Application of inorganic nanoparticles in diagnosis and therapy has become a critical component in the targeted treatment of diseases. The surface modification of inorganic oxides is important for providing diversity in size, shape, solubility, long-term stability, and attachment of selective functional groups. This Minireview describes the role of polyethylene glycol (PEG) in the surface modification of oxides and focuses on their biomedical applications. Such a PEGylation of surfaces provides "stealth" characteristics to nanomaterials otherwise identified as foreign materials by human body. The role of PEG as structure-directing agent in synthesis of oxides is also presented.
Aims: Melanoma is the most aggressive type of malignant skin cancer derived from uncontrolled proliferation of melanocytes. Melanoma cells possess a high potential to metastasize, and the prognosis for advanced melanoma is rather poor due to its strong resistance to conventional chemotherapeutics. Nanomaterials are at the cutting edge of the rapidly developing area of nanomedicine. The potential of nanoparticles for use as carrier in cancer drug delivery is infinite with novel applications constantly being tested. The noncarrier use of cerium oxide nanoparticles (CNPs) is a novel and promising approach, as those particles per se show an anticancer activity via their oxygen vacancy-mediated chemical reactivity. Results: In this study, the question was addressed of whether the use of CNPs might be a valuable tool to counteract the invasive capacity and metastasis of melanoma cells in the future. Therefore, the effect of those nanoparticles on human melanoma cells was investigated in vitro and in vivo. Concentrations of polymer-coated CNPs being nontoxic for stromal cells showed a cytotoxic, proapoptotic, and anti-invasive capacity on melanoma cells. In vivo xenograft studies with immunodeficient nude mice showed a decrease of tumor weight and volume after treatment with CNPs. Innovation: In summary, the redox-active CNPs have selective pro-oxidative and antioxidative properties, and this study is the first to show that CNPs prevent tumor growth in vivo. Conclusion: The application of redox-active CNPs may form the basis of new paradigms in the treatment and prevention of cancers. Antioxid. Redox Signal. 19,[765][766][767][768][769][770][771][772][773][774][775][776][777][778]
The facile synthesis of high molecular weight water-soluble O-glycopolypeptide polymers by the ring-opening polymerization of their corresponding N-carboxyanhydride (NCA) in very high yield (overall yield > 70%) is reported. The per-acetylated-O-glycosylated lysine-NCA monomers, synthesized using stable glycosyl donors and a commercially available protected amino acid in very high yield, was polymerized using commercially available amine initiators. The synthesized water-soluble glycopolypeptides were found to be α-helical in aqueous solution. However, we were able to control the secondary conformation of the glycopolypeptides (α-helix vs nonhelical structures) by polymerizing racemic amino acid glyco NCAs. We have also investigated the binding of the glycopolypeptide poly(α-manno-O-lys) with the lectin Con-A using precipitation and hemagglutination assays as well as by isothermal titration calorimetry (ITC). The ITC results clearly show that the binding process is enthalpy driven for both α-helical and nonhelical structures, with negative entropic contribution. Binding stoichiometry for the glycopolypeptide poly(α-manno-O-lys) having a nonhelical structure was slightly higher as compared to the corresponding polypeptide which adopted an α-helical structure.
Glycopolypeptides (GPs) were synthesized by ring-opening polymerization of glycosylated N-carboxyanhydride monomer and attached to hydrophobic dendrons at one chain end by "click" reaction to obtain amphiphilic anisotropic macromolecules. We show that by varying polypeptide chain length and dendron generation, an organogel was obtained in dimethylsulfoxide, while nanorods and micellar aggregates were observed in aqueous solutions. Assemblies in water were characterized by electron microscopy and dye encapsulation. Secondary structure of the GP chain was shown to affect the morphology, whereas the chain length of the poly(ethylene glycol) linker between the GP and dendron did not alter rod-like assemblies. Bioactive surface chemistry of these assemblies displaying carbohydrate groups was demonstrated by interaction of mannose-functionalized nanorods with ConA.
Nanocarriers with carbohydrates on the surface represent a very interesting class of drug-delivery vehicles because carbohydrates are involved in biomolecular recognition events in vivo. We have synthesized biocompatible miktoarm star copolymers comprising glycopolypeptide and poly(ε-caprolactone) chains using ring-opening polymerization and "click chemistry". The amphiphilic copolymers were self-assembled in water into morphologies such as nanorods, polymersomes, and micelles with carbohydrates displayed on the surface. We demonstrate that the formation of nanostructure could be tuned by chain length of the blocks and was not affected by the type of sugar residue. These nanostructures were characterized in detail using a variety of techniques such as TEM, AFM, cryogenic electron microscopy, spectrally resolved fluorescence imaging, and dye encapsulation techniques. We show that it is possible to sequester both hydrophobic as well as hydrophilic dyes within the nanostructures. Finally, we show that these noncytotoxic mannosylated rods and polymersomes were selectively and efficiently taken up by MDA-MB-231 breast cancer cells, demonstrating their potential as nanocarriers for drug delivery.
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The ubiquitous expression of the mannose-6-phosphate receptor on the majority of human cells makes it a valid target in the quest to deliver therapeutics selectively to the lysosome. In this work end-functionalized polyvalent mannose-6-phosphate glycopolypeptides (M6P-GPs) with high molecular weights (up to 22 kDa) have been synthesized via NCA polymerization. These synthetic M6P-GPs were found to display minimal toxicity to cells in vitro and show exceptional selectivity for trafficking into lysosomes in various cell lines. Comparison of the cellular uptake behavior of M6P-GP and the corresponding mannose-GP polymer reveals that incorporation of the phosphate moiety at the 6-position of mannose completely alters its trafficking behavior and becomes exclusively lysosome specific. We also demonstrate that trafficking of M6P-GPs in mammalian cells is likely associated with the CI-MPR receptor pathway. I n mammalian cells, mannose-6-phosphate receptors play a critical role in the sorting of lysosomal enzymes from secretory proteins and their subsequent delivery into lysosomes. 1 These receptors, which include the ∼300 kDa insulin-like growth factor-II (IGF-II)/cation-independent (CI) multifunctional transmembrane glycoprotein mannose-6-phosphate (M6P) receptor (CI-MPR), bind lysosomal enzymes containing phosphomannosyl residues in the trans-golgi network (TGN) and transport them to endosomes where the low pH leads to the dissociation of the ligand−receptor complex. 2 The receptors then return to the TGN to repeat another round of this process. As a result, the receptor CI-MPR is largely localized in the intracellular compartments and shuttles between TGN and endosomes with ∼10% of the receptor being present on the cell surface. 3 Additionally, the CI-MPR receptor is overexpressed in the early stage of several cancers, particularly in breast and prostate cancer, and hence can serve as an early marker for these cancers. 4,5 The ability of CI-MPR to deliver cargo specifically to the lysosome can thus be selectively targeted using M6P-labeled carriers to dispatch cytotoxic drugs inside lysosomes for destroying cancer cells. 6−8 In addition, CI-MPR can be targeted to deliver M6P-labeled enzymes into lysosomes for enzyme replacement therapies (ERTs) in non-neural lysosomal storage disorders (LSDs). 9,10 LSDs are a group of more than 40 metabolic disorders that result from the deficient activity of specific lysosomal enzymes inside the lysosomes leading to progressive accumulation of its substrate inside the cell. Nowadays several M6P-modified enzymes are used clinically for the treatment of LSD. However, the low levels of M6P modification dramatically reduce its binding efficiency to the receptor, and hence relatively high doses of these enzymes need to be administered to achieve significant therapeutic efficacy. 11 Modification of lysosomal enzymes with higher amounts of M6P residues for enhanced targeted delivery remains a critical challenge. 12 Previous studies demonstrate that CI-MPR exists as a dimer in the membrane ...
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