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Development of delivery methods for carbohydrate-based drugs: controlled release of biologically-active short chain fatty acid-hexosamine analogs

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Abstract

Carbohydrates are attractive candidates for drug development because sugars are involved in many, if not most, complex human diseases including cancer, immune dysfunction, congenital disorders, and infectious diseases. Unfortunately, potential therapeutic benefits of sugar-based drugs are offset by poor pharmacologic properties that include rapid serum clearance, poor cellular uptake, and relatively high concentrations required for efficacy. To address these issues, pilot studies are reported here where ‘Bu4ManNAc’, a short chain fatty acid-monosaccharide hybrid molecule with anti-cancer activities, was encapsulated in polyethylene glycol-sebacic acid (PEG-SA) polymers. Sustained release of biologically active compound was achieved for over a week from drug-laden polymer formulated into microparticles thus offering a dramatic improvement over the twice daily administration currently used for in vivo studies. In a second strategy, a tributanoylated ManNAc analog (3,4,6-O-Bu3ManNAc) with anti-cancer activities was covalently linked to PEG-SA and formulated into nanoparticles suitable for drug delivery; once again release of biologically active compound was demonstrated.

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Abbreviations

PEG:

poly(ethylene glycol)

poly(PEG-SA):

poly(polyethylene glycol-co-sebacic anhydride)

poly(PEG-SA):1 :

Compound 1 (Bu4ManNAc) non-covalently encapsulated in poly(PEG-SA)

polySA-2 :

Compound 2 (3,4,6-O-Bu3ManNAc) covalently linked to polySA-2

polySA-2-NP:

nanoparticles formulated from polySA-2

PVA:

poly(vinyl alcohol).

AUC:

area under the curve

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Acknowledgments

Funding for this project was provided by the National Institutes of Health (CA11231404) for SCFA-hexosamine synthesis and analysis of anti-metastatic responses in MDA-MB-231 cells, (EB005692-03 for synthesis and evaluation of sebacic acid-PEG polymers), and the Johns Hopkins Institute for NanoBioTechnology (INBT, for the synthesis and biological evaluation of the covalently-conjugated nanoparticles).

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Author notes

  1. Udayanath Aich

    Present address: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

  2. Srinivasa-Gopalan Sampathkumar

    Present address: Laboratory of Chemical Glycobiology, National Institute of Immunology Aruna Asaf Ali Marg, New Delhi, 110067, India

Authors and Affiliations

  1. Department of Biomedical Engineering, The Johns Hopkins University, Clark Hall 106A, 3400 North Charles Street, Baltimore, MD, 21218, USA

    M. Adam Meledeo, Mark B. Jones, Christopher A. Weier, Sung Yun Chung, Ming Yang & Kevin J. Yarema

  2. Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA

    Jie Fu, Benjamin C. Tang & Justin Hanes

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  1. Udayanath Aich
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Corresponding author

Correspondence to Kevin J. Yarema.

Additional information

Udayanath Aich, M. Adam Meledeo, Srinivasa-Gopalan Sampathkumar and Jie Fu contributed equally.

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Aich, U., Meledeo, M.A., Sampathkumar, SG. et al. Development of delivery methods for carbohydrate-based drugs: controlled release of biologically-active short chain fatty acid-hexosamine analogs. Glycoconj J 27, 445–459 (2010). https://doi.org/10.1007/s10719-010-9292-3

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