Gelatin Nanoparticles Deliver Anticancer Gene Therapy
Using an engineered gelatin nanoparticle designed to remain in circulation long enough to be taken up by tumors and then fall apart once inside a malignant cell, investigators at Northeastern University have successfully delivered an anticancer gene to tumors in mice. The delivered gene was therapeutically active and stopped tumor growth. This work appears in the journal Cancer Gene Therapy.
Mansoor Amiji, Ph.D., principal investigator of the Nanotherapeutic Strategy for Multidrug Resistant Tumors Platform Partnership, led this effort to develop nanoparticles for delivering therapeutic genes to tumors. In this work, the investigators started with nanoparticles made of gelatin modified with crosslinking sulfur groups. Sulfur-enabled crosslinking not only stabilizes the nanoparticles at the body's pH, but also creates a molecular network that will fall apart when exposed to the high levels of glutathione, a biomolecule found inside cancer cells.
The researchers also added a coating of poly(ethylene glycol), or (PEG) in order to reduce the immune system's ability to remove the nanoparticles from circulation. With a half-life in blood exceeding 15 hours, these nanoparticles were able to accumulate in tumors. Indeed, the investigators found that as much as 15 percent of the nanoparticles injected into tumor-bearing mice accumulated inside the tumors.
Once the researchers had successfully engineered this nanoparticle for tumor accumulation, they loaded it with a gene that codes for a fragment of the vascular endothelial growth factor (VEGF) receptor known as psFlt-1. Normally, VEGF secreted by malignant cells binds to its receptor, triggering the growth of new blood vessels capable of providing rapidly growing cancer cells with needed nutrients. However, the psFlt-1 fragment can act as a decoy, binding VEGF before it can reach the full receptor, thereby stopping blood vessel growth and starving the tumor.
When the investigators added the gene-carrying nanoparticles to human breast cancer cells growing in culture, psFlt-1 levels rose dramatically, indicating that gene expression was occuring, leading to psFlt-1 production. Based on these results, the researchers then injected the nanoparticles into mice bearing human breast tumors, and they again observed high levels of psFlt-1 production by the tumors for up to 40 days after treatment. More importantly, the density of new blood vessels surrounding the tumors dropped significantly, and the tumors stopped growing. In comparison, tumor size doubled in 19 days when animals were treated instead with a similar nanoparticle lacking the crosslinking sulfur groups.
This work, which was supported by the National Cancer Institute's Alliance for Nanotechnology in Cancer, is detailed in the paper "Antiangiogenic gene therapy with systemically administered sFlt-1 plasmid DNA in engineered gelatin-based nanovectors." An abstract of this paper is available through PubMed.