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Prolonged Release of Bioactive Model Proteins from Anionic Microgels Fabricated with a New Microemulsion Approach

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Abstract

Purpose

Therapeutic proteins have become an integral part of health care. However, their controlled delivery remains a challenge. Protein function depends on a delicate three dimensional structure, which can be damaged during the fabrication of controlled release systems. This study presents a microgel-based controlled release system capable of high loading efficiencies, prolonged release and retention of protein function.

Methods

A new DMSO/Pluronic microemulsion served as a reaction template for the crosslinking of poly(acrylic acid) and oligo (ethylene glycol) to form microgels. Poly(acylic acid) molecular weights and microgel crosslinking densities were altered to make a series of microgels. Microgel capacity to capture and retain proteins of different sizes and isoelectric points, to control their release rate (over ~30 days) and to maintain the biofunctionality of the released proteins were evaluated.

Results

Microgels of different sizes and morphologies were synthesized. Loading efficiencies of 100% were achieved with lysozyme in all formulations. The loading efficiency of all other proteins was formulation dependent. Release of lysozyme was achieved for up to 30 days and the released lysozyme retained over 90% of its activity.

Conclusions

High loading efficiencies and prolonged release of different proteins was achieved. Furthermore, lysozyme’s functionality remained uncompromised after encapsulation and release. This work begins to lay the foundation for a broad platform for the delivery of therapeutic proteins.

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Abbreviations

AA:

Acrylic acid

A-CPA:

4,4’-azobis(4-cyanopentanoic acid)

CPA-DB:

4-cyanopentanoic acid dithiobenzoate

DMTMM:

4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

GPC:

Gel permeation chromatography

NMM:

4-methylmorpholine

OEG:

Oligo(ethylene glycol)

pAA:

Poly(acrylic acid)

PBS:

Phosphate buffered saline

pI:

Isoelectric point

RAFT:

Reversible addition-fragmentation chain transfer

SEM:

Scanning electron microscopy

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ACKNOWLEDGMENTS AND DISCLOSURES

We would like to gratefully acknowledge the Coleman Foundation and the NSF Graduate Research Fellowship for their support (J.L.R.). The authors would like to acknowledge Dr. Lindsey Crawford for her assistance with cell culture and MTT assay. This work made use of Cornell Center for Materials Research facilities funded through NSF MRSEC DMR-1120296 and the Cornell University NMR Chemistry facility.

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Authors and Affiliations

  1. Meinig School of Biomedical Engineering, Cornell University, 147 Weill Hall, Ithaca, New York, 14853, USA

    Jose L. Rios, Gongcheng Lu & David Putnam

  2. Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York, 14853, USA

    Na Eun Seo & Tamara Lambert

  3. School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York, 14853, USA

    David Putnam

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  1. Jose L. Rios
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  2. Gongcheng Lu
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Correspondence to David Putnam.

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Rios, J.L., Lu, G., Seo, N.E. et al. Prolonged Release of Bioactive Model Proteins from Anionic Microgels Fabricated with a New Microemulsion Approach. Pharm Res 33, 879–892 (2016). https://doi.org/10.1007/s11095-015-1834-8

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  • DOI: https://doi.org/10.1007/s11095-015-1834-8

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