Translating Biomedical Nanotechnology into Commercially Viable, Nutritionally Enhanced Plant Feeds for the Horticultural Industries

NTU’s patented research in nanoparticle coating and production, originally for cancer drug delivery, have been commercialised in ‘nano fertiliser’ plant and crop mineral biofortification products by new NTU spin-out Pharm2Farm Ltd. Pharm2Farm was acquired by Nonosynth PLC. through a £2.37 million share issue, a £5 million market raise, and has a current market valuation of £40 million. Pharm2Farm’s global sales of biofortification products, direct and via third parties, span the territories of Australia, South Korea, India, Canada, and USA, and have provided increases in turnover for suppliers and retailers and yield and income for farmers.

NTU iron oxide nanoparticle technology was developed originally by Principle Lecturer Gareth Cave in immunology research to allow MRI detection and tracking of exosomes in cancer drug delivery, working alongside colleagues Robert Rees and Selman Ali in the NTU Biomedical Research Unit, and in collaboration with MRI Imaging experts in the NTU Engineering Research Unit. The 13 nm size super paramagnetic iron oxide nano particles were synthesized by translating standard literature batch protocols into a scaled-up continual flow process. Cave’s continuing work in collaboration with MRI Imaging experts in the NTU Engineering Research Unit demonstrated how super paramagnetic iron oxide nano particles could be exploited in a novel localised MRI readable DNA system, replacing the traditional approach of using fluorescent markers.

Realising the yet greater potential for further innovation in new nano-bio-technology systems, Cave extended the scope of the research into developing new coating and high throughput synthetic methods to scale up nano particle fabrications significantly above research volumes and into extending the techniques to metal compounds beyond iron. Innovations followed that built on the expertise that Cave developed on fabricating the iron oxide nanoparticles for MRI contrast agents that underpinned the above research accomplishments in cancer immunology and in MRI readable DNA systems.

The first key innovation to result from this research was a patented method to coat a range of different varying metal oxide nanoparticles, typically in the size range 2 nm to 100 nm, with organic compounds, by mechanically combining the mineral nanoparticles with an organic biomolecule, via electrostatic interactions, in a dry mixing process. The fields of the work disclosed in the invention encompassed creating bioavailable materials to address trace element deficiency in humans, as well as new methods to increase levels of micronutrients in food crops. The second key innovation to result from this research was a patented continuous flow process for producing suspensions of mineral nanoparticles.

In the proof-of-concept research Cave demonstrated volume production of high uniformity (size and shape) nanoparticles based on a process whereby liquid materials react on the surface of a spinning disk, with particle size controlled by temperature, concentration and the retention time on the spinning disc. This reactor was capable of producing over one kilogram of nanoparticles per hour compared with one kilogram per day with the commercially available technology at the time, reducing solvent use, and providing a high level of nanoparticle uniformity. The patented reactor design and processing techniques were further optimised with commercial partners to produce over ten kilograms per hour with a reactor footprint of only one square meter.

A confidential clinical trial conducted by NTU researchers and a major pharmaceutical company in 2013 demonstrated the efficacy of the bioavailability concepts in humans (n = 40), demonstrating that NTU’s vitamin C coated iron mineral nanoparticles significantly increased ferritin levels by 21%, with respect to the control, and 3% more compared to traditional iron supplements. In animals, NTU researchers conducted a study in Ross-308 broiler chickens (n = 384) over 35 days, which demonstrated that supplementing the bird’s diet with nanoparticles of zinc coated with methionine, in place of conventional zinc supplements, resulted in a 5% increase in bird growth. Cave’s innovative biofortification ideas and techniques were applied to commercial livestock production within the joint NTU-Agrimin Innovate UK research translation KTP grant. This project developed, and demonstrated the efficacy of, boluses with embedded mineral nanoparticles of a range of trace elements to provide slow-release bioavailable copper, cobalt, zinc, manganese and selenium nutrients for cattle and sheep for up to 6 months. An independent trial, commissioned by Agrimin, in a herd of Holstein (n = 20) cows demonstrated that nanoparticles of copper coated in lysine, improved the bioavailability of the mineral by 50%. In addition, unlike conventional copper supplements, the nanoparticles were not affected by dietary antagonist such as molybdenum and sulphur.

Cave’s crop biofortification concepts were developed, working with NTU colleague and protein purification expert Philip Bonner, in on a BBSRC funded research collaboration with the Agriculture and Horticultural Development Board. This research led to a novel way to enrich potatoes with iron, zinc, selenium and calcium via their parent mineral nanoparticles, coated with amino acids as a nanoparticle fertiliser formulation. The amino acid coating enables a sustained breakdown and delivery of the mineral to the plant via the root zone, achieved by the transportermediated root uptake of amino acid metal chelate formed in situ. This biofortification of staple food crops process offers a far cheaper alternative to vitamin supplements and a tool kit towards fighting hidden hunger. The process was also demonstrated in tomato and chilli plants and then optimised to triple the levels of trace minerals in the crops, reduce harvest time by up to two weeks and typically improve yields by 40%.

Spin-out company Pharm2Farm Ltd. has commercialised NTU’s patented technologies, created jobs, attracted investment, and significant growth led to the company’s £2.37 million acquisition

Braveheart Investment Group PLC., a fund management and strategic investment group, acquired a 33% holding in Pharm2Farm Ltd. on 8 July 2019. Braveheart invested a further £200k into Pharm2Farm Ltd. on 2 December 2019, to increase its holding from 33.33% to 51.72%. Braveheart’s Chief Executive Officer said, “The interest shown in P2F products and technology since we acquired our original investment has significantly exceeded our expectations”.

AIM-listed Nonosynth PLC. acquired Pharm2Farm Ltd. from Braveheart Investment Group and Cave in August 2020 through the issue of 600 million new shares. The Director of Nonosynth PLC wrote, “Acquisition was satisfied by the issue of 600,000,000 new ordinary shares of 0.01 pence each in RMS, equating to approximately £2,370,000 based on RMS's closing share price on 20 August 2020 (0.38p; £5.4 million market capital)”, and added, “The market valuation of P2F was based primarily on Dr Cave's knowledge and know-how and the underpinning patented process, licensed from Nottingham Trent University, for producing and functionalising nanoparticles”. The Director of Nonosynth PLC added that the share price had risen from to 0.38p on 20 August 2020 to 3.00p by the date of their testimonial letter, the close of trading day 15 Jan 2021, and “This rapid and dramatic increase in the current market valuation of RMS is widely attributed to the step changes that Dr Cave and his team have achieved in implementing their platform nano technology into real work applications”.

The Director of Innovation, Pharm2Farm Ltd. commented that, “the licensing of Dr Cave’s nanoparticle manufacturing scale-up technology from NTU has led to significant investment from both the Braveheart Investment Group plc and new investors, Nonosynth PLC.” This funding facilitated Pharm2Farm’s move into a new 400 m2 commercial clean room manufacturing and distribution facility that employed 10 full time staff, in addition to contracted support staff. In January 2021, the Director of Innovation at Pharm2Farm Ltd. attributes, “Dr Cave’s research and technology breakthroughs, support, drive and commitment has been instrumental for Pharm2Farm’s rapid expiation from a company valued at £75,000 in August 2019 to a current valuation (31 December 2020) of over £40,000,000”.

Pharm2Farm Ltd. created a new a product range, incorporating NTU’s patented technologies, which has achieved global  sales,  andhave providedincreases in turnover for suppliers and retailers and yield and income for farmer

The product range created by Pharm2Farm Ltd. includes their home and garden plant foods, Seasons™ “that incorporates Dr Cave’s advanced nanoparticle plant feed”, and their hydroponic feeds range, SpectrumTM, “designed with Dr Cave and incorporate his plant feed nanotechnology”. Seasons™ is sold throughout the UK, at nurseries, national garden centre chains and at Asda supermarkets and Spectrum™ products are sold in many shops in the UK.

Pharm2Farm Ltd. also supply directly to commercial growers , including supermarket suppliers of tomato, chilli and strawberries, and supply the nanoparticles as active ingredients into third party agrochemical manufacturers with the UK and EU. The Director of Innovation at Parm2Farm Ltd. confirmed that, “Dr Cave’s technology and the corresponding global license agreement has opened new markets and territories to Pham2farm, examples include South Korea, India, Canada, and USA”.

ÔpennLabs Europe Ltd., a nanotechnology firm based in the UK and France, has created a new line of plant nutrient and growth stimulant products as a direct result of adapting bespoke nanoparticles supplied by Pharm2Farm, with direct support from Cave. This has allowed the company to “disrupt existing markets for silicon-based nutrient products and compete in sectors, including North America and Australia”.  . It has resulted in a “3,500% increase in turnover since 2018 and the creation of three new full-time employment positions”.

End retailer Liverpool-based hydroponic shop NPK Technology Ltd. took on nanoparticle Iron and Silicon products in 2015 for their business, and reported that “Since then we have sold over 12,500 units of nano particle material to our customers who have had excellent results and are now repeat customers for that product. Financially, the product has helped our business increase its nutrition turnover, which we believe having this novel product allowed us to gain more customers for other products as well”.

South Korean urban basil farmers, Griin Co Ltd., utilise nano silica and iron, supplied by Pharm2Farm Ltd. They report that the nanoparticle plant food has increased their average harvest yield and, in addition, the aroma, shelf-life and leaf quality is also improved.

Srirama Raithu Sangham, a co-operative agricultural organisation in India, have been using nano fertiliser formulations, supplied by Pharm2Farm Ltd. to grow their chilli crops over a land area of over 750 hectares since 2017. This has “…reduced the time for fruit ripening and harvesting time from 155 days to 118 days” with the impact that “on average each farmer has secured annual agricultural income of Rs.250000/Hectare (£2500 GBP)”.

• “Artificial exosomes as tools for basic and clinical immunology”. De la Pena H, Madrigal JA, Rusakiewicz S, Bencsik M, Cave GWV, Selman A, Rees R, Travers PJ, Dodi IA, Journal of Immunological Methods 2009, 344(2), pp 121-132. doi:10.1016/j.jim.2009.03.011
• “Towards MRI microarrays”. Hall A, Mundell VJ, Blanco-Andujar C, Bencsik M, McHale G, Newton MI, Cave GWV, Chemical Comms. 2010, 46(14), pp 2420-2422. doi:10.1039/b925020d
• “Coating Metal Oxide Particles”, Cave GWV, Mundell JL, UK Patent GB201204579A, (15 March 2012), equivalents EP2825515A2/US10154628B2/US2015027050A1/WO2013136082A3 R4. “Reactor”, Cave GWV, UK Patent GB201515000A, Priority Date 24 August 2015, equivalents EP3341117A1/US2018280910A1/WO2017033005A1
• “Bioavailability of Methionine-Coated Zinc Nanoparticles as a Dietary Supplement Leads to Improved Performance and Bone Strength in Broiler Chicken Production”, Ashraf Alkhtib, Dawn Scholey, Nicholas Carter, Gareth W.V. Cave, Belal I. Hanafy, Siani R.J. Kempster, Subbareddy Mekapothula, Eve T. Roxborough and Emily J. Burton, Animals 2020, 10(9), p1482. doi:10.3390/ani10091482 [Publication delayed until after commentarial licensing embargo]