Researchers at Johns Hopkins University are combining diagnostics, therapeutics and drug delivery in a "nanoplex" to kill cancer cells without damaging healthy tissue and causing the side effects associated with many cancer therapies. The approach, which the researchers describe as "theranostic imaging," targets drugs specifically to tumor cells, and the research is published in American Chemical Society Nano. Theranostics, using a diagnostic to tailor choice of therapeutics, are a key part of personalized medicine.
The nanoplex included the nontoxic prodrug 5-fluorocytosine (5-FC), the inactive form of the cytotoxic chemotherapeutic 5-fluorouracil (5-FU), and the enzyme that activates the prodrug. The nanoplex is designed to bind to prostate-specific membrane antigen (PSMA), a protein that is expressed in the vessels of most solid tumors, making this a potential target for many types of cancer. Once the complex is taken inside the cell, the enzyme activates the cancer chemotherapy, which then kills the cell.
The researchers added radioactive and florescent molecules to the prodrug-enzyme nanoplex so that they could use imaging to follow the location and activity of the nanoplex, and included small interfering RNA (siRNA) to reduce the activity of choline kinase, an enzyme whose levels increase as tumors grow.
In mice, the nanoplex was taken up specifically by tumor cells expressing PSMA. The prodrug was converted to active drug, and within 48 hours, the siRNA-loaded nanoplexes reduced enzyme activity 80%. None of the mice receiving the nanoplexes showed any damage to organs such as the kidney and liver, or any increase in immune response.
"Our results show a non-invasive imaging approach to following and delivering targeted therapy to any cancer that expresses PSMA," says senior study investigator Zaver Bhujwalla. However, this technique could have potential in any cancer that has increased levels of specific proteins on its surface, for example breast cancers expressing HER-2/neu or CXCR4 proteins, and has potential to impact more than one molecular target at a time, potentially reducing the risk of resistance. It could be used as a single agent, or in combination with other forms of treatment.
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