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12/2011: pages 513 - 551; , ISBN: 9783527634057
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ABSTRACT: Nanotechnology has resulted in materials that have greatly improved the effectiveness of drug delivery because of their ability to control matter on the nanoscale. Advanced forms of nanomedicine have been synthesized for better pharmacokinetics to obtain higher efficacy, less systemic toxicity, and better targeting. These criteria have long been the goal in nanomedicine, in particular, for systemic applications in oncological disorders. Now, the "holy grail" in nanomedicine is to design and synthesize new advanced macromolecular nanocarriers and to translate them from lab to clinic. This review describes the current and future perspectives of nanomedicine with particular emphasis on the clinical targets in cancer and inflammation. The advanced forms of liposomes and polyethylene glycol (PEG) based nanocarriers, as well as dendritic polymer conjugates will be discussed with particular attention paid to designs, synthetic strategies, and chemical pathways. In this critical review, we also report on the current status and perspective of dendritic polymer nanoconjugate platforms (e.g. polyamidoamine dendrimers and dendritic polyglycerols) for cellular localization and targeting of specific tissues (192 references).
Chemical Society Reviews 12/2011; 41(7):2824-48. · 28.76 Impact Factor
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ABSTRACT: To study the mechanism of cellular internalization, hyperbranched polyether derivatives consisting of amino-bearing hyperbranched polyglycerols (HPGs) of varied molecular mass and size range are designed and synthesized. HPGs were further fluorescently labelled by conjugating maleimido indocarbocyanine dye (ICC-mal). The conjugates are characterized by UV-vis spectroscopy, fluorescence profile, zeta potential, and dynamic light scattering. The uptake mechanism is studied by fluorescence-activated cell sorting (FACS) analysis, fluorescence spectroscopy, and confocal microscopy with human lung cancer cells A549, human epidermoid carcinoma cells A431, and human umbilical vein endothelial cells (HUVEC) cells. For the first time, the results suggest that the higher-molecular-weight HPGs (40-870 kDa) predominantly accumulate in the cytoplasm much better than their low-molecular-weight counterparts (2-20 kDa). The HPG nanocarriers discussed here have many biomedical implications, particularly for delivering drugs to the targeted site.
Small 02/2011; 7(6):820-9. · 8.35 Impact Factor
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ABSTRACT: In an attempt to explore the potential of dendritic systems for the development of effective anticancer drug delivery systems, we explored a simple modular approach of preparing polyglycerol doxorubicin prodrugs, with flexibility for drug loading using an acid-sensitive hydrazone linker and further post-modification with poly(ethylene glycol) shell. The resulting drug polymer conjugates showed optimal properties for in vitro and in vivo applications because of their high water solubility, an appropriate size for passive tumor targeting, a high stability at physiological conditions, pronounced acid-sensitive properties, cellular internalization, and a favorable toxicity profile. Doxorubicin polyglycerol conjugates with a high drug loading ratio showed clearly improved antitumor efficacy over doxorubicin in an ovarian xenograft tumor model (A2780) inducing transient complete remissions thus demonstrating the potential of developing efficient multifunctional dendritic drug delivery using our modular approach.
Journal of Controlled Release 01/2011; 151(3):295-301. · 5.73 Impact Factor
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Journal of Controlled Release 11/2010; 148(1):e24-5. · 5.73 Impact Factor
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ABSTRACT: RNA interference provides great opportunities for treating diseases from genetic disorders, infection, and cancer. The successful application of small interference RNA (siRNA) in cells with high transfection efficiency and low cytotoxicity is, however, a major challenge in gene-mediated therapy. Several pH-responsive core shell architectures have been designed that contain a nitrogen shell motif and a polyglycerol core, which has been prepared by a two-step protocol involving the activation of primary and secondary hydroxyl groups by phenyl chloroformate and amine substitution. Each polymer was analyzed by particle size and ζ potential measurements, whereas the respective polyplex formation was determined by ethidium bromide displacement assay, atomic force microscopy (AFM), and surface charge analysis. The in vitro gene silencing properties of the different polymers were evaluated by using a human epithelial carcinoma cell (HeLaS3) line with different proteins (Lamin, CDC2, MAPK2). Polyplexes yielded similar knockdown efficiencies as HiPerFect controls, with comparably low cytotoxicity. Therefore, these efficient and highly biocompatible dendritic polyamines are promising candidates for siRNA delivery in vivo.
Bioconjugate Chemistry 10/2010; 21(10):1744-52. · 4.93 Impact Factor
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ABSTRACT: In the present work, we have developed a highly efficient temperature-dependent chemo-enzymatic methodology for the regioselective synthesis of novel esters of glycerol, G1 tri-glycerol dendrons and related esters for the first time using 4-nitrophenyl 2-(tert-butoxycarbonyl)acetate (Boc-gly-Ph-pNO(2)) (2) as the acylating agent. This methodology offers efficient and controlled loading of amino acid (glycine) on polyhydroxy compounds.
Organic & Biomolecular Chemistry 05/2010; 8(9):2228-37. · 3.70 Impact Factor
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ABSTRACT: New targets for RNA interference (RNAi)-based cancer therapy are constantly emerging from the increasing knowledge on key molecular pathways that are paramount for carcinogenesis. Nevertheless, in vivo delivery of small interfering RNA (siRNA) remains a crucial challenge for therapeutic success. siRNAs on their own are not taken up by most mammalian cells in a way that preserves their activity. Moreover, when applied in vivo, siRNA-based approaches are all limited by poor penetration into the target tissue and low silencing efficiency. To circumvent these limitations, we have developed novel polymerized polyglycerol-based dendrimer core shell structures to deliver siRNA to tumors in vivo. These cationic dendrimers can strongly improve the stability of the siRNA, its intracellular trafficking, its silencing efficacy, and its accumulation in the tumor environment owing to the enhanced permeability and retention effect. Here, we show that our dendritic nanocarriers exhibited low cytotoxicity and high efficacy in delivering active siRNA into cells. With use of human glioblastoma and murine mammary adenocarcinoma cell lines as model systems, these siRNA-dendrimer polyplexes silenced the luciferase gene, ectopically overexpressed in these cells. Importantly, significant gene silencing was accomplished in vivo within 24 h of treatment with our luciferase siRNA-nanocarrier polyplexes, as measured by noninvasive intravital bioluminescence imaging. Moreover, our siRNA-nanocarriers show very low levels of toxicity as no significant weight loss was observed after intravenous administration of the polyplexes. We show a proof of concept for siRNA delivery in vivo using a luciferase-based model. We predict that in vivo silencing of important cell growth and angiogenesis regulator genes in a selective manner will justify this approach as a successful anticancer therapy.
The FASEB Journal 04/2010; 24(9):3122-34. · 5.71 Impact Factor
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ABSTRACT: Nanocarriers possess advanced physicochemical properties that improve bioavailability, enhance cellular dynamics, and control targetability in drug delivery. In particular, dendritic polyglycerol is a promising new biocompatible scaffold for drug delivery. The present explores the structure-biocompatibility relationship of dendritic polyglycerol (dPG) derivatives possessing neutral, cationic, and anionic charges. The effect of solution pH on the surface charge was studied in buffered aqueous solution between pH 4.8 and 7.4. Surface charge properties of dPG derivatives are discussed in terms of surface functionalities and compared with amine and hydroxyl terminated polyamidoamine (PAMAM) dendrimers. Zeta potential measurements and fluorescence quenching studies address the binding interactions of dPGs to bovine serum albumin in order to explore the applicability of dPG derivatives for systemic delivery. Cellular entry of dPG-dye conjugate was evaluated using A549 lung epithelial cells, while in vitro toxicity was studied for various dPGs and compared to PAMAM dendrimers, polyethyleneimine (PEI), dextran, and linear polyethylene glycol (PEG) using human hematopoietic cell line U-937. Cellular uptake studies of dye labelled dPGs inferred that the charged derivatives (dPG-sulfate and dPG-amine) are more rapidly internalized primarily inside the cytosol of A549 cells compared to the neutral dPG. The cell compatibility results show that the dendritic polyglycerols are as safe as linear PEG polymer or dextran, which indicates the suitability of dPG derivatives in delivering therapeutic agents systemically.
Biomaterials 03/2010; 31(15):4268-77. · 7.40 Impact Factor
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ABSTRACT: Stimuli-responsive polymer architectures are molecular systems which evolve with an external signal. The observed changes are mainly decomposition, isomerization, polymerization, activation, supramolecular aggregation, and structural modifications of these molecules. The external stimuli, which can be combined in order to provoke these molecular changes, are numerous. In this review, we have chosen to present an overview on different mechanisms to impart responsiveness to dendritic polymers, with the particular aim of delivery and release of bioactive molecules.
Biochimie 03/2010; 92(9):1242-51. · 3.02 Impact Factor
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ABSTRACT: The application of nanotechnology in medicine and pharmaceuticals is a rapidly advancing field that is quickly gaining acceptance and recognition as an independent area of research called "nanomedicine". Urgent needs in this field, however, are biocompatible and bioactive materials for antifouling surfaces and nanoparticles for drug delivery. Therefore, extensive attention has been given to the design and development of new macromolecular structures. Among the various polymeric architectures, dendritic ("treelike") polymers have experienced an exponential development due to their highly branched, multifunctional, and well-defined structures. This Review describes the diverse syntheses and biomedical applications of dendritic polyglycerols (PGs). These polymers exhibit good chemical stability and inertness under biological conditions and are highly biocompatible. Oligoglycerols and their fatty acid esters are FDA-approved and are already being used in a variety of consumer applications, e.g., cosmetics and toiletries, food industries, cleaning and softening agents, pharmaceuticals, polymers and polymer additives, printing photographing materials, and electronics. Herein, we present the current status of dendritic PGs as functional dendritic architectures with particular focus on their application in nanomedicine, in drug, dye, and gene delivery, as well as in regenerative medicine in the form of non-fouling surfaces and matrix materials.
Advanced Materials 01/2010; 22(2):190-218. · 13.88 Impact Factor
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ABSTRACT: The successful application of gene therapy through DNA transfection into the cell is still a great challenge in ongoing research. Hyperbranched polyamines are highly branched macromolecules, and have gained significant attention in the last two decades, due to their relative ease of preparation, their shape, and their multi-functionality. This review deals with the syntheses of various hyperbranched polyamines that are prepared through a one-step polymerization process. Furthermore, we present the current status of polyamines as gene carriers and describe their versatility, and their properties such as structure-property dependency, gene transfection efficiency, and cytotoxicity profiles of hyperbranched polyamines.
Topics in current chemistry 01/2010; 296:95-129. · 4.29 Impact Factor
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ABSTRACT: In this Letter we report the synthesis and in vitro studies of cleavable polymer-drug conjugates derived from dendritic polyglycerol and maleimide-bearing prodrugs of doxorubicin and methotrexate that are cleaved by cathepsin B. Cleavage properties and cytotoxicity of the new conjugates are presented.
Bioorganic & medicinal chemistry letters 06/2009; 19(14):3725-8. · 2.65 Impact Factor
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Journal of Physical Organic Chemistry 09/2008; 21(12):1079 - 1085. · 1.96 Impact Factor
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Revista Iberoamericana de Polímeros, ISSN 0121-6651, Vol. 8, Nº. 1, 2007, pags. 64-76.
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Revista Iberoamericana de Polímeros, ISSN 0121-6651, Vol. 9, Nº. 3, 2008, pags. 148-157.
