Effective siRNA therapy against cancers must not only target the primary tumor but also must reach metastatic lesions, indicated Esther Chang, Ph.D., professor, Georgetown University Medical Center. She also employs nanotechnology and has developed a tumor-targeting approach to attack both.
“Solid tumors are difficult to treat because you must deliver the therapeutic systemically and still penetrate deeply enough into the tumor through very small blood vessels to treat the entire tumor,” she explained. “Moreover, if the treatment doesn’t also reach distant metastatic tumor cells, there will be continued cancer growth.
“We developed a platform nanodelivery system composed of self-assembled, biodegradable, cationic liposomal nanoparticles with targeting molecules that home to receptors prevalent on cancer cells such as the transferrin receptor. The nanocomplex systemically delivers siRNAs and other nucleic acid-based molecules to the target. The nanoparticles also can be engineered to carry diagnostic MRI contrast agents and small molecules.
“It was quite exciting to find that this strategy could reach both primary and metastatic tumors. We also verified that this nanotechnology platform fulfilled the three key requirements of effective tumor-targeting delivery: demonstrated presence of the therapeutic payload in the tumor, localization only to tumor and not to normal tissue, and a dose-dependent presence of the therapeutic payload in the tumor cells. We have performed studies using this approach to deliver various therapeutic payloads including siRNA in 15 to 16 solid-tumor models such as melanomas, breast, prostate, pancreatic, cervical, and lung cancers.”
Significantly, she also found that these nanocomplexes can dramatically sensitize human tumors in these mouse models to radiotherapy and chemotherapy. Long-term tumor elimination and prolonged life span of the animals was observed.
Additionally, Dr. Chang has utilized her platform for delivery of the human tumor suppressor gene, p53. Those studies are completing a Phase I trial as a single agent. “So far minimal side effects have been noticed and in some cases, there have been significant tumor responses, even at the lowest dose.
“This is truly a platform technology. For example, incorporating the imaging agents into this 100 nanometer complex allows much greater sensitivity of detection and visualization of even minute metastatic lesions in the lungs,” Dr. Chang said.
What is the next challenge? “Funding! We hope to enlist the help of pharma to carry out further clinical studies.”