Medical miracles from plant grown platinum

Platinum is best known as a catalyst – and as the precious metal one rank better than gold. However, it is also has near-miraculous medical applications.

Chemotherapy drugs like cisplatin and carboplatin harness platinum’s ability to inhibit DNA replication and cause cell death. Thanks to their superlative array of physiochemical properties, platinum nanoparticles (PtNPs) could also be used in targeted drug delivery, photothermal therapy, radiotherapy, antimicrobial ointments, bioimaging, and biosensors.

Their possibilities are tantalising, but PtNPs come with twin costs: monetary and environmental.

PtNPs are created through physical and chemical processes. The former approach uses high pressures and temperatures to produce pure nanoparticles of uniform size and shape, with enormous cost and energy consumption.

The latter family of processes, such as the sol-gel process and pyrolysis, applies chemical agents to reduce precursor metal ions to their corresponding nanoparticles and then to stabilise them. This tends to be more cost-effective, but uses chemicals hazardous to human and environmental health. These are a headache to dispose of responsibly, but also leave behind a toxic coating on the nanoparticles, seriously undermining their biocompatibility.

There is a need for greener routes for synthesising PtNPs, and many researchers hope the answer could lie in biology.

“The major challenges in the therapeutic application of PtNPs include biocompatibility, bioavailability, degradation in the gastro-intestinal tract, stability, and immune response,” explained Dr Cristina Satriano, a professor of physical chemistry at the University of Catania, Italy. “The biogenic synthesis route [...] can overcome these limitations in chemical and physical methods.”

Though PtNP biosynthesis is at an early stage compared with gold and silver nanoparticle biosynthesis, there is a growing body of research on how to grow and harvest these tiny balls of precious metal from bacteria such as E. coli, as well as from viruses, fungi, algae, and plants.

Dr Michael Capeness is lab manager at the University of Edinburgh’s Horsfall Group, a biotechnology group whose activities include using bacteria to synthesise metallic nanoparticles. Capeness explains: “We’re kind of hijacking bacteria’s native ability to produce these particles from ions. Wherever the bacteria were isolated from, they’ve developed this ability to deal with that insult to their physicality [from that adverse environment]. They do this by making nanoparticles.”

The obvious advantage of biological approaches is that, unlike physical and chemical approaches, they tend to be environmentally benign.

Energy consumption is far lower than for physical processes, and biological entities perform the reduction and stabilisation which would otherwise require toxic chemical agents. Biological approaches also do not necessitate pure raw materials, which are becoming harder and harder to acquire given bubbling geopolitical tensions. Organisms can be genetically engineered to pick out specific metal ions to synthesise PtNPs from diluted samples, and researchers hope that specialised bacteria will eventually be able to synthesise high-value nanoparticles from waste, including e-waste, on an industrial scale.

The advantages of biosynthesised PtNPs are perhaps most remarkable when it comes to their medical applications. Research has demonstrated that biosynthesised PtNPs tend to have higher antimicrobial, antioxidant, and anticancer activity compared with physically and chemically synthesised nanoparticles. How can this be?

When we talk about nanoparticles, we could be referring to any particle with at least one dimension between one and 100nm. Like a bag of Bombay mix, PtNPs come in all shapes and sizes, and a variety of properties such as charge, coating, and crystallinity. Depending on the conditions under which they are synthesised, there can be a world of difference between two PtNPs. In general, biosynthesis – such as through the ‘slow and steady’ enzyme-mediated bacterial processes – allows for smaller nanoparticles than the ‘vigorous’ physical and chemical processes. Biosynthesised PtNPs can be as small as 1nm in diameter, while those created through chemical synthesis usually measure in the tens of nm and can even stick together in messy macro-scale blobs. Smaller nanoparticles are more effective antimicrobial agents (for instance, they can easily pass into the cell of a S. aureas and cause reactive oxygen species production) and their larger surface-area-to-volume ratio permits more anticancer activity.

Biosynthesised PtNPs are also more biocompatible. Their coatings tend to consist of proteins, sugars, and other substances which are easier for the body to process than the toxic coatings left on chemically synthesised PtNPs.

Biosynthesised PtNPs are not yet being produced at scale. First, scientists need to optimise these biological processes, such as by genetically engineering platinum-producing bacteria to work faster, better, and without the irritations that prevent them from becoming industrially relevant.

“Generally, we try to engineer them so they’re more resistant to the metal that we’re giving them,” says Capeness. “That way, we can make nanoparticles faster [...] and as we’re using impure feedstocks, we can genetically tune them to only respond to certain metals.”

One of the most tedious parts of the process is recovering the platinum from the bacteria after it has reduced the metal ion to a nanoparticle. Like a pearl within an oyster, the nanoparticle is trapped inside the cell. Recovering nanoparticles produced intracellularly calls for approaches like grinding, application of sound waves, and chemically treating the cells to make them more porous. Then, once the ion is extracted, it has to be purified. This adds yet another cost of recovery. Capeness explains: “You have to crack open the cell, as it were. That releases all the innards of the bacteria into the soup, which you then have to pull your nanoparticles out of. So that’s a problem.”

Making it easier to wrestle the PtNPs from the bacteria – such as genetically engineering them to produce nanoparticles extracellularly – is a major focus of research in this field.

In the meantime, some researchers are turning to organisms more willing to cede their precious booty. Dr Sougata Ghosh, a microbiologist and associate professor at RK University in Gujarat, says: “Although I am a microbiologist, I mostly prefer the phytochemistry, the plant-mediated synthesis, where the nanoparticle is extracellular and then it is easier to recover.”

Plants, which have not been explored as thoroughly as bacteria as PtNP factories, produce these nanoparticles through entirely different mechanics. For a start, the process is not generally enzyme-mediated. “We like green tea because it has lots of phenols; it has a lot of antioxidants. These antioxidants are a very, very good reducing agent and that’s why green tea extract is one of the best methods for reducing metal ions to metal nanoparticles,” says Ghosh. “When it comes to [plant-based nanoparticle synthesis], it is generally due to the polyphenols, flavonoids, or the ingredients or the chemicals that are present in the plant, not the enzymes.”

Of course, plants come with their own complications, such as the slowness of their growth and their enormous complexity compared with bacteria. The tea plant Ghosh works with in India has a distinct phytochemistry when compared with a tea plant in Western Europe thanks to differences in soil quality, age, and climate. This makes it considerably harder to replicate studies. With their extra layer of complication, however, this wild taxonomic kingdom offers a widened world of possibility.

There is lots of work to be done before platinum grown in bacteria and tea plants is a regular fixture on NHS wards. To compete with physical and chemical approaches, biosynthesised PtNPs need to be produced faster and with more consistent size and shape.

“A fine control of size and shape of PtNPs can be easily obtained by chemical or physical synthesis route with a control on the precursor reduction conditions,” says the University of Catania’s Satriano. “The biggest challenge that biosynthesised PtNPs face is the control in their size, morphology, as well as polydisperity, which are all needed for commercial use of biogenic nanoparticles. Another challenge is the difficulty in replicability because of the intrinsic differences – and related biochemical activities – of the living systems that originate them.”

It is a nascent area of research, but one with a huge amount of potential. A wealth of medical treatments could be derived from the latter-day goose that lays the golden egg: the bacteria that lay the platinum particles.