In the biomedical space, a technology is earning a reputation for enabling personalised medical solutions, and the bespoke drug delivery capabilities of enzymes is gaining traction too.
At the convergence of the two is a research effort being led by Amy Locks, a PhD candidate at the University College London School of Pharmacy and Department of Chemistry.
Backed by the EPSRC Centre for Doctoral Training in Transformative Pharmaceutical Technologies, Lock is exploring the incorporation of enzymes into 3D printable polymers to catalyse the tailored release of therapeutics. In doing so, Lock is taking inspiration from Invisalign moulds and hearing aid shells to take advantage of 3D printing’s capacity to enable personalised medical devices, and the selectivity and specificity of enzymes to facilitate the development of more effective drug delivery products. All the while, she is considering the prevalence of microplastics all over the world and in the human body, so has set her focus on biocompatible materials that can be fully degraded by the enzymes to leave no presence of microplastics.
Working with PLA and PCL materials, Lock prints 3D lattice structures and integrates enzymes onto the part post-print – the lattice structure providing a high surface area for the enzymes to be loaded on. Enzymes are loaded onto the polymer via simple load absorption or covalent bonding, with an enzyme screening process being carried out beforehand using a compound that acts as a drug mimic. Once cleaved by enzymes, this generates a brightly coloured para nitrophenoxide ion that can be easily quantitatively assed by absorbance.
“I screened many enzymes based on what had already been done in literature,” Locks told TCT. “And this was narrowed down into kinetic analysis of what produced that phenoxide ion most quickly to the three best performing enzymes, and then I tested those three best performing enzymes on my 3D printed constructs.”
Having tested those enzymes – Esterase from Porcine Liver, Lipase B from Candida antartica, and a metageomically sequenced enzyme called PLAse that has been purified in-house and specifically degrades PLA – Locks has reported that they successfully integrate and stay active within 3D printable biodegradable polymers, delivering customisable release strengths. The PLA and PCL constructs
are said to keep the enzyme stable for up to four months before use without a significant loss of activity and can be reused. Locks has also observed that the enzymes cause formation of pores in the 3D construct, proving that the structure is breaking down.
As Locks looks forward, she identifies prostate cancer treatment as one application of her 3D printed structures for enzyme-controlled drug release. The drug mimic she has used so far is Abiraterone, a pro drug for prostate cancer, with the pH of her enzymes aligning with the pH of cancerous tumours. While further testing is still to come, Locks is confident her research could lead to alternative and less invasive treatments for what is the second most common cause of cancer death in males in the UK.
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“It could improve the efficacy of treatments while reducing systemic side effects
because it is more personalised and targeted to the tumour site,” Locks said. “It would also reduce the environmental impact because it wouldn’t need to be an implant that would need to be removed.”
When the enzyme is degrading the structure, it is producing lactic acid, a chemical the body will tolerate since it already produces it naturally. Since the application of proteins and 3D printing continue to grow in the biomedical space, and the 3D printing enabled Spritam drug for the treatment of partial-onset seizures has been FDA-approved, Locks also has confidence that her method could one day also receive regulatory approvals.
For now, though, her research continues. One area of focus has been to synthesize and test custom material formulations, engineered to provide tailored mechanical properties to control degradation rate and thermal behaviours. With this work, Locks has printed formulations that provided high stiffness that would be more suitable for applications like scaffolds, and softer parts able to be rapidly degraded in a few hours that would be more suitable for implants that eliminate the need for surgical removal. There is also scope to create structures with memory properties, so they return to their original shape once implanted within the body.
But what comes next is this: “Testing with the pro drug compounds now that I have a robust system with the drug mimic. Testing on biological models to help assess that applicability to prostate cancer and translation from current in vitro testing. And some more 3D printing of other shapes so that I can assess how much I can customise the release profile of that drug.”
To learn more, contact Amy Locks at: amy.locks.21@ucl.ac.uk
