Nano therapy for ischemia
doi:10.1038/nindia.2010.113 Published online 18 August 2010
The managerial role of therapeutic angiogenesis — growing new blood vessels from pre-existing vessels — in treatment of ischemia marked by decrease of blood supply to certain body organs or tissues, is well known. But the inability to reach factors that would help in vessel growth (angiogenic factors) to the ischemia site in a sustained manner has been a stumbling block in treatment till now.
An international team of researchers has tried to overcome this problem by using an FDA approved nanoparticle loaded with 1K1, a protein derived from the hepatocyte growth factor or scatter factor (HGF/SF), to enhance the angiogenic process. They adopted therapeutic angiogenesis, a tool in which new blood vessels are grown to restore blood supply to body parts with deficient blood supply.
The team of researchers from Harvard Medical School, Boston; Harvard-Massachusetts Institute of Technology; Massachusetts Institute of Technology; Medical Research Council Center and University of Cambridge; and National Chemical Laboratory, Pune has demonstrated the efficacy of HGF in limb ischemia, a severe obstruction of the arteries.
Early studies conducted by the same team demonstrated the efficacy of HGF in limb ischemia. Patients reported significant improvement and tolerance towards high doses in clinical trials.
However, the heterogenic structure and need for extensive glycosylation of the growth factor (HGF) imposed regulatory challenges in its manufacturing. This led the researchers to derive a non-glycosylated variant of HGF, 1K1 which could be expressed in yeast. "We used the technique of incorporating the protein in the nanoparticle to further improve its biological activity," says Shiladitya Sengupta, one of the researchers.
This newly designed therapeutic agent 1K1-NP enhanced production of new blood vessels as compared to 1K1. When 1K1-NP was injected in the yolk sac of zebrafish, it exerted greater angiogenesis as compared to free 1K1. Similar results were observed in mice models.
Sengupta said the team had coupled protein engineering with nanotechnology for the first time to devise a technique that enables controlled release of the angiogenic agent in proximity to the site, maximizing the therapeutic potential of HGF/SF.
The technique could be seen as an emerging paradigm in therapeutic angiogenesis and a robust strategy for the management of ischemic diseases. Contrary to its promising role in the treatment of cancer and other disorders that inhibits angiogenesis, therapeutic angiogenesis has emerged as an exciting frontier of cardiovascular medicine, the researchers say. This novel technique, which merges protein engineering and nanotechnology, offers possibilities for the treatment of ischemic diseases that include cardiovascular diseases.
- Roy R. S. et al. Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis. P. Natl. Acad. Sci. USA. doi: 10.1073/pnas.1006007107 (2010)