the delivery system. To reach a compromise in this regard we employed a multi-component (MC) lipid system with uncommon properties of cell uptake and endosomal escape and increasing length of PEG chains. Nano liquid chromatography coupled with tandem mass spectrometry (nanoLC-MS/MS) analysis allowed us to accurately determine the corona composition showing that apolipoproteins are the most abundant class in the corona and that increasing the PEG length reduced the protein adsorption and the liposomal surface affinity for apolipoproteins. Due to the abundance of apolipoproteins, we exploited the "protein corona effect" to deliver cationic liposome-human plasma complexes to human prostate cancer PC3 cells that express a high level of scavenger receptor class B type 1 in order to evaluate the cellular uptake efficiency of the systems used. Combining laser scanning confocal microscopy with flow cytometry analysis in PC3 cells we demonstrated that MC-PEG2k is the best compromise between an anti-opsonization strategy and active targeting and could be a promising candidate to treat prostate cancer in vivo. † Electronic supplementary information (ESI) available: . The slope of the lines tting the temporal evolution of size and zeta-potential of MC, MC-PEG1k, MC-PEG2k and MC-PEG5k liposomes. . The full list of the most abundant corona proteins associated with MC, MC-PEG1k, MC-PEG2k and MC-PEG5k liposomes as identied by NanoLC-MS/MS. See
PEGylated nanoparticles for biological and pharmaceutical applications
Advanced Drug Delivery Reviews, 2012
The utility of polymeric micelles formed through the multimolecular assembly of block copolymer was comprehensively described as novel core-shell typed colloidal carriers for drug and gene targeting. Particularly, novel approaches for the formation of functionalized poly(ethylene glycol) (PEG) layers as hydrophilic outer shell were focused to attain receptormediated drug and gene delivery through PEG-conjugated ligands with a minimal non-specific interaction with other proteins. Surface organization of block copolymer micelles with cross-linking core was also described from a standpoint of the preparation of a new functional surface-coating with a unique macromolecular architecture. The micelle-attached surface and the thin hydrogel layer made by layered micelles exhibited nonfouling properties and worked as the reservoir for hydrophobic reagents. Furthermore, the potential utility of multimolecular assembly derived from heterobifunctional PEGs and block copolymers were explored to systematically modify the properties of metal and semiconductor nanostructures by controlling their structure and their surface properties, making them extremely attractive for use in biological and biomedical applications.
Polymeric micelle as a nanocarrier for delivery of therapeutic agents: A comprehensive review
Journal of Drug Delivery and Therapeutics
For selective and effective drug delivery of therapeutic agent nanocarriers are the most effective agents. Micelles are an aggregate of surfactant molecules that dispersed in a liquid colloid. Micelles have a variety of shapes such as spheres, rods, vesicles, tubules, and lamellae. The shape and size of a micelle are a function of the molecular geometry of its surfactant molecules and solution conditions such as surfactant concentration, temperature, pH, and ionic strength. Poly Ethylene Glycol (PEG) is the most commonly used hydrophilic segment of micelles for drug delivery. Besides PEG, other polymers including poly (N-vinyl pyrrolidone) (PVP) and poly (N-isopropyl acrylamide) (pNIPAM) have also been used as hydrophilic portion of micelles. In this review we all discus about the polymeric micelles (PMs) as a nanocarriers for delivery of therapeutic agents. Keywords: Polymeric Micelles, Colloids, Nanocarriers, Drug Delivery, Poly Ethylene Glycol(PEG)
Journal of Controlled Release, 2011
The aim of this study was to develop poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAm-Lac(n))) core-crosslinked thermosensitive biodegradable polymeric micelles suitable for active tumor targeting, by coupling the anti-EGFR (epidermal growth factor receptor) EGa1 nanobody to their surface. To this end, PEG was functionalized with N-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP) to yield a PDP-PEG-b-p(HPMAm-Lac(n)) block copolymer. Micelles composed of 80% mPEG-b-p(HPMAm-Lac(n)) and 20% PDP-PEG-b-p(HPMAm-Lac(n)) were prepared and lysozyme (as a model protein) was modified with N-succinimidyl-S-acetylthioacetate, deprotected with hydroxylamine hydrochloride and subsequently coupled to the micellar surface. The micellar conjugates were characterized using SDS-PAGE and gel permeation chromatography (GPC). Using the knowledge obtained with lysozyme conjugation, the EGa1 nanobody was coupled to mPEG/PDP-PEG micelles and the conjugation was successful as demonstrated by western blot and dot blot analysis. Rhodamine labeled EGa1-micelles showed substantially higher binding as well as uptake by EGFR over-expressing cancer cells (A431 and UM-SCC-14C) than untargeted rhodamine labeled micelles. Interestingly, no binding of the nanobody micelles was observed to EGFR negative cells (3T3) as well as to14C cells in the presence of an excess of free nanobody. This demonstrates that the binding of the nanobody micelles is indeed by interaction with the EGF receptor. In conclusion, EGa1 decorated (mPEG/PDP-PEG)-b-(pHPMAm-Lac(n)) polymeric micelles are highly promising systems for active drug targeting.
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.
Polymeric micelles as a drug carrier fro tumor targeting
Polymeric micelle can be targeted to tumor site by passive and active mechanism. Some inherent properties of polymeric micelle such as size in nanorange, stability in plasma, longevity in vivo, and pathological characteristics of tumor make polymeric micelles to be targeted at the tumor site by passive mechanism called enhanced permeability and retention effect. Polymeric micelle formed from the amphiphilic block copolymer is suitable for encapsulation of poorly water soluble, hydrophobic anticancer drugs. Other characteristics of polymeric micelles such as separated functionality at the outer shell are useful for targeting the anticancer drug to tumor by active mechanisms. Polymeric micelles can be conjugated with many ligands such as antibodies fragments, epidermal growth factors, α 2 -glycoprotein, transferrine, and folate to target micelles to cancer cells. Application of heat and ultrasound are the alternative methods to enhance drug accumulation in tumoral cells. Targeting using micelles can also be done to tumor angiogenesis which is the potentially promising target for anticancer drugs. This review summarizes about recently available information regarding targeting the anticancer drug to the tumor site using polymeric micelles.