Nano-scale ionic liquids prove key to drug repurposing

An Assistant Professor of Pharmaceutical Sciences at the R. Ken Coit College of Pharmacy and Director of its Drug Preformulation, Repurposing and Delivery (D-PReD) laboratory, Abhijit Date, PhD, is on a mission.

 

“Since as long as I can remember, all I've been thinking about is pharmaceutical sciences, drug delivery, and how we can really make drugs better, safer,” he said. 

From his drug delivery studies as an undergraduate to predoc in Mumbai, India, to his work on treatments for infectious diseases in his postdoc and faculty appointments across the United States, Date’s work in the pharmaceutical sciences has focused on bringing vital, effective, accessible and appropriate treatment to those in need.

First drawn to the field through an interest in chemistry, Date credits his undergraduate and graduate research mentors Mrs. Sulabha Phadnis, Vandana Patravale, PhD, and Mangal Nagarsenker, PhD, for creating an engaging learning experience, increasing his awareness of drug chemistry, human physiology, disease pathology and other elements related to pharmaceutical science.

Understanding of each of these, Date says, is key to developing effective drugs with appropriate delivery mechanisms.

With an extensive background in drug development and delivery, Date’s recent research has earned him the Coit College of Pharmacy’s A. Jay Gandolfi New Investigator Award in December 2023. Honored to receive the award, Date attributes the nomination to his work on repurposing drugs using nano-scale ionic liquids.

“University of Arizona,” he said, “provided excellent opportunities, facilities, and fantastic support to be able to expand further on the research that I was doing.”

Why repurpose drugs?

Research into anti-infective agents, particularly antibacterial and antifungal agents, Date said, is slow when compared to research into cancer treatment or certain antivirals. Companies invest less in drug development in these areas because it is considered less profitable.

“The issue is that with such diseases, the drug discovery efforts are fairly limited,” said Date, “so what we are left with is reimagining the tools that are currently there.”

So, scientists like Date must repurpose known drugs, adjusting their form and delivery to create viable treatments for diseases that do not benefit from new drug discovery research.

From a translational perspective, Date emphasized that ease of scalability also impacts drug development and affordability. Keeping this in mind, any reformulation he works on uses readily available components.

Nano-scale ionic liquids

Date’s recent reformulations and their scalability are made possible through technology he has patented since beginning his appointment at UArizona.

Ionic liquid is a delivery technology that allows Date to modify the physicochemical properties of drugs – including highly hydrophobic or highly hydrophilic ones, which are the most challenging to deliver – reformulating them to have better solubility, permeability and bioavailability. Combined, this allows for more effective treatments with fewer side effects, since these improvements help target the affected areas, with a minimal dose.

Ionic liquid technology can be applied to various drugs, allowing Date to utilize these liquids in multiple repurposing efforts – often in combination with nanoparticles.

Because nanoparticles are so small, they have excellent translocation capabilities, allowing them to move across barriers like tissue or cell membranes. Despite their size, when correctly engineered, these nanoparticles can contain a large quantity of the drug – or drug converted into ionic liquids – inside them and even prolong its release, allowing for fewer doses.

At UArizona, Date is working on repurposing and delivery of drugs targeting two main viral infections – herpes simplex virus (HSV) and human immunodeficiency viruses (HIV) – and cryptococcal meningitis, a fungal infection caused by Cryptococcus neoformans.

Ocular HSV

In 2022, Date began work as a co-PI on a five-year, translational research grant[1], awarded by the National Eye Institute, that funds research into a novel treatment of ocular HSV infections, which are a leading cause of infectious disease–related blindness. Since the current treatment involves taking eye drops five to nine times a day, patients are greatly in need of improved delivery.

Together with the PI on the grant, Deepak Shukla, PhD, with the University of Illinois, Chicago, Date has been leading the repurposing and reformulation of an FDA-approved low cost drug, phenylbutyric acid sodium, to treat ocular HSV infection.

“We have excellent data now,” Date said. “This drug and its reformulated version are really excellent in terms of efficacy.”

If all goes well, Date said, they may be able to file an Investigational New Drug (IND) application in a few years. If approved, they could begin human clinical trials.

In a separate project focused on the mission of developing once-daily antiviral eye drops for ocular herpes therapy, Date, in collaboration with Shukla, has been able to create a nano-scale ionic liquid of antiviral drug that reveals excellent therapeutic outcomes in mouse models.

Cryptococcal meningitis

On another project in collaboration with Kirsten Nielsen, PhD, with the University of Minnesota, and Qing-Yu Zhang, PhD, at UArizona, Date works to repurpose a class of deworming agents, called anthelmintic benzimidazoles, to treat a fungal infection caused by Cryptococcus neoformans.

For the immunocompetent (those whose immune system is not compromised) this fungus is typically not detrimental, says Date. However, when people are immunocompromised because of HIV infection, a recent organ transplant or other factors, these fungi can cause issues with the lungs before invading the brain and causing cryptococcal meningitis – a life-threatening condition with a high mortality rate across the globe.

Current treatments for cryptococcal meningitis are few, are highly cost prohibitive and have many side effects.

Because most of the readily available deworming agents are intended for local action in the gut rather than translocation to the brain, Date has again utilized nano-scale ionic liquid technology to reformulate them.

“We have succeeded already,” said Date.

In mouse models, the fungi are so invasive that within 20 days, there is a 100% fatality rate in the untreated mice, Date said. When a particular benzimidazole is administered orally that rate declines to about 50%.

“But if we convert this drug into this delivery technology called ‘ionic liquids,’ coupled with nanoparticles, we don’t have any mortality in the infected animals even after 75 days with good safety and low or no traces of fungi in the brain,” Date said. “So this is a very, very remarkable data and we have already filed another provisional patent on this data.”

HIV

In his third recent endeavor, Date has utilized this same nano-scale ionic liquid to develop more targeted anti-HIV drugs.

A widespread disease, HIV is an immunocompromising disorder that currently requires a lifetime of treatment to mitigate the effects of the illness, but never fully eradicate it.

“Any discontinuation can actually lead to the rebound of the virus,” Date said, “because even though on the drug therapy, you are able to get the virus below the detectable level in your blood or in your plasma, the other sites – such as brain, or such as lymph nodes, or gut, or spleen or genital tract – they will still harbor the virus in its latent form and act as sanctuary sites for HIV. And the drugs actually are not able to adequately penetrate these sites.”

Date explains that while he had taken a break from research into HIV treatments, he has been able to renew his efforts due to the recent grant from the National Institute of Infectious Diseases[2], the breakthroughs in the patented ionic liquids technology and the institutional support he receives from the University of Arizona.

With these in place, Date said he has good, early data to indicate his reformulated drugs will penetrate the sanctuary sites more efficiently than the currently available formulations of anti-HIV drugs.

As a pharmaceutical sciences researcher who also teaches pharmacy students in the clinical track, Date emphasizes that the two are interconnected – and the main goal of each is to deliver better patient care. 

For pharmacists, this takes the form of direct patient interaction, personalizing patient therapies and calculating doses. While in work like Date’s in the pharmaceutical sciences, the aim of the research is to develop better therapies and technologies for patients. 

“That,” said Date, “really is the ultimate goal.”
 

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[1] R24EY033598

[2] R21AI176907