Adelaide researchers have developed a targeted nanoparticle platform that dramatically improves the delivery of lung cancer drugs to tumours while reducing exposure to healthy organs.
Australian researchers have developed a hybrid nanoparticle system that increases the bioavailability of a promising lung cancer drug by more than 30-fold while redirecting it to the lungs and away from the liver.
The technology, developed at Adelaide University and supported by Cancer Council SA and Tour de Cure, could help overcome one of the biggest obstacles facing cancer therapeutics: getting enough drug to the tumour while minimising damage to healthy tissue.
An article about the technology has been published in the Journal of Controlled Release.
Senior research fellow Dr Paul Joyce said the research addresses one of the biggest barriers in cancer treatment: getting drugs to the right place at the right time.
“One of the major challenges in treating lung cancer is that many drugs don’t stay in the body long enough, or they spread to healthy organs and cause toxic side effects,” he said.
“Normally, much of a drug ends up in the liver – the body’s filtering system – instead of reaching the lungs.
“We’ve developed nanoparticles that act like a delivery vehicle, helping the drug circulate for longer and directing it to the lungs, where it can have the greatest impact.
“The nanoparticles ensure that more of the drug actually gets to where it’s needed – instead of being lost in the body – or affecting other organs.”
The research centred on RB-012, an experimental anti-cancer compound that has shown promise against non-small cell lung cancer but suffers from the same limitations that hamper many oncology drugs.
When administered conventionally, RB-012 is rapidly cleared from the bloodstream and accumulates in the liver, reducing the amount of drug available to attack tumours.
To address this problem, researchers designed polymeric-lipid nanoparticles (P-LNPs) that encapsulate RB-012 within a hybrid structure made from lipids, cholesterol, polyethylene glycol (PEG)-lipids, and polyacrylic acid.
The nanoparticles measure between 100 and 150 nanometres in diameter and are engineered to protect the drug while it circulates through the body before releasing it in target tissues.
Laboratory testing showed the nanoparticles dramatically reduced premature drug release.
While conventional liposomes released almost all of their RB-012 payload within five hours, the hybrid nanoparticles retained between 60% and 80% of the drug over the same period under physiological conditions.
Importantly, the particles were designed to release their payload in acidic environments similar to those found inside tumour cells, creating a pH-triggered delivery mechanism that may help improve therapeutic precision, the researchers said.
They also found that altering the composition of the nanoparticles changed where the drug accumulated in the body.
By incorporating the positively charged lipid DOTAP, the team was able to shift drug distribution away from the liver and towards the lungs.
The highest-DOTAP formulation showed the greatest lung accumulation and the lowest liver concentrations eight hours after administration, highlighting the potential for organ-specific targeting.
Further analysis suggested this redistribution was driven by changes in the “protein corona” that forms around nanoparticles when they enter the bloodstream.
Proteomic studies revealed DOTAP-containing nanoparticles attracted greater quantities of plasma proteins, particularly apolipoproteins involved in lipid transport.
The researchers said they believed these protein interactions, combined with electrostatic interactions between the nanoparticles and lung tissue, contributed to the preferential accumulation observed in the lungs.
Another formulation reduced the spread of cancer cells to distant tissue, suggesting potential anti-metastatic effects.
“This is about giving promising drugs the best chance to work,” Dr Joyce said.
“An easy way to picture it is like this: administering a cancer drug in the standard way is like pouring water into a leaky bucket. But administer the drug via our nanoparticles, and it’s like sealing that bucket so that 30 times more water stays inside.
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“By improving how cancer drugs are delivered, we can potentially increase effectiveness while reducing harm to healthy tissue.”
However, the study also highlighted the challenge of balancing efficacy and safety. The formulation that achieved the strongest lung targeting and tumour reduction also produced the highest toxicity in the embryo model, likely due to the effects of highly cationic lipids.
The researchers concluded that a moderately cationic formulation may offer the most favourable balance between circulation time, lung targeting, anti-tumour activity, and safety.
While human trials remain some years away, the researchers said they believed the platform had applications beyond lung cancer.
“These findings reinforce the need to validate these observations in human plasma and orthotopic mammalian tumour models, which will be essential for establishing the clinical potential of RB-012-loaded P-LNPs for lung cancer treatment,” the researchers concluded.
