Comparison of PEG chain length and density on amphiphilic macromolecular nanocarriers: Self-assembled and unimolecular micelles

Atherogenesis, the uncontrolled deposition of modified lipoproteins in inflamed arteries, serves as a focal trigger of cardiovascular disease (CVD). Polymeric biomaterials have been envisioned to counteract atherogenesis based on their ability to repress scavenger mediated uptake of oxidized lipoprotein (oxLDL) in macrophages. Following the conceptualization in our laboratories of a new library of amphiphilic macromolecules (AMs), assembled from sugar backbones, aliphatic chains and poly(-ethylene glycol) tails, a more rational approach is necessary to parse the diverse features such as charge, hydrophobicity, sugar composition and stereochemistry. In this study, we advance a computational biomaterials design approach to screen and elucidate anti-atherogenic biomaterials with high efficacy. AMs were quantified in terms of not only 1D (molecular formula) and 2D (molecular connectivity) descriptors, but also new 3D (molecular geometry) descriptors of AMs modeled by coarse-grained molecular dynamics (MD) followed by all-atom MD simulations. Quantitative structure-activity relationship (QSAR) models for anti-atherogenic activity were then constructed by screening a total of 1164 descriptors against the corresponding, experimentally measured potency of AM inhibition of oxLDL uptake in human monocyte-derived macrophages. Five key descriptors were identified to provide a strong linear correlation between the predicted and observed anti-atherogenic activity values, and were then used to correctly forecast the efficacy of three newly designed AMs. Thus, a new ligand-based drug design framework was successfully adapted to computationally screen and design biomaterials with cardiovascular therapeutic properties.

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“…AMs were synthesized as previously described [10–14,39–41]. The pKa values were estimated based on ionizable functional groups.…”

Section: Methodsmentioning

confidence: 99%

In silico design of anti-atherogenic biomaterials

et al. 2013

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“…Additionally, high water solubilities are achieved for the surface of micelles which is an attempt to get a clearer picture of the protein repellence mechanisms. 28) The interactions between drug and protein molecules could be liable for rapid dissociation of the drug from the vector which results in the fate of the drug delivery system in vivo. 29) In Vitro Cytotoxicity of Cadmium-Loaded Polymer Micelles To examine whether cadmium incorporated in the block ionomer complex micelles can exhibit cytotoxic effect in cell culture by MTT assay, SMMC-7721 cells were exposed to PEG-b-PAA (0.125, 0.065 mg/ml), cadmium-loaded polymer micelles (10, 20 mM on cadmium basis), or cadmium chloride(10, 20 mM) for 48 h and blank (equal volume of cell culture medium) as control group.…”

Section: Resultsmentioning

confidence: 99%

Block Ionomer Complex Micelles Based on the Self-Assembly of Poly(ethylene glycol)-block-poly(acrylic acid) and CdCl2 for Anti-tumor Drug Delivery

Wang

Liu

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Regular ArticleSelf-assembly of amphiphilic block copolymers induces polymeric micelles which have attracted significant attention as potential delivery vehicles for genes, 1,2) imaging agents, 3) and anticancer drugs. 4,5) Normally, these polymeric micelles are characterized by unique core-shell architectures which have nanoscale size (10 to 100 nm diameter) and a fairly narrow size distribution. These unique structures endow the formed assemblies with good loading capacity and releasing efficiency. However, the incorporation of metal ions is not successful by amphiphilic block copolymer aggregates, due to the poor compatibility between the hydrophobic cores and metal ions. Recently, double-hydrophilic block copolymers (DHBCs) were developed, which contain ionic and nonionic water-soluble segments (block ionomers), as novel functional materials for pharmaceutical applications. 6) Among the DHBCs, poly(ethylene glycol)-block-poly(acrylic acid), PEG-b-PAA, is one of the most popular polymers and has been employed to prepare the polymeric micelles by the electrostatic complexation with positive-charged functional species. The PAA core of the micelles is a loading space that accommodates various positive-charged therapeutic or diagnostic molecules. The hydrophilic PEG shell is a brush-like corona that stabilizes the nanostructure in aqueous dispersion. Meanwhile, PEG is biocompatible for these physicochemical properties such as hydrophilicity, anticoagulant, solubility, non-immunogenecity, and able to resist protein adsorption, thus, it has been approved by food and drug administration (FDA) for clinical using. 7) PEG shell on the surface of micelles increases the residence time of circulation in blood, preventing interactions with serum proteins and minimizes the detection by the immune system. 8) Therefore, it is frequently used as the hydrophilic block of amphiphilic block copolymers to create some polymersomes.Chemotherapy has become an integral component of cancer treatment for most cancers. The metal anticancer drugs occupy the most promising space in the field of pharmaceutical chemotherapy. In 1991, Waalkes et al. found cadmium injection suppressed spontaneous liver tumor proliferation on the research for initiate or promote tumors on B6C3F1 mouse liver. 9) This result indicated cadmium might be used for tumor treatment. From then on, more and more attention has been paid about the effect of cadmium on antitumor. Our team has been some studies on effects of cadmium on human carcinoma cell. Likewise, our results showed that cadmium could significantly inhibit cellular proliferation, induce DNA damage, cause cell cycle arrest and apoptosis in vitro, and suppresse the growth of hepatocellular carcinoma cells xenografts in vivo. 10,11) Cadmium can induce metallothionein (MT), a non-specific protective protein which could combine with cadmium to reduce toxicity. Furthermore, due to the lower MT expression in hepatoma tissues, compared with normal liver tissue, free cadmium would preferably accumulate in hepatoma...

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“…There has been intensive research on amphiphilic biodegradable block polymers in biomedical application for such characteristic properties as stability in dynamics and thermodynamics, controllable chemical structures and versatile self-assembly [1][2][3][4]. Poly(-caprolactone) (PCL) and poly (lactic acid) (PLA) are the most widely used biodegradable polymers as the hydrophobic blocks to construct amphiphilic block polymers due to their approval by FDA for internal implantation and application in human bodies, while several water-soluble polymers have been reported as hydrophilic blocks for the copolymers.…”

Section: Introductionmentioning

confidence: 99%

Biodegradable amphiphilic block copolymers containing functionalized PEO blocks: Controlled synthesis and biomedical potentials

Peng

Gan

2010

Sci. China Chem.

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A series of controllable amphiphilic block copolymers composed of poly(ethylene oxide) (PEO) as the hydrophilic block and poly(-caprolactone) (PCL) as the hydrophobic block with the amino terminal group at the end of the PEO chain (PCL-b-PEO-NH 2 ) were synthesized. Based on the further reaction of reactive amino groups, diblock copolymers with functional carboxyl groups (PCL-b-PEO-COOH) and functional compounds RGD (PCL-b-PEO-RGD) as well as the triblock copolymers with thermosensitive PNIPAAm blocks (PCL-b-PEO-b-PNIPAAM) were synthesized. The well-controlled structures of these copolymers with functional groups and blocks were characterized by gel permeation chromatography (GPC) and 1 H NMR spectroscopy. These copolymers with functionalized hydrophilic blocks were fabricated into microspheres for the examination of biofunctions via cell culture experiments and in vitro drug release. The results indicated the significance of introducing functional groups (e.g., NH 2 , COOH and RGD) into the end of the hydrophilic block of amphiphilic block copolymers for biomedical potentials in tissue engineering and controlled drug release. amphiphilic block copolymers, biodegradable polymers, functional terminal group, cell growth, drug release

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Comparison of PEG chain length and density on amphiphilic macromolecular nanocarriers: Self-assembled and unimolecular micelles

Cited by 13 publications

References 33 publications

In silico design of anti-atherogenic biomaterials

In silico design of anti-atherogenic biomaterials

Block Ionomer Complex Micelles Based on the Self-Assembly of Poly(ethylene glycol)-block-poly(acrylic acid) and CdCl2 for Anti-tumor Drug Delivery

Biodegradable amphiphilic block copolymers containing functionalized PEO blocks: Controlled synthesis and biomedical potentials

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