A platform based on red blood cells has provided a powerful antibiotic intended to Escherichia coli in a preclinical trial.
For several years, “we have been developing experimental and computational techniques to study how proteins and drugs interact with membranes,” Hannah Krivić, PhD, graduate student, and Maikel C. Rheinstädter, PhD, professor of physics, both at McMaster University in Hamilton, Ontario, Canada, says Medscape Medical News.
In Previous work, these researchers studied how antibiotics target bacterial membranes and how these membranes allow the development of antibiotic resistance. Then, they said, “we started to…manipulate the membranes by adjusting their properties [with] synthetic lipid molecules to create “hybrid” membranes, ie functionalized biological membranes with optimized properties.
“We are now using this approach to functionalize red blood cells using them as drug vectors. We optimize these cells to carry certain payloads, such as drug molecules, and anchor proteins in their membranes that target bacteria receptors to deliver that payload selectively and efficiently.
The strategy, they said, “has evolved into a universal red blood cell-based delivery platform that we call ‘smart blood’…which can safely and selectively deliver antibiotics to certain bacterial targets.”
The platform is currently being tested in vitro with in vivo testing expected to begin in early 2023. Their study was published online on September 29 in ACS Infectious Diseases.
Polymyxin B (PmB) is one of the few potent antibiotics with promising efficacy against drug-resistant bacteria such as E coli. However, PmB is widely considered a treatment of last resort due to its toxic side effects (which include nephrotoxicity, neurotoxicityand neuromuscular blockade) especially at higher doses.
The researchers hypothesized that targeted delivery of PmB could lead to optimized dosing and potentially reduce the need for higher or repeat doses. In the current study, they tested the smart blood platform’s ability to deliver PmB to E coli.
Creating “erythro-PmB” involves removing the internal components of red blood cells, loading the cells with PmB, and coating the cell membranes (liposomes) with antibacterial antibodies (in this case, anti-E coli).
In vitro experiments showed that cells could be loaded with PmB and selectively retain and deliver the drug to E coli, without apparent haemolytic activity or nephrotoxicity. Specifically, erythro-PmBs had a loading efficiency of approximately 90% and delivered PmB to E coli with minimum inhibitory concentration (MIC) values comparable to those of free PmB.
“Unlike drug delivery systems based on synthetic carriers, our erythrocytes have high biocompatibility and can remain in circulation in the body for several weeks to provide sustained and targeted drug delivery,” Krivić and Rheinstädter said. “This [profile] can make existing drugs safer, for example by increasing their effectiveness while reducing the dosage required, thereby reducing side effects.
Researchers are currently exploring the smart blood platform’s ability to deliver neurotrophic factors across the blood-brain barrier to potentially treat neurodegenerative diseases. Their approach is identical to that used in the current study, they said, except that in this case, red blood cell membranes are designed to deliver neurotrophic factors specifically to the blood-brain barrier.
David W. Deamer, PhD, research professor of biomolecular engineering at the University of California, Santa Cruz, commented on the study for Medscape Medical News. “It’s certainly promising. Erythro-PmBs have a higher load capacity and longer circulation time than ordinary liposomes used for drug delivery. They can also be prepared with specific antibodies so that the antibiotic is delivered more directly when they bind to bacterial pathogens.
The effect on bacterial growth, however, was tested in a model system, not an actual infection, he said, adding that an important next step will be animal testing. “One of the simplest tests is induced sepsis in mice, which mimics a burst appendix. If erythro-PmBs can effectively treat sepsis, this will be an encouraging sign of their potential therapeutic value. It will also be interesting to see if the antigens responsible for the ABO blood groups are retained on the surfaces of the erythro-PmBs. If this is the case, it may be necessary to match the blood of the donor to that of the recipient.
“Preparing a product for clinical use will require a partnership with a major pharmaceutical company, several years of animal testing, and then several more years of conducting Phase 1, 2 and 3 clinical trials in human patients,” Deamer concluded. .
No commercial funding was disclosed. Krivić, Rheinstädter and Deamer reported no conflicts of interest.
ACS Infect. Say. Published online September 29, 2022. Summary.
Follow Marilynn Larkin on Twitter: @MarilynnL.