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1.
Glycobiology ; 27(11): 1062-1074, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29044377

RESUMO

Liposomal encapsulation is a useful drug delivery strategy for small molecules, especially chemotherapeutic agents such as doxorubicin. Doxil® is a doxorubicin-containing liposome ("dox-liposome") that passively targets drug to tumors while reducing side effects caused by free drug permeating and poisoning healthy tissues. Polyethylene glycol (PEG) is the hydrophilic coating of Doxil® that protects the formulation from triggering the mononuclear phagocyte system (MPS). Evading the MPS prolongs dox-liposome circulation time thus increasing drug deposition at the tumor site. However, multiple doses of Doxil® sometimes activate an anti-PEG immune response that enhances liposome clearance from circulation and causes hypersensitivity, further limiting its effectiveness against disease. These side effects constrain the utility of PEG-coated liposomes in certain populations, justifying the need for investigation into alternative coatings that could improve drug delivery for better patient quality of life and outcome. We hypothesized that heparosan (HEP; [-4-GlcA-ß1-4-GlcNAc-α1-]n) may serve as a PEG alternative for coating liposomes. HEP is a natural precursor to heparin biosynthesis in mammals. Also, bacteria expressing an HEP extracellular capsule during infection escape detection and are recognized as "self," not a foreign threat. By analogy, coating drug-carrying liposomes with HEP should camouflage the delivery vehicle from the MPS, extending circulation time and potentially avoiding immune-mediated clearance. In this study, we characterize the postmodification insertion of HEP-lipids into liposomes by dynamic light scattering and coarse-grain computer modeling, test HEP-lipid immunogenicity in rats, and compare the efficacy of drug delivered by HEP-coated liposomes to PEG-coated liposomes in a human breast cancer xenograft mouse model.


Assuntos
Dissacarídeos/química , Lipossomos/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Dissacarídeos/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Feminino , Humanos , Lipossomos/efeitos adversos , Masculino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Camundongos Endogâmicos NOD , Ratos , Ratos Sprague-Dawley
2.
Nat Commun ; 13(1): 7438, 2022 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-36460670

RESUMO

Complex carbohydrates (glycans) are major players in all organisms due to their structural, energy, and communication roles. This last essential role involves interacting and/or signaling through a plethora of glycan-binding proteins. The design and synthesis of glycans as potential drug candidates that selectively alter or perturb metabolic processes is challenging. Here we describe the first reported sulfur-linked polysaccharides with potentially altered conformational state(s) that are recalcitrant to digestion by heparanase, an enzyme important in human health and disease. An artificial sugar donor with a sulfhydryl functionality is synthesized and enzymatically incorporated into polysaccharide chains utilizing heparosan synthase. Used alone, this donor adds a single thio-sugar onto the termini of nascent chains. Surprisingly, in chain co-polymerization reactions with a second donor, this thiol-terminated heparosan also serves as an acceptor to form an unnatural thio-glycosidic bond ('S-link') between sugar residues in place of a natural 'O-linked' bond. S-linked heparan sulfate analogs are not cleaved by human heparanase. Furthermore, the analogs act as competitive inhibitors with > ~200-fold higher potency than expected; as a rationale, molecular dynamic simulations suggest that the S-link polymer conformations mimic aspects of the transition state. Our analogs form the basis for future cancer therapeutics and modulators of protein/sugar interactions.


Assuntos
Polímeros , Açúcares , Humanos , Glucuronidase , Enxofre , Compostos de Sulfidrila
3.
J Am Chem Soc ; 132(31): 10654-5, 2010 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-20681688

RESUMO

The structural characterization of carbohydrate polymers is important for understanding their functions and behavior. However, mainstream structural biology tools are not applicable to many carbohydrate polymers, particularly at physiological concentrations. We report Raman and Raman optical activity spectra of hyaluronan polymer, the hyaluronan tetramer building block, and the two monosaccharide components glucuronic acid and N-acetylglucosamine and identify marker bands corresponding to primary and secondary structure in glycosaminoglycans. Furthermore, we show that the hyaluronan polymer does not adopt tertiary structure under near-physiological conditions, confirming a proposed model of hyaluronan structural organization.


Assuntos
Ácido Hialurônico/química , Polímeros/química , Configuração de Carboidratos , Análise Espectral Raman
4.
Glycobiology ; 13(4): 255-64, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12626381

RESUMO

How simple monosaccharides, once polymerized, become the basis for structural materials remains a mystery. A framework is developed to investigate the role of water in the emergence of dynamic structure in polysaccharides, using the important beta(1-->4) linkage as an example. This linkage is studied within decasaccharide fragments of cellulose, chitin, mannan, xylan, and hyaluronan, using molecular simulations in the presence of explicit water solvent. Although cellulose, mannan, chitin, and xylan are chemically similar, their intramolecular hydrogen-bond dynamics and interaction with water are predicted to differ. Cellulose, mannan, and chitin favor relatively static intramolecular hydrogen bonds, xylan prefers dynamic water bridges, and multiple water configurations are predicted at the beta(1-->4) linkages of hyaluronan. With such a variety of predicted dynamics, the hypothesis that the beta(1-->4) linkage is stabilized by intramolecular hydrogen bonds was rejected. Instead, it is proposed that favored molecular configurations are consistent with maximum rotamer and water degrees of freedom, explaining observations made previously by X-ray diffraction. Furthermore, polysaccharides predicted to be conformationally restricted in simulations (cellulose, chitin, and mannan) prefer the solid state in reality, even as oligosaccharides. Those predicted to be more flexible (xylan and hyaluronan) are known to be soluble, even as high polymers. Therefore an intriguing correlation between chemical composition, water organization, polymer properties, and biological function is proposed.


Assuntos
Polissacarídeos/química , Água/química , Configuração de Carboidratos , Celulose/química , Celulose/metabolismo , Fenômenos Químicos , Físico-Química , Quitina/química , Quitina/metabolismo , Ácido Hialurônico/química , Ácido Hialurônico/metabolismo , Ligação de Hidrogênio , Manose/química , Manose/metabolismo , Modelos Moleculares , Estrutura Molecular , Polissacarídeos/metabolismo , Soluções , Fatores de Tempo , Água/metabolismo , Xilanos/química , Xilanos/metabolismo
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