The laboratories of Omid Farokhzad, HMS assistant professor of anesthesia at Brigham and Women’s Hospital, and Robert Langer, a scientist at the Massachusetts Institute of Technology, have engineered a novel self-assembling targeted nanoparticle to maximize the efficiency of drug delivery to prostate cancer cells.
The challenge of this nanotechnology is to create a “maximally stealth” and “maximally targeted” delivery vehicle that can be consistently reproduced. Although the first targeted nanocarrier was developed nearly 30 years ago, these investigators are at the forefront in reproducibly creating the delicate balance among cell targeting, immune evasion, and drug release necessary for efficient drug delivery.
“Until now, there has been no good way to ensure that a targeted nanoparticle is consistently successful,” said Langer. Designing a drug-encapsulated nanoparticle with targeting ability has been challenging because each parameter requires optimal conditions that are difficult to reproduce using traditional methodologies, which require a chemical reaction for each step of the carrier design.
The study, published online Feb. 13 in Proceedings of the National Academy of Sciences, reports a nanoparticle self-assembly method that needs no chemistry once the biopolymers are made. Two of the components have Food and Drug Administration approval for use in other drugs: poly(D,L-lactide-co-glycolide), a biodegradable matrix used for encapsulation and sustained release of drugs, and polyethylene glycol, which enables immune system evasion. The third component is an RNA aptamer, which recognizes prostate cancer cells. It is stable in organic solvents during polymer synthesis and nanoparticle formation, making it uniquely suitable for self-assembly. By precipitating this triblock copolymer of PLGA, PEG, and RNA in water, the polymer self-assembles to form a nanoparticle for drug delivery and uptake in a cell-specific manner.
Working in culture and in a mouse model of prostate cancer, the researchers tested nanoparticles encapsulating docetaxel, a standard chemotherapeutic drug for prostate cancer. They determined the optimal aptamer density on the nanoparticle surface required for maximal uptake by prostate cancer cells. Maximal tumor targeting resulted from nanoparticles with a very low aptamer density. Increasing the aptamers caused more nanoparticle clearance by the liver and less accumulation in tumors.
“More isn’t always better when it comes to attaching targeting molecules or other functionalities to the surface of nanoparticles. A narrow window exists when the properties of a targeted particle are optimally engineered to work well,” said Farokhzad.
“This exciting finding adds validation to the role that nanotechnology can play in treating cancer and has application to any disease that can be targeted with nanoparticles,” said first author Frank Gu, a researcher in the Harvard–MIT Division of Health Sciences and Technology.
