Rational Ligand Design To Improve Agrochemical Delivery

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Rational Ligand Design to Improve Agrochemical Delivery Efficiency and Advance Agriculture Sustainability Ashley M. Smith, and Leanne M. Gilbertson ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b03457 • Publication Date (Web): 09 Oct 2018 Downloaded from http://pubs.acs.org on October 13, 2018

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ACS Sustainable Chemistry & Engineering

Rational Ligand Design to Improve Agrochemical Delivery Efficiency and Advance Agriculture Sustainability

Ashley M. Smith and Leanne M. Gilbertson*

Department of Civil and Environmental Engineering, University of Pittsburgh, 3700 O’Hara Street, Pittsburgh, PA 15261

In Preparation for Resubmission to: ACS Sustainable Chemistry & Engineering

October 9, 2018

*Corresponding Author: Phone: (412) 624-1683, e-mail: [email protected] 1 ACS Paragon Plus Environment

ACS Sustainable Chemistry & Engineering 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

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Abstract The use of agrochemicals – fertilizers and pesticides – in crop production is inefficient resulting in cascading adverse impacts on the environment and public health. Engineered nanomaterials have the potential to offer innovative solutions for effective, precise, and timed delivery of active ingredients to crops, yielding increased production while preventing overapplication. While promising, there remains an opportunity to realize this targeting capability for enhanced sustainability of crop production. Many studies have demonstrated the efficacy of nanomaterials for agrochemical delivery, yet few exploit the tunable surface chemistry to specifically target the delivery to specific regions of the crop. The primary approach to introducing this capability is through modification of the surface chemistry, typically with ligands. This perspective presents a ligand design strategy for targeting delivery and considers three primary ligand components: the nanomaterial binder, ligand body, and terminal functionality. In addition, we discuss the selection of unique compounds in two target regions that can be leveraged for targeted delivery. We identify ligand terminal functionalities that can be used to interact with these specific compounds enabling enhanced interaction between the agrochemical active ingredient and the root or leaf. The result is a proposed set of guidelines to design nano-enabled solutions for enhanced delivery efficiency.

Keywords Sustainable agriculture, nanoparticle design, agrochemical delivery, nano-enabled agriculture, nanoscale delivery, sustainable design, ligand selection

2 ACS Paragon Plus Environment

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Introduction Advancements in agricultural technologies, including the use of fertilizers to deliver external nutrients to crops and the application of pesticides to protect crops from pests and disease, have enabled global food production to support human population growth.1 However, current techniques remain indisputably inefficient. With conventional methods, approximately 30-55% of N-based and 18-20% of P-based fertilizers are reaching the intended target for use by the crop, meaning a significant amount of these fertilizers are released to the environment annually.2-3 Excess fertilizer nutrients induce stress on the surrounding ecosystems, resulting in eutrophication and groundwater contamination that threaten environmental habitats, economic investments, and public health.4-6 Tangible enhancements in efficient use of these products translates into significant savings that have cascading benefits across the fertilizer life cycle. For example, nearly 55 million metric tons (MMT) of N-based fertilizer applied to farmland globally in 2014 were not assimilated by the crop.7 If the nutrient use efficiency (NUE) were increased by 20%, an annual savings of 22 MMT of fertilizer would be realized. Additionally, fertilizer runoff can be correlated with freshwater eutrophication;5 more efficient use of fertilizers will contribute to decreasing impaired waterways across the United States, which currently results in $2.2 billion annual economic loss.8 Similar inefficiencies exist for pesticides, with an estimated 30-40% of the annually applied 1-2.5 MMT of active ingredients (A.I.s) reaching the crop.9-10 The excess A.I.s lost to the environment introduce harmful unintended consequences, including the decline of beneficial insects, such as bees and butterflies, and natural pest predators.11 The two most common pesticides in the U.S., glyphosate and atrazine, have soil half-lives on the order of months.12-13 Given their environmental persistence, decreasing the concentrations at which they are added to



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the environment will have cascading benefits across global ecosystems. Moreover, human exposure to pesticides has been linked to both short term (i.e., rash, respiratory irritation, nausea) and chronic (i.e., diabetes, asthma, cancer) conditions.14 As with fertilizers, increasing the delivery efficiency of these A.I.s will have both economic and environmental benefits. With the United States applying more than 500,000 MT of various pesticides with an annual cost of $10 billion, an increasing use efficiency would result in millions of dollars saved as well as decreased impacts to surrounding ecosystems.11 The projected growth in the global population (an increase of 30% to 9.7 billion people by 2050)15 will only exacerbate the detrimental impacts of inefficient agrochemical use. Therefore, it is imperative to develop mechanisms that enhance efficiency of agrochemical delivery to support increasing food supply demands in an environmentally sustainable and efficient manner. Engineered nanomaterials (ENMs) are emerging as potential innovative solutions to address some agricultural shortcomings while reducing environmental impacts,16-17 enhancing crop production,18-19 and improving agrochemical use efficiency.20-21 Within this context, ENMs maintain the established definition of having at least one dimension that is 1 – 100 nm and exhibiting new properties that deviate from those observed in their bulk counterparts.22 Yet, within the field of agrochemical delivery applications, there is also the potential for innovative solutions leveraging unique properties of ENMs at the submicron length scale (100 nm - 1 μm). However, in order to realize the full potential of ENMs for these pivotal opportunities, it is critical to thoughtfully design nano-enabled solutions, considering the potential tradeoffs introduced through ENM composition, physicochemical properties, and the life cycle of all components.7, 23 ENMs discussed here range from solid nanomaterials to liquid-based platforms, which include nanoemulsions and capsules. In any of their forms, ENMs promise the potential to


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revolutionize the agriculture industry by enabling a higher degree of effective, precise, and timed delivery of A.I.s to crops, yielding increased production while preventing the over-application of agrochemicals.24-28 While there have been numerous examples of ENMs used for the delivery of nutrients and pesticides to crop leaves and roots, few studies leverage unique surface properties of ENMs to target the delivery of their agrochemicals to the desired location. This capability can be enabled through rational design of ligands to manipulate and control the surface chemistry. This perspective presents an approach to designing ENMs in which the chemistry of three primary ligand components are identified for directing ENM platforms containing agrochemical A.I.s to desired target endpoints on crops. This rational design will advance the promise of nanotechnology for enhancing agrochemical use efficiency. The result is not only an approach to design but also a library of options for each component of the ligand depending on the ENM host composition and target (the rhizosphere or leaf under healthy and stressed or diseased conditions). In addition to serving the intended function of targeting, the inherent toxicity of each ligand constituent is considered such that the chemistries are chosen to be benign and/or biocompatible with the surrounding environment. Current Strategies for ENM Agrochemical Delivery This section focuses on the current state of practice on ENMs for the delivery of agrochemicals within academic literature. Given the lack of standardized labeling regulations, it is difficult to ascertain current agrochemical products on the market that utilize the nano-scale and ENMs.26 Yet the number of current patents that involve “nano” stabilization or delivery of agrochemicals signals the movement towards exploiting the nano-scale to advance agriculture productivity and efficiency.



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There are three primary ways that ENMs can be leveraged to deliver agrochemical A.I.s (Figure 1). First, the A.I. can be entrapped and protected by a nanocapsule or nanoemulsion in which polymeric compounds or surfactants form the structure surrounding the A.I. Second, the ENM serves as the host for the A.I., which can be adsorbed or chemically bound to the external and/or internal surfaces (e.g., as in porous materials like silica). Finally, the ENM itself can serve as the A.I., such as with metal nanoparticles serving as micronutrients (e.g., Fe, Zn) or pesticides (e.g., Ag, Cu). Regardless of the form and role of the ENM in delivering the A.I., there remains the opportunity to design the surface chemistry in a way that enables targeting to a specific endpoint. The following outlines the current state of agrochemical delivery approaches and considers three primary A.I.s: macronutrients, micronutrients, and pesticides. Here, studies from the current literature using ENMs for the delivery of an agriculturally-relevant compound are considered in terms of the A.I., the benefit to agrochemical delivery, and the ENM composition and surface chemistry. However, only studies that specify the ligand identity and use a biocompatible and non-toxic ligand are included.

Figure 1: Schematic illustration of the ways that the nano-scale and ENMs can be used to deliver A.I.s: through encapsulation, sorbed to an ENM, or direct use of the ENM as the A.I. ENMs for Macronutrient Delivery Fertilizers contain primary macronutrients (N, P, K, and C) necessary for healthy crop production and allow farmers to continuously use arable land by reducing the need for fallow 6 ACS Paragon Plus Environment

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periods to restore soil nutrients naturally.29 However, the continued annual increase in global demand for N-, P-, and K-based fertilizers (approximately 186.7 MMT in the 2016-2017 growing season)30 and decreasing efficacy (the amount required to yield one ton of grain has increased from 27 kg/ha to 109 kg/ha from 1970 to 2008),2 motivates exploration of new mechanisms for increased delivery efficiency. Biocompatible matrices, such as minerals or polymers, are commonly used as hosts to deliver desired fertilizer A.I.s. Hydroxyapatite (HA), a main constituent of bone, has been studied for the slow release of N and P. The incorporation of urea into the HA particle matrix31 or grafting onto the HA particle surface 32-33 reduced the solubility and decreased the release times compared to unincorporated N. P has also been shown to be effectively delivered with bare HA nanoparticles34-35 (i.e., using HA as the P source) and through the use of surface modification with citric acid36-37 or cellulose solutions38 to improve ENM dispersion and stability. In all cases, the HA nanoparticles show effective slow release of macronutrients compared to conventional fertilizers. Chitosan, a naturally-derived polymer that is biodegradable and has bactericidal properties, can be polymerized with methacrylic acid to obtain ENMs that can be loaded with macronutrients (N, P, and K) for delivery to crops39 and also demonstrates promise as a controlled-release fertilizer.40-41 Finally, silica NPs have been used as a platform of controlled release. Kong and co-workers pioneered the development of these particles, surface functionalized with thiolated “gatekeeper” molecules for the controlled release of salicylic acid, an important phytohormone, which was incorporated into the silica pores.42 Using the ENM as the A.I. has been studied with various ENM compositions with environmentally benign ligands. Carbon-based nanomaterials, especially carbon nanotubes (CNTs), have been shown to enhance the growth of crops (e.g., rice, corn, and wheat) through



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their proposed ability to penetrate cell walls.43-44 Though further study is required to resolve the mechanism, it is hypothesized that CNTs regulate the expression of genes involved in cell division and extension.43 The positive effects range from increased length in roots and shoots45 to a higher volume of flower and fruit production.46 However, conflicting results on the positive and negative effects of CNTs on crop growth have been reported.47 Water insolubility remains a challenge for agricultural applications, yet this barrier can be overcome by functionalizing with carboxylic acid terminated ligands to enhance water solubility.48-49 While these are all examples of ways that ENMs can enhance production of a variety of crops, there remains an opportunity to exploit the targeting capabilities of the ENMs. ENMs for Micronutrient Delivery ENMs can also be used for micronutrient delivery, including Fe, Mn, and Zn, which are essential for crop growth but are required in lower concentrations than macronutrients.50 ENMs composed of these micronutrients have been extensively studied with the goal of quantifying potential environmental implications introduced through their use and release from wide-ranging applications.51-52 While an understanding of the effects of ENMs on crop growth and genetic response is increasingly well-studied53-55 and essential for wide-spread use of these ENMs and their products, such reports are outside the scope of this perspective. Rather, the focus here is on studies that examine beneficial effects of these micronutrient ENMs on crop growth. Nanoparticles composed of micronutrients that are used either as vehicles for the delivery of or as pesticide A.I.s themselves are discussed in the subsequent section (vide infra). Similar to macronutrient delivery, there remains an opportunity to demonstrate the ability to target micronutrient delivery.


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Zn is an important component in P solubilizing enzymes, resulting in increased secretion and subsequent availability of natural P for crops.56 Thus, ZnO nanoparticles have attracted attention in recent years both for their effect on P availability57 and for their own merit as a micronutrient to enhance the growth of corn58 and other cash crops.59-60 Cornelis and co-workers further investigated the impact of a ZnO coating on conventional fertilizers and while they did not observe a quantifiable benefit, they recommend that further investigations considering different ligands could improve dissolution of the nanoformulations.61 Fe nanoparticles have also been evaluated for their growth-promoting effects.62-63 Elmer and White investigated the benefits of adding Fe, Zn, Mn, and other nanoparticle oxides to disease-infested soil and found reduced disease occurrence in tomato and eggplant compared to untreated controls.64 However, conflicting reports exist, with some research indicating that Fe65-66 and ZnO67 nanoparticles display phytotoxic effects. ENMs for Pesticide Delivery Like fertilizers, pesticides (i.e., insecticides, herbicides, or fungicides) contribute to enhanced crop production and crop quality.68 However, pesticides also suffer from low use efficiencies, with a maximum of 40% of the applied pesticide reaching its intended target.9-10, 69 This translates into significant unintended consequences, including impacts to non-target and beneficial species,70 particularly for cash crops, such as wheat or corn, which can require as much as 4.8 and 3.8 kg of pesticide A.I. per hectare, respectively.69 With ever-expanding demands on agriculture production, there is an increasingly urgent need to more efficient methods for delivering pesticide A.I.s. Encapsulation of the pesticide A.I. inside a biocompatible, unreactive shell remains the most studied nano-enabled delivery method with the external shell protecting and stabilizing the



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A.I. to increase the A.I. lifetime.71 Nanoemulsions,72 nanocapsules,73-74 nanosuspensions,75 and nanoscale dendrimers76 are currently being evaluated as effective pesticide A.I. delivery vehicles. For agriculture applications, naturally-derived or environmentally-friendly constituents for each of these platforms are considered. For example, poly(oxyethylenes) have been used to form oil in water (O/W) nanoemulsions demonstrating improved A.I. (e.g., triazophos, β-cypermethrin, bifenthrin, or essential oil) stability77-80 and increased performance (including enhanced spreading properties, lower ED50 values, and equal injury rates) under reduced application quantities.81-84 Various natural or biocompatible polymers as well as lipids have also been exploited for the encapsulation of insecticides,85-90 essential oils,91-93 herbicides,94 and fungicides95 to improve A.I. stability and control the agrochemical release. For platforms using a host ENM, silica is most commonly used due to its low cost, biocompatibility, and facile preparation strategies and surface modification.96 While unfunctionalized silica ENMs have been used as the host to study the release properties of pesticides,97-101 the anti-fungal efficiency of essential oils,102 and the delivery of pesticide A.I.s to crops,103-104 techniques are emerging to take advantage of the flexible surface chemistry of these materials. For example, the surfactant used during synthesis (and ultimately evaporated) of silica nanoparticles can modify the porous structure and thus, the available surface area for A.I. binding.105-107 This tunability is particularly advantageous for approaches that aim to adsorb the A.I. to the surfaces of the silica particles.108-109 The surface chemistry can also be modified postsynthetically to alter the ENM to possess the desired characteristics. For example, non-toxic trimethylammonium ligands were amended to the silica surface to optimize the loading and release of 2,4-dichlorophenoxy acetic acid or pyraclostrobin pesticides in the silica pores.110-111


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Using the ENM itself as a pesticide is another nanoscale method currently being explored. Ag, which has long been known for its bactericidal properties,112 is now being evaluated for its antimicrobial and fungicidal abilities, both alone113-115 and in combination with silica116 or chitosan.117 Cu salts have historically been used as a fungicide against smut and blunt diseases in grains,118 and the agriculture industry is motivated to reduce its use for economic and environmental reasons.119-120 Nanoparticles offer one potential opportunity for more efficient and effective use of Cu due to the ability to be taken up and delivered to specific parts of the crop.121122

For example, functionalizing the Cu nanoparticles with a range of biocompatible polymers

(e.g., polyvinyl alcohol or poly(ethylene glycol) have demonstrated effective fungicidal capabilities,123 with enhanced effectiveness compared to commercially available products.124 Zn nanoparticles have also demonstrated promise as an antifungal agent.125 Similar to ENM enabled macro- and micronutrient delivery, the ability to achieve targeted nano-enabled delivery with a pesticide A.I. has not yet been demonstrated and there is the potential to do so through choice and design of the surface chemistry. Rational Ligand Design As research progresses demonstrating the promise of ENMs to improve crop health and production, there is a need to consider how we might design ligands to direct and target the platforms for efficient agrochemical use. As discussed previously, the agrochemical A.I. will either be associated with an ENM or is the ENM (Figure 1). Regardless of the A.I. location in or on the ENM, the host is typically appended with ligands126 to enhance solubility127-129 and biocompatibility.130-131 Ligands are appended to the ENM surface to lend stability132-133 and functionality,134 and they can range in size from monoatomic ions135 to larger macromolecules.136-137 Here, we present an approach to consider ligand design as a way to



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enhance the interaction of the ENM platform with the intended target for more efficient agrochemical delivery. Lessons learned from the last 20 years of ENM platform development for applications in health diagnostics138-139 and drug delivery140-141 suggest targeting capabilities through rational ligand design is possible for agrochemical delivery in agriculture. For biomedical uses, careful consideration must be devoted to every aspect of the ENM, including composition, size, shape, and surface chemistry,142 to avoid toxicity or adverse consequences in the body. These desired properties can be achieved through ligand modification to enhance delivery efficiency of the A.I.143-144 While few studies examine the use of targeted delivery of agrochemicals to the external components of plants, strides have been made in inserting chemicals or DNA into plant cells by using nanoparticles that are sufficiently small (5 – 20 nm) to be transported through pores in the plant cell walls.21 For example, DNA-functionalized mesoporous silica nanoparticles were loaded with the green fluorescent protein (GFP) gene and capped with gold nanoparticles to prevent the gene from leaching. After exposing embryonic leaves to these particles, expression of the GFP was observed, indicating that these silica particles can be used to deliver genes into plants.145 ENM design for agriculture has multiple parallels with design for biomedical applications, such as the necessity for the nano-system to be environmentally benign, non-toxic, and to target a specific endpoint within a complex system. However, there are additional unique constraints in designing ligands for targeted delivery in agriculture, such as lower cost demands driven by large scale application of comparatively much lower value commodities (a human life versus a bushel of corn) and different degradation timescales (i.e., the A.I. in the body is often desired to be released as soon as it enters the targeted cell, while ideal fertilizer release will occur


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days to weeks after application). With these qualifications in mind, the components of the ligand shell that will allow for the desired enhanced interaction of the A.I. with the target can be examined. Overall Ligand Considerations Ligands appended to the ENM surface can be conceived as having three main regions: the ENM binder, the ligand body, and the terminal functionality (Figure 2). The subsequent sections outline the function, selection options, and other relevant considerations for ligand design, focusing individually on each of these ligand regions. While we consider ligands as a single entity containing these three regions, there may be scenarios in which new ligands that chemically ‘connect’ one or more discrete units may be necessary to achieve the desired function. There are numerous approaches to connect these three primary components, the most suitable of which will depend on the chemistries of each component. Given the sheer number of possibilities and chemistries, a detailed discussion of this topic is outside the scope of this perspective. Similarly, there may be cases where the ligand is sufficiently small (i.e. ions or small molecules), where there may exist overlap between the three regions (e.g. where the ENM binder and ligand body are also the terminal functionality). For all components, however, there are universal considerations. First, the function: the ENM must serve the intended purpose, working effectively as a fertilizer or pesticide. Second, inherent toxicity: since ENMs will be applied directly to crops and the environment, the materials and their degradation products must be environmentally benign. Moreover, if the agrochemical-bearing ENMs are internalized and accumulated by edible crops, their potential risk to human health must be considered. Third, cost: agrochemicals are applied over vast areas to produce commodity crops that demand affordability in large quantities. To mitigate cost, a



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mixed ligand system, or a stabilizing ligand shell composed of two or more ligand types, can be considered in which potentially more expensive targeting ligands are used with other costeffective stabilizing ligands. A multifunctional particle, combining multiple relevant agrochemicals can also be envisioned. Fourth, embodied energy: the synthesis of the ENMagrochemical platform must be straight-forward and low energy to make the large-scale manufacturing process feasible. Finally, the method of application: for a novel ENM-based agrochemical to be widely applicable, it must be easily adaptable to current end-user technologies. This aspect can be considered in terms of the final ENM platform – water soluble ENMs would be amenable to fertigation, injection or foliar applications, while ENMs that are dried to pellets can be applied through surface broadcast application methods for soil treatments. Of course, novel application approaches and technologies can be developed alongside the ENM platform. However, for immediate or shorter-term adoption, available existing methods must be taken into account.

Figure 2: Scheme depicting the three regions of a ligand: ENM binder (red), ligand body (green), and terminal functionality (blue). ENM Binder The ENM binder is the moiety that appends the ligand to the ENM host. The identity of this binder is entirely dependent upon the ENM composition and therefore, well-defined for a 14 ACS Paragon Plus Environment

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given composition. Various binding moieties can be identified for agriculturally relevant ENM hosts146-153 that are used in the literature for the delivery of agrochemicals (Table 1). While not an exhaustive compilation of all binding moieties for each particle type, the moieties included are most relevant for agrochemical applications given the considerations outlined above. Representative, known ENM hosts for each moiety are included, some being more relevant for agriculture applications and others are demonstrative host examples. Table 1: Table listing ENM binding moieties for various solid ENM hosts. Binding moiety ENM host Ag Au Cu Fe3O4 Pd silica TiO2 ZnO

SH

NH2

• • •

• • •

• •

• •

PR3 • • • • •

COOH

-O-

OH

• • • •

• • • • • • • •

• •

• • •

Inorganic Compounds

Alkynes

• • • • •

Certain O-based binding moieties, including carboxylic acids, oxygen (i.e., polyether compounds), and alcohols, are useful with a variety of ENM hosts (Table 1). The composition of the ENM host and the strength of the desired interaction are important considerations when selecting the appropriate moiety. A more robust ENM-ligand bond may be desired if the ligand serves a purely stabilizing purpose, while a weaker, more readily dissociated interaction may be necessary if the ligand is intended to release at the target to deliver the A.I. For example, the Authiol bond is very strong (~45 kcal/mol),154 while the interaction of trisodium citrate with Au is electrostatic and much more easily disrupted (~10-12 kcal/mol).155 More tightly adsorbed ligands tend to give more stable particles, while weakly adsorbed ligands yield ENMs that are stable for 15 ACS Paragon Plus Environment


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shorter periods of time. The latter may be desirable if the ENM is the A.I. and rapid dissolution is necessary upon delivery to the target location. Notably absent from Table 1 are polymeric and liquid-based ENM platforms, as well as a few types of solid nanomaterials (i.e., calcium carbonate or CNTs). While present in the literature for agrochemical delivery, these ENM types do not require the use of ligands for their synthesis, stability, or subsequent application. However, ligands can be appended during synthesis or post-synthetically added to impart additional functions or stability, such as the addition of citric acid to HA nanoparticles to achieve a slower P release rate.37 Ligand Body The ligand body is one of the most variable portions of the ligand, responsible for connecting the ENM binder to the terminal functionality. The primary functions of the ligand body are to add stability, structure, and functionality to the ENM. It introduces stability and structure by providing electrostatic and steric stabilization to the ENM,156 which can be influenced by various properties of the body, including ligand chain length and ligand packing density (vide infra). Additional functionality can be introduced by the composition of the ligand body. For example, the addition of a poly(ethylene glycol) (PEG) ligand shell to an ENM can impart the benefits of water solubility157 and improved circulation times within the human body.158 Three main aspects influence the ability of the ligand body to impart these functions (Figure 3). First, the size of the ENM can impact the manner in which the ligands orient on the surface of the nanomaterial. Smaller ENMs (d < 10 nm)159 have a higher radius of curvature, which allows for more space between neighboring ligand bodies.160 Second, the size and composition of the ligand body also influence how the ligands behave on the ENM surface.


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Ligands composed of straight hydrocarbon chains tend to pack more densely than their more bulky, functionalized, or branched counterparts. The length of the hydrocarbon chain also plays a role, in that chains of ~12 carbons have a strong preference for organization based on favorable energetics and will have a higher degree of organization than much shorter or longer hydrocarbon chains.22 The composition of the ligand body can range from standard hydrocarbon or polyether chains to more complex biological molecules or polymers.142 Finally, the behavior of the ligand shell, which is the corona of ligands surrounding the ENM, is influenced by the ligand packing density. This descriptor is defined as the number of ligands on a given area of the particle (i.e., ligands/nm2 or ligands/Å2). Typically, a denser ligand shell (i.e., an ENM with a high number of ligands appended to it) yields a more stable material that can be resistant to degradation and protects the ENM surface from reactive species.161 Depending on the terminal chemistry and structure of the ligand, the density of the ligand shell can also promote hydrogen bonding, which can shift the effective pKa of ionizable headgroups.

Figure 3: Scheme illustrating the dependence of ligand surface behavior on ENM size and ligand body composition. Terminal Functionality The terminal functionality, or the end portion of the ligand, offers perhaps the most versatility in terms of identity and opportunity to impart a targeting ability to the ENM. 17 ACS Paragon Plus Environment


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Considering the use of ENMs for agriculture, two main zones exist in which promising target compounds can be found: the rhizosphere and the leaves. The rhizosphere is the narrow area of soil immediately surrounding the roots and is typically rich in exudates and bacteria. It is responsible for the flow of nutrients into and out of the crop roots and activities related to disease suppression.162 The leaf is an organ of a vascular crop, covered in a thick cuticle that provides a water-permeability barrier to regulate the intake and release of water from the leaf.163 The leaf is the main organ of photosynthesis and transpiration (the process of water movement through the crop, where it is converted to vapor and released to the atmosphere), whose integrity is critical to a healthy crop. In order to effectively direct the agrochemical of interest to either the rhizosphere or the leaf, specific target compounds must be selected. Various target compounds within the rhizosphere or leaf as well as information on at least one potential targeting moiety (terminal functionality), including the type of interaction between the compound and moiety, are compiled in Table 2. The suggested targets are not intended to be an exhaustive list – more target compounds and targeting moieties will emerge as further studies are conducted that allow for a better understanding of the functions of rhizosphere components and leaf disease biology, for example. Table 2: Table identifying potential target compounds from either the rhizosphere or the leaf with proposed targeting moieties. Location

Target compound

Glycine Rhizosphere Serine

Targeting moiety N-methyl-Daspartate (NMDA) glutamate receptor164 Serine/threoninespecific protein kinase165

Origin

Type of interaction*

Natural

Protein-ligand interaction

A.I. class of interest

Fertilizers Natural

Enzyme-substrate interaction


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Natural

Synthetic lectin167

Synthetic

Sucrase168

Natural


Natural


Fertilizers

Natural


Fertilizers

Natural


Fertilizers

Dependent upon selected targeting moiety


Fertilizers (esp. P-based)

Pesticides

Glucose Rhizosphere Sucrose Rhizosphere

Thiamine

Rhizosphere (under stress)

Citrate


Flavonoids


Acid phosphatases

CH-π and polar interactions CH-π and polar interactions

Lectin from pea166

Thiamine binding protein169 Mitochondrial malate dehydrogenase170 Bovine serum albumin (BSA)171 Phosphate terminal group172

Fertilizers

Leaf

Long chain alkanes

Alkane binding proteins173

Natural

Non-specific interactions between hydrophobic amino acids and hydrocarbon chains

Leaf

1° and 2 ° alcohols

Poly-l-proline (homopolymer)174

Natural

H-bonding

Pesticides

Leaf with soybean rust

Esters

Esterase175

Natural


Fungicides (e.g., triazole or strobilurin)

Natural

Urediniospores

Poplar rustinduced secreted protein176


Lectins177

Natural or synthetic

CH-π and polar interactions

Phenols

Bovine serum albumin (BSA)178

Natural


Trimethylamine

Casein179

Natural


Leaf with various rust diseases

Leaf with Karnal bunt

Fungicides

Fungicides (e.g., propiconozol or mancozeb)

* Hydrogen bonding = a non-covalent interaction between hydrogen bound to a more electronegative atom (i.e. N, O, or F) and a nearby atom with an available lone pair of electrons. CH-π = a class of hydrogen bonding, similar in nature to van der Waals interactions. Polar interactions = result from dipole-dipole and van der Waals forces.



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Potential target compounds from the rhizosphere and the leaf are identified under two different conditions – healthy production and under stress. The compounds were identified as those that are abundant and unique to the intended target crop region such that ligand chemistries with complementary targeting moieties can be designed accordingly. For the rhizosphere, potential target compounds under healthy conditions include amino acids (glycine and serine), carbohydrates (glucose and sucrose) and vitamins (thiamine), which are consistently released as exudates from the rhizosphere in readily detectable concentrations.162,

180

However, under

conditions of stress (i.e., nutrient deficiency, drought, etc.), the rhizosphere responds by releasing exudates at different rates and concentrations. Citrate is released when the soil is P deficient,181 flavonoids are exuded in high amounts when macronutrient deficient,162 and acid phosphatases are released in P-deficient conditions.162 Similarly, for the leaf under healthy conditions, target compounds include alkanes and alcohols, found in the epicuticular wax.182 Targets for the leaf under disease conditions (i.e., if the crop is infected with rust diseases or Karnal Bunt) include both targets released by the crop (esters, phenols, or trimethylamine) or by the infecting fungus (urediniospores). After identifying potential target compounds, one or more targeting moieties that can serve as the ligand terminal functionality and will ultimately direct the A.I. to the leaf or rhizosphere are outlined (Table 2). For example, targeting thiamine in the rhizosphere under normal conditions using a thiamine-binding protein takes advantage of the interaction between the thiamine and its binding protein to provide a naturally-based ligand terminal functionality for fertilizer delivery to the root.169 In another example, the interaction between the A.I. and leaves infected with various rust diseases can be enhanced by targeting the urediniospores produced by the fungus. This target is amenable to either direct targeting with a poplar rust-induced secreted


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protein (through a protein-ligand interaction)176 or indirect targeting via the carbohydrate molecules on the surface of the urediniospores though natural or synthetic lectins (through pi and polar interactions).177 In addition to other targeting moieties for the rhizosphere and leaf under different conditions, information on the origin of the terminal functionality (i.e., is it a natural or synthetic compound) is presented. Along with this information, a brief description of the interaction between the target compound and the proposed targeting moiety (e.g., protein-ligand interaction, enzyme-substrate interaction, covalent bonding, etc.) is outlined to give an idea on the type and strength of the interaction between the compound and binding moiety to facilitate application of the proposed targeting functionality. Finally, a relevant class of A.I.s whose delivery efficiency could be improved when used with ENMs possessing ligands with the proposed terminal functionalities is proposed (Table 2). Taken together, the suggested target compound-moiety pairings are meant to serve as guidelines for researchers looking to improve the delivery of their ENMs to the rhizosphere or leaf. A final consideration for the terminal functionality is the formation of a mixed ligand system on the ENM. Such a system would be composed of two or more distinct types ligands appended to the same host that can vary in ENM binding moiety, ligand body, and terminal functionality. A mixed ligand shell can allow for the introduction of multiple functionalities on a single ENM host. Given that not every ligand on an ENM requires a targeting group to guide the material to the target location, benefits such as reduced cost due to expensive terminal functionalities can be realized without sacrificing the ENM stability. Mixed ligand shells have demonstrated promise in cellular targeting and photoluminescence applications.183-184 Future Outlook



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ENMs have the potential to address many of the current limitations in agrochemical delivery, with the benefits of increased efficiency resulting in reduced environmental impacts and economic savings. The most commonly studied method for agrochemical delivery to date involves incorporating the agrochemical onto or within a porous ENM host. While the efficacy of these delivery vehicles has been demonstrated, there remains an opportunity to exploit the tunability of surface chemistry for these ENMs to realize their full potential in sustainably advancing crop production. Identifying and using ligands to direct the agrochemical to the target will ultimately serve to enhance the efficacy of the A.I., reducing over-application, diminishing negative environmental consequences, and increasing economic savings. It is critical that future development of delivery platforms make use of environmentally benign, non-toxic ligands to avoid unintended and unnecessary consequences to surrounding ecosystems. There is a need for further research into the long-term impacts of ENM application to crops, soils, and the environment before these delivery methods can become widespread. Moreover, there remain potential challenges that merit investigation to ensure successful adoption of ENM platforms for agrochemical delivery. For example, the formation and impact of coronas (similar to protein coronas observed for ENM applications in therapeutic delivery) and the potential association of platforms with undesired environmental compounds, particularly in a soil environment, that could interfere with targeting the rhizosphere. Once these potential challenges and associated phenomena are better understood, ligand chemistry can also be manipulated to effectively combat some of these challenges as has been demonstrated for other applications,158 where ligands reduced the association of undesired compounds allowing the ENMs to reach their target. Careful selection of ligands for their targeting, stabilizing, and environmentally-friendly properties will advance the field of ENM A.I. delivery towards a


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sustainable, widely applicable solution with long-term benefits for end users, consumers, and investors. Acknowledgements The authors acknowledge the generous funding support from the Department of Civil and Environmental Engineering in the Swanson School of Engineering at the University of Pittsburgh and the Gordon and Betty Moore Foundation.



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Biographical Information Ashley M. Smith Ashley M. Smith earned her B.A. in chemistry from Washington & Jefferson College in 2011 and her Ph.D. in inorganic chemistry at the University of Pittsburgh in 2017 under the direction of Prof. Jill Millstone, where she developed a method to quantify the ligand shells on metal nanoparticles. She completed her post-doctoral research at the University of Pittsburgh with Prof. Leanne Gilbertson in the department of civil and environmental engineering. Ashley is currently a visiting assistant professor in the department of chemistry at Washington & Jefferson College.


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Leanne M. Gilbertson Leanne M. Gilbertson is an Assistant Professor in the Department of Civil and Environmental Engineering at the University of Pittsburgh. Her research group focuses broadly on sustainable design of emerging materials and technologies proposed for use in areas at the nexus of the environment and public health. Dr. Gilbertson earned her bachelor’s degree in chemistry from Hamilton College, and her PhD in chemical and environmental engineering from Yale University, supported by the NSF and EPA STAR Graduate Research Fellowships. She was a postdoctoral associate in the Center for Green Chemistry and Green Engineering at Yale prior to joining the faculty at the University of Pittsburgh.


ACS Sustainable Chemistry & Engineering 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

Increased agricultural productivity

Reduced environmental impacts

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Rational Ligand Design To Improve Agrochemical Delivery

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