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. 2012 Jan 24;6(1):81-8.
doi: 10.1021/nn202607r. Epub 2011 Dec 29.

Graphene multilayers as gates for multi-week sequential release of proteins from surfaces

Jinkee Hong  1 , Nisarg J Shah, Adam C Drake, Peter C DeMuth, Jong Bum Lee, Jianzhu Chen, Paula T Hammond
Affiliations

Graphene multilayers as gates for multi-week sequential release of proteins from surfaces

Jinkee Hong et al. ACS Nano. .

Abstract

The ability to control the timing and order of release of different therapeutic drugs will play a pivotal role in improving patient care and simplifying treatment regimes in the clinic. The controlled sequential release of a broad range of small and macromolecules from thin film coatings offers a simple way to provide complex localized dosing in vivo. Here we show that it is possible to take advantage of the structure of certain nanomaterials to control release regimes from a scale of hours to months. Graphene oxide (GO) is a two-dimensional charged nanomaterial that can be used to create barrier layers in multilayer thin films, trapping molecules of interest for controlled release. Protein-loaded polyelectrolyte multilayer films were fabricated using layer-by-layer assembly incorporating a hydrolytically degradable cationic poly(β-amino ester) (Poly1) with a model protein antigen, ovalbumin (ova), in a bilayer architecture along with positively and negatively functionalized GO capping layers for the degradable protein films. Ova release without the GO layers takes place in less than 1 h but can be tuned to release from 30 to 90 days by varying the number of bilayers of functionalized GO in the multilayer architecture. We demonstrate that proteins can be released in sequence with multi-day gaps between the release of each species by incorporating GO layers between protein loaded layers. In vitro toxicity assays of the individual materials on proliferating hematopoietic stem cells (HSCs) indicated limited cytotoxic effects with HSCs able to survive for the full 10 days of normal culture in the presence of Poly1 and the GO sheets. This approach provides a new route for storage of therapeutics in a solid-state thin film for subsequent delivery in a time-controlled and sequential fashion.

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Figures

Figure 1
Figure 1
Overall schematic illustrations of architecture toolbox for desired sustained release of ova.
Figure 2
Figure 2
(a) Schematic representation of chemically modified graphene oxide GO-COO− and GO-NH3+. (b) Schematic illustrations of (Poly1/ova)20(GO/GO)5(Poly1/ova)20 multilayer films. (c) Growth curve of electrostatically assembled (Poly1/ova)20(GO/GO)5(Poly1/ova)20 multilayer films as a function of bilayer number.
Figure 3
Figure 3
Representative surface morphology of a multilayer films: SEM image of as-assembled (a) (GO/GO)5 (b) (GO/GO)10 and (c) (GO/GO)20 multilayer on substrate/(Poly1/ova)20 multilayer film. (d) The influence of different number of graphene layers in the film architecture based on substrate/(Poly1/ova) 20 in the multilayer films on the release profile: Normalized release profiles of ovalbumin from substrate/(Poly1/ova)20(GO/RO)5 (■-blue line), substrate/(Poly1/ova)20(GO/GO)10 (●-purple line), and substrate/(Poly1/ova)20(GO/GO)20 (▲-black line) measured by ELISA.
Figure 4
Figure 4
The various kinetics of ova release from dried multilayer films: Normalized cumulative release from: (a) substrate/(Poly1/ova-TR)20(GO/GO)2(Poly1/ova-FL)20 (b) substrate/(Poly1/ova-TR)20(GO/GO)5(Poly1/ova-FL)20 (c) substrate/(Poly1/ova-AF555)20(GO/GO)5(Poly1/ova-TR)20(GO/GO)2(Poly1/ova-FL)20 multilayer films. (d) substrate/(GO/ova-FL)20 The release experiments were conducted in PBS buffer (pH 7.4 at 37 °C, 5% of CO2). ●-(green line), ■-(pink line) and ▲-(yellow line) indicate the ova released from (Poly1/ova-FL)20, (Poly1/ova-TR)20 and(Poly1/ova-AF555)20 respectively.
Figure 5
Figure 5
Photo images of thin film of substrate/(Poly1/ova-TR)20(GO/GO)20(Poly1/ova-FL)20 multilayer film: (a) A large-area film transferred on a 6.7-inch PET sheet, (b) An assembled multilayer film showing outstanding flexibility.
Figure 6
Figure 6
The proliferation was compared between CD133-APC and CD34-FITC subpopulations of hematopoietic stem cell using a cell proliferation from (a) cord blood (1 day) (b) feeder free cytokine culture condition for HSCs expansion and in the presence of (c) Poly1 (d) GO-COO− in control condition for 10 day assay. The expression levels of CD133 and CD34 were examined by FACS analysis. (e and f) Summary of the proportion of cells surviving in culture (e) and assessment of HSC retention in culture (f), data are normalized to a culture without added polymers.
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