Polymer Nanogels as Reservoirs to Inhibit Hydrophobic Drug Crystallization

Ziang Li; Nicholas J. Van Zee; Frank S. Bates; Timothy P Lodge

doi:10.1021/acsnano.8b06393

Polymer Nanogels as Reservoirs to Inhibit Hydrophobic Drug Crystallization

Ziang Li, Nicholas J. Van Zee, Frank S. Bates, Timothy P Lodge

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34 Scopus citations

Abstract

The effects of cross-link density and composition on the loading and in vitro dissolution of the drug phenytoin as amorphous solid dispersions in emulsion polymerized poly(N-isopropylacrylamide) (PNIPAm) and poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) nanogels were investigated near the lower critical solution temperature (LCST). Nanogel size and particle density in phosphate buffered saline were quantified by dynamic light scattering (DLS) and viscometry experiments, while drug-nanogel interactions were revealed by cross peaks in aqueous-state nuclear Overhauser effect spectroscopy measurements. Spray-dried dispersions (SDDs) of drug-loaded PNIPAm nanogel particles (R ≈ 43 nm) were directly visualized by cryogenic transmission electron microscopy and further quantified by small-angle X-ray scattering during in vitro dissolution. SDD dissolution profiles were highly dependent on the nanogel cross-link density and directly correlated with the state of dispersion of the drug-loaded nanogel particles. A balance between net particle hydrophobicity and hydrophilicity along with the distance in temperature from the LCST are shown to dictate the in vitro dissolution of the amorphous solid dispersions. Solubility enhancement mechanisms disclosed in this study provide essential guidance for the design of effective nanogels for oral drug delivery applications.

Original language	English (US)
Pages (from-to)	1232-1243
Number of pages	12
Journal	ACS nano
Volume	13
Issue number	2
DOIs	https://doi.org/10.1021/acsnano.8b06393
State	Published - Feb 26 2019

Bibliographical note

Funding Information:
The Bruker HD NMR was supported by the Office of the Director, National Institutes of Health of the National Institutes of Health under award no. S10OD011952.

Funding Information:
The authors gratefully thank M. A. Hillmyer, T. M. Reineke, R. L. Schmitt, W. W. Porter, III, J. M. Mecca, J. Zhao, P. W. Schmidt, L. M. Johnson, A. A. Purchel, M. L. Ohnsorg, L. J. Yao, and T. I. Lenk for helpful discussions. The authors also thank T. I. Lenk, L. J. Yao, and C. Frethem for the help with the viscometry, NMR, and SEM experiments, respectively. This study was funded by The Dow Chemical Company through agreement 224249AT with the University of Minnesota. Parts of this work were carried out in the College of Science and Engineering Characterization Facility, Uni- versity of Minnesota, which has received capital equipment funding from the NSF through the UMN MRSEC program under award no. DMR-1420013. Parts of this work were performed at the DuPont−Northwestern−Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source (APS). DND-CAT is supported by E.I. DuPont de Nemours & Co., the Dow Chemical Company, and Northwestern University. Use of the APS, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under contract no. DE-AC02-06CH11357. This work also benefited from the use of the SASView application, originally developed under NSF award DMR-0520547. SASView contains code developed with funding from the European Union’s Horizon 2020 research and innovation programme under the SINE2020 project, grant agreement no. 654000. The Bruker HD NMR was supported by the Office of the Director, National Institutes of Health of the National Institutes of Health under award no. S10OD011952. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2019 American Chemical Society.

Keywords

cryo-TEM
drug delivery
lower critical solution temperature
N-isopropylacrylamide
nanogel
nanoparticle

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PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

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10.1021/acsnano.8b06393

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title = "Polymer Nanogels as Reservoirs to Inhibit Hydrophobic Drug Crystallization",

abstract = "The effects of cross-link density and composition on the loading and in vitro dissolution of the drug phenytoin as amorphous solid dispersions in emulsion polymerized poly(N-isopropylacrylamide) (PNIPAm) and poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) nanogels were investigated near the lower critical solution temperature (LCST). Nanogel size and particle density in phosphate buffered saline were quantified by dynamic light scattering (DLS) and viscometry experiments, while drug-nanogel interactions were revealed by cross peaks in aqueous-state nuclear Overhauser effect spectroscopy measurements. Spray-dried dispersions (SDDs) of drug-loaded PNIPAm nanogel particles (R ≈ 43 nm) were directly visualized by cryogenic transmission electron microscopy and further quantified by small-angle X-ray scattering during in vitro dissolution. SDD dissolution profiles were highly dependent on the nanogel cross-link density and directly correlated with the state of dispersion of the drug-loaded nanogel particles. A balance between net particle hydrophobicity and hydrophilicity along with the distance in temperature from the LCST are shown to dictate the in vitro dissolution of the amorphous solid dispersions. Solubility enhancement mechanisms disclosed in this study provide essential guidance for the design of effective nanogels for oral drug delivery applications.",

keywords = "cryo-TEM, drug delivery, lower critical solution temperature, N-isopropylacrylamide, nanogel, nanoparticle",

author = "Ziang Li and {Van Zee}, {Nicholas J.} and Bates, {Frank S.} and Lodge, {Timothy P}",

note = "Funding Information: The Bruker HD NMR was supported by the Office of the Director, National Institutes of Health of the National Institutes of Health under award no. S10OD011952. Funding Information: The authors gratefully thank M. A. Hillmyer, T. M. Reineke, R. L. Schmitt, W. W. Porter, III, J. M. Mecca, J. Zhao, P. W. Schmidt, L. M. Johnson, A. A. Purchel, M. L. Ohnsorg, L. J. Yao, and T. I. Lenk for helpful discussions. The authors also thank T. I. Lenk, L. J. Yao, and C. Frethem for the help with the viscometry, NMR, and SEM experiments, respectively. This study was funded by The Dow Chemical Company through agreement 224249AT with the University of Minnesota. Parts of this work were carried out in the College of Science and Engineering Characterization Facility, Uni- versity of Minnesota, which has received capital equipment funding from the NSF through the UMN MRSEC program under award no. DMR-1420013. Parts of this work were performed at the DuPont−Northwestern−Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source (APS). DND-CAT is supported by E.I. DuPont de Nemours & Co., the Dow Chemical Company, and Northwestern University. Use of the APS, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under contract no. DE-AC02-06CH11357. This work also benefited from the use of the SASView application, originally developed under NSF award DMR-0520547. SASView contains code developed with funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the SINE2020 project, grant agreement no. 654000. The Bruker HD NMR was supported by the Office of the Director, National Institutes of Health of the National Institutes of Health under award no. S10OD011952. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

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Polymer Nanogels as Reservoirs to Inhibit Hydrophobic Drug Crystallization

Abstract

Bibliographical note

Keywords

How much support was provided by MRSEC?

Reporting period for MRSEC

PubMed: MeSH publication types

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MRSEC IRG-3: Hierarchical Multifunctional Macromolecular Materials

University of Minnesota MRSEC (DMR-1420013)

Cite this

Polymer Nanogels as Reservoirs to Inhibit Hydrophobic Drug Crystallization

Abstract

Bibliographical note

Keywords

How much support was provided by MRSEC?

Reporting period for MRSEC

PubMed: MeSH publication types

Access

OpenUrl availability

Other files and links

Fingerprint

Projects

MRSEC IRG-3: Hierarchical Multifunctional Macromolecular Materials

University of Minnesota MRSEC (DMR-1420013)

Cite this