Nanocarriers from GRAS Zein Proteins to Encapsulate Hydrophobic

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Nanocarriers from GRAS Zein Proteins to Encapsulate Hydrophobic Actives Nikolas T. Weissmueller, Hoang Dung Lu, Amanda Hurley, and Robert K Prud'homme Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.6b01440 • Publication Date (Web): 16 Oct 2016 Downloaded from http://pubs.acs.org on October 18, 2016

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Nanocarriers from GRAS Zein Proteins to Encapsulate

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Hydrophobic Actives

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Nikolas T. Weissmueller†1, Hoang D. Lu†1, Amanda Hurley2, Robert K. Prud’homme*1

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1. Department of Chemical and Biological Engineering, Princeton University, Princeton, New

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Jersey 08544, United States.

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2. Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, United

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States.

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Keywords:

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Nanoparticle, zein, casein, autoinducer, drug-delivery, GRAS, cholera

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Abstract

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One factor limiting the expansion of nanomedicines has been the high cost of the materials and

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processes required for their production. We present a continuous, scalable, low cost nano-

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encapsulation process, Flash Nanoprecipitation (FNP) that enables the production of nanocarriers

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(NCs) with a narrow size distribution using zein corn proteins. Zein is a low cost, GRAS protein

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(having the FDA status of “Generally Regarded as Safe”) currently used in food applications,

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which acts as an effective encapsulant for hydrophobic compounds using FNP. The four-stream

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FNP configuration allows the encapsulation of very hydrophobic compounds in a way that is not

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possible with previous precipitation processes. We present the encapsulation of several model

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active compounds with as high as 45 wt% drug loading with respect to zein concentration into

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~100 nm nanocarriers. Three examples are presented: (1) the pro-drug antioxidant, vitamin E-

ACS Paragon Plus Environment

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acetate, (2) an anti-cholera quorum-sensing modulator CAI-1 ((S)-3-hydroxytridecan-4-one).

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CAI-1 that reduces Vibrio cholerae virulence by modulating cellular communication, and (3)

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hydrophobic fluorescent dyes with a range of hydrophobicities. The specific interaction between

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zein and the milk protein, sodium caseinate, provides stabilization of the NCs in PBS, LB

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medium, and in pH 2 solutions. The stability and size changes in the three media provide

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information on the mechanism of assembly of the zein:active:casein NC.

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Background

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Nanomedicines: Nanotechnology has been an area of intense research commitment over

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that last two decades, and nanocarriers (NCs) for the delivery of therapeutics has been one of the

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successful areas in biomedical nanotechnology. Most successes in NC delivery have been in

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oncology, where the high value of treatment has allowed the application of relatively expensive

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formulations. Formulations most often employ block copolymers with polyethylene glycol

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(PEG) blocks to provide biocompatible surface properties.1-2 NCs for oral administration, most

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often, have as their aim increased bioavailability of very hydrophobic drug compounds.

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formulations must balance the advantage of increased bioavailabilty against the increased costs

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of NC processing and of the excipients required for NC formation. Using materials that are

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accepted by regulatory agencies as GRAS (Generally Regarded as Safe) are preferred in oral

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delivery applications, as they reduce the complexity of regulatory approval.

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Oral

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Our interest is in the encapsulation of hydrophobic compounds for oral delivery using

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low-cost, GRAS excipients. Biodegradable protein polymers, such as albumin, casein, gelatin,

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and chitosan, have been investigated as all-natural low-cost encapsulants.

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soluble proteins generally provide poor coupling with hydrophobic compounds and, therefore,

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result in low loading and low encapsulation efficiency. Excellent work by the Johnston and


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However, these

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Elder’s group on direct precipitation of hydrophobic drugs with hydroxypropyl methylcellulose

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(HPMC) has demonstrated significant increases in drug supersaturation upon dissolution of the

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resulting powders.5-8 Direct precipitations rely upon highly hydrophobic compounds to achieve

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high nucleation rates, and encapsulation by HPMC relies solely on hydrophobic interactions

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between the polymer and compounds. Both hydrophobic and electrostatic interactions between

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zein and the compounds being encapsulated provides increased flexibility in compounds that can

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be processed into NC form.

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In this paper we present the new process for the encapsulation of hydrophobic actives

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with zein proteins using the kinetically controlled, rapid precipitation process Flash

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NanoPrecipitation (FNP) using a Multi-inlet Vortex Mixer (MIVM). The MIVM, with multiple

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inlet streams enables the encapsulation of actives at higher loading, control of size, and narrow

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size distributions than have been reported for alternate NC formation processes. The specific

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interaction between zein and the milk protein casein provides effective stabilization of the NCs.

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We provide three examples to show the generality of the process: (1) the pro-drug antioxidant,

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vitamin E-acetate, (2) an anti-cholera quorum-sensing modulator CAI-1 ((S)-3-hydroxytridecan-

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4-one) and (3) hydrophobic fluorescent dyes with a range of hydrophobicities.

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Zein prolamin proteins: In this study we present NC formation based on rapid

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precipitation with zein as the encapsulating agent. Zein is a low cost, GRAS prolamin protein

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found in the endoplasmic reticulum-derived protein vesicles in maize seeds.9 It finds application

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as a film coating excipient of pharmaceuticals. Zein is water-insoluble owing to its high content

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(>50%) of non-polar amino acids such as leucine, proline, alanine, and phenylalanine.10 It is also

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insoluble in pure alcohol or most organics. It is soluble in water:alcohol mixed solvents, which


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provides a route for processing zein into water insoluble particles by mixing with excess water.

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However, this presents a barrier for incorporating highly hydrophobic actives and zein in simple

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mixing/phase separation processes because the highly hydrophobic active will not be soluble in

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high enough concentrations in an alcohol:water mixture to ensure adequate active loading.

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Globular zein consists of four fractions that vary in molecular weight, composition,

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structure and solubility.9, 11 These include α-zein (MW, 19–24 kDa; 75–80% of total protein) 12,

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β-zein (17–18 kDa, 10– 15%), γ-zein (27 kDa, 5–10%), and δ-zein (10kDa)

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subcomponents are arranged into a tertiary structure that comprises nine homologous repeating

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units oriented in an anti-parallel sense, and stabilized by hydrogen bonds.11 The majority of the

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molecular surface area comprises the hydrophobic α-helixes in anti-parallel orientation 16, while

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the glutamine rich turns create a hydrophilic surface at their top and bottom.

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assembly bestows zein with amphiphilic characteristics. These properties are reported to drive

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self-assembly into a variety of mesostructures, 17 including ribbons, sheets, tori, pores, and micro

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and nanospheres15. The amphilicity of zein allows it to encapsulate a variety of biological

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compounds: heparin

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D3

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thymol

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unique, and points to the encapsulation being driven both by hydrophobic and electrostatic

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interactions. A limitation has been that reported loading capacities are generally 98% for all stable formulations as determined by absorbance measurement of the flow through

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after centrifugal filtration (SI Figure 1). With increasing Nile Red concentration in the core, the

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mean NC diameter increases (Fig. 7b). The florescence intensity increased with higher dye

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loading per particle. This can be seen in Fig. 7c and 7d for two different wavelengths (500nm

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excitation, 690nm emission) and core loadings of 0.2-1% wt. However, at dye content higher

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than 1%wt. the fluorescence intensity decreases, as intermolecular interactions lead to

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quenching.61


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A

B

Nile Red Pyrene Methyl Red

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NP Mean Diameter

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Size (d.nm)

Intensity (%)

108 107

12 10 8 6 4

105 104 103 102 101

2 100 0 100

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10000

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Size (d.nm)

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C

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Nile Red % wt.

D 1400

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Excitation Maximum

Emission Maximum

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Fluorescence

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Fluorescence

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2000 1500 1000 500

1000 800 600 400 200

0

0 0

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0

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Nile Red % wt.

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2

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Nile Red % wt.

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Figure 7: Characterization of NC loading. (A) Sizes of dye-containing Zein:CAS:VitE-Ac NCs by dynamic light

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scattering. Formulations contained 2 mg/mL zein in 60% EtOH at 12mL/min, flashed with 1mg/mL casein in

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sodium citrate buffer (36mL/min), flashed with 0.33 mg/mL VitE-Ac and 0.01wt % of dye in 100% EtOH at

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12mL/min. (B) Mean diameter size of NC formulations with Nile Red loading from 0.25-5% wt. Fluorescence

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maxima for either (C) 500nm excitation, or (D) 690nm emission, at 0.25-5% wt. Nile Red loading for

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Zein:CAS:VitE-Ac NCs.

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Conclusion


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Zein protein-based NC formulations were prepared using sodium caseinate (CAS) as a

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stabilizer. Particles at sub-100 nm sizes, with high loading of highly hydrophobic components

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such as VitE-Ac, CAI-1, and hydrophobic dyes is enabled by the ability to form NCs with a

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multi-inlet vortex mixing geometry (MIVM) that enables independent control over multiple inlet

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streams. The amphiphilic molecular structure of zein enables both assembly of the NCs, and also

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synergistic interactions with casein proteins to produce stable NCs. The components in the

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formulations are all GRAS, which means that translation to food and oral drug delivery

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therapeutics is facilitated. The dramatically lower cost of zein and casein, relative to the

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amphiphilic block copolymers previously used in block copolymer stabilized NCs, expands the

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range of applications that will be of interest. The precise NC size control, and the scalability of

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the FNP process suggests applications in food (e.g. nutraceutical), pharmaceutical and

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agricultural formulations.

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Encapsulation of the quorum sensing therapeutic, CAI-1 demonstrated that the NCs

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remained colloidally stable in ionic buffers and simulated intestinal fluid for 24 hrs. Efficacy of

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CAI-1 in NCs was similar to CAI-1 in DMSO, while enabling CAI-1 delivery as an aqueous

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dispersion. Within the context of cholera, the low-cost GRAS components and the scalability of

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the FNP process may enable an auxiliary prophylactic treatment that could limit the need for

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antibiotics.

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The encapsulation of both purely hydrophobic compounds (VitE-Ac, CAI-1) has been

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demonstrated by FNP previously. The encapsulation of the ionizable methyl red and Nile Red

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point out the interesting ability of zein to interact both hydrophobically and ionically with

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compounds during NC assembly.

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ASSOCIATED CONTENT

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Supporting Information. Additional information on particle characterization is available free of

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charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

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Nikolas t. Weissmueller† Hoang D. Lu† Amanda Hurley Robert K. Prud’homme

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Corresponding Author

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*E-mail: [email protected]

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Acknowledgements

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The authors would like to thank Dr. Christina Tang for assistance with TEM imaging. We would

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like to thank Professor Martin Semmelhack for CAI-1 material, and Professor Bonnie Bassler for

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materials used in cell work.

†

Co-first authors

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Funding

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Funds were provided by Princeton University’s internal SEAS Old Guard grant, Princeton

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University Center for Health and Wellbeing, and the Woodrow Wilson School of Public and

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International Affairs Program in Science, Technology, and Environmental Policy.

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51. Higgins, D. A.; Pomianek, M. E.; Kraml, C. M.; Taylor, R. K.; Semmelhack, M. F.; Bassler, B. L., The major Vibrio cholerae autoinducer and its role in virulence factor production. Nature 2007, 450 (7171), 883-6. 52. van Henegouwen, G. M. B.; Junginger, H. E.; de Vries, H., Hydrolysis of RRR-αtocopheryl acetate (vitamin E acetate) in the skin and its UV protecting activity (an in vivo study with the rat). Journal of Photochemistry and Photobiology B: Biology 1995, 29 (1), 45-51. 53. Khdour, O. M.; Lu, J.; Hecht, S. M., An acetate prodrug of a pyridinol-based vitamin E analogue. Pharmaceutical research 2011, 28 (11), 2896-2909. 54. Figueroa, C. E.; Reider, P.; Burckel, P.; Pinkerton, A. A.; Prud'homme, R. K., Highly loaded nanoparticulate formulation of progesterone for emergency traumatic brain injury treatment. Therapeutic Delivery 2012, 3 (11), 1269-1279. 55. Lu, H. D.; Spiegel, A. C.; Hurley, A.; Perez, L. J.; Maisel, K.; Ensign, L. M.; Hanes, J.; Bassler, B. L.; Semmelhack, M. F.; Prud’homme, R. K., Modulating Vibrio cholerae QuorumSensing-Controlled Communication Using Autoinducer-Loaded Nanoparticles. Nano letters 2015, 15 (4), 2235-2241. 56. Luo, Y.; Teng, Z.; Wang, T. T.; Wang, Q., Cellular uptake and transport of zein nanoparticles: effects of sodium caseinate. J Agric Food Chem 2013, 61 (31), 7621-9. 57. Kumar, V.; Wang, L.; Riebe, M.; Tung, H. H.; Prud'homme, R. K., Formulation and Stability of ltraconazole and Odanacatib Nanoparticles: Governing Physical Parameters. Mol Pharmaceut 2009, 6 (4), 1118-1124. 58. Liu, Y.; Kathan, K.; Saad, W.; Prud'homme, R. K., Ostwald ripening of beta-carotene nanoparticles. Physical Review Letters 2007, 98 (3), 036102. 59. Ogawa, K., Effects of salt on intermolecular polyelectrolyte complexes formation between cationic microgel and polyanion. Advances in colloid and interface science 2015, 226, 115-121. 60. Solomatin, S. V.; Bronich, T. K.; Eisenberg, A.; Kabanov, V. A.; Kabanov, A. V., Colloidal stability of aqueous dispersions of block ionomer complexes: effects of temperature and salt. Langmuir 2004, 20 (6), 2066-2068. 61. Pansare, V. J.; Bruzek, M. J.; Adamson, D. H.; Anthony, J.; Prud'homme, R. K., Composite Fluorescent Nanoparticles for Biomedical Imaging. Molecular Imaging and Biology 2014, 16 (2), 180-188.

625 626 627 628 629 630 631

TOC graphic summary:


27

Biomacromolecules

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 29

632 Mixer Geometry

V. cholerae (inactive)

Organic 100% EtOH

Core (VitE-Ac) Drug (Dye, CAI-1) Hydroalcoholic 60% EtOH

Zein

CAI-1 in NP (Aqueous)

Aqueous

Free CAI-1 (DMSO)

Buffer: 10mM Sodium citrate, 150µM citric acid, pH 7.5 Aqueous

MIVM FNP

V. cholerae (active)

Casein in buffer

633


28

Page 29 of 29

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Mixer Geometry

Organic 100% EtOH

Core (VitE-Ac) Drug (Dye, CAI-1) Hydroalcoholic 60% EtOH

Zein Aqueous

Buffer: 10mM Sodium citrate, 150μM citric acid, pH 7.5 Aqueous

MIVM FNP

Casein in buffer


Nanocarriers from GRAS Zein Proteins to Encapsulate Hydrophobic

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