Image-Guided siRNA Delivery
As RNAi gains momentum as a therapeutic strategy, new noninvasive methods for detection of siRNA delivery and verification of silencing become paramount. Zdravka Medarova, Ph.D., assistant professor, Massachusetts General Hospital and Harvard Medical School, and colleagues have developed dual-purpose nanoparticle probes that not only facilitate in vivo transfer of siRNAs but also simultaneous imaging of their accumulation in tumors via magnetic resonance imaging (MRI) and near-infrared optical imaging (NIRF).
“Our probes have four major advantages,” Dr. Medarova reported. “They can be detected noninvasively, increase circulation half-life, enhance versatility, and hone in on their target. They consist of magnetic nanoparticles labeled with a near-infrared dye and conjugated to siRNA molecules specific to therapeutic targets. These nanoparticles have excellent biodistribution and blood half-lives. The half-life in humans is about 24 hours and in mice 10–12 hours. Additionally, we have seen no signs of any systemic toxicity.”
Aside from engineering for easy detection via MRI or NIRF, special targeting features can also be included. “We can modify the nanoparticles to include antigen targeting or membrane translocation modules for cell-specific intracellular delivery. Imaging allows in vivo tracking of the tumor uptake of these probes. We demonstrated this in two separate tumor models.”
Dr. Medarova said since her initial findings there has been an explosion of additional studies. “siRNA delivery via nanoparticles is becoming a trend. Many companies have shown an interest in this type of technology.”
The next phase of her studies is to further develop coated nanoparticles for miRNA applications. “The idea is to stop the metastatic processes at very early stages, at the level of epigenetics. We hope to exert such control via our technology.”
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.”