Northeastern University professor Mansoor Amiji and graduate student Sushma Kommareddy have published a new paper that examines the potential of engineered gelatin-based nanoparticles to deliver therapeutic genes to human breast cancer tumors implanted in mice.
Their research shows that these nanoparticles – or nanovectors – can serve as a safe and effective gene delivery vehicle to inhibit solid tumor growth. The paper is published in the most recent issue of Cancer Gene Therapy, available at: http://www.nature.com/cgt/index.html.
In the experiment, the nanoparticles were injected into the blood stream, and 15% of the dose found its way into the tumor, where it produced a protein, sFlt-1 or soluble receptor for an angiogenic factor, that cut off blood supply to the tumor.
“Essentially, what this treatment does,” says Amiji, “is make the tumor a factory for its own destruction. The treatment shuts off the blood supply to a tumor – thereby effectively closing down the ‘road' for oxygen and nutrients to travel to the tumor and for cancerous cells to escape from the tumor and spread throughout the rest of the body.”
In the past, this kind of gene delivery system had been attempted, but with viral vectors, which, although effective, are in many cases toxic to the recipient. Non-viral vectors for gene delivery applications are becoming increasingly popular owing to several advantages, which include lack of toxicity, no upper limit on the plasmid DNA size, and ease of manufacture.
“Non-viral gene therapy has tremendous promise when it comes to treating and curing diseases,” says Amiji, “because you avoid the issues of toxicity that arise any time you introduce a viral element into the human body.”
The researchers chose to work with gelatin in making the nanoparticles because it has a long history of safe use in the human body. In order to enhance the intracellular delivery potential of the gelatin, Northeastern researchers synthesized thiolated gelatin by covalent modification of the epsilon-amino groups of gelatin with 2-iminothiolane. Nanoparticles were then prepared with thiolated gelatin using a mild solvent exchange method that has been optimized in Northeastern laboratories.
In this study, the surface of both gelatin and thiolated gelatin nanoparticles was modified by reacting with methoxy-poly(ethylene glycol) (PEG)-succinimidyl glutarate to prolong in vivo circulation time – enabling the medication to stay in the body for up to 15 hours, a significant increase from just three hours with unmodified nanoparticles. PEG modification also enhanced tumor uptake and retention of the nanoparticles after administration.
Amiji notes that they are seeing positive results in pre-clinical studies and hope to begin clinical trials in the near future.
“We believe there are applications for this system of drug delivery in other diseases besides just cancer,” said Amiji. “From heart disease and diabetes to glaucoma and macular degeneration, this is a versatile platform solution that could prove successful in a variety of applications.”
“When I look at all of the drugs that are in clinical trials and some of the horrible side affects that patients must endure, all I can think is: We can do better – we must do better,” says Amiji.
This study was supported by a grant from the National Cancer Institute of the National Institutes of Health (NIH).