For cancer therapies to work, they need to stay in proximity to the target diseased tissues for long enough. To help with that challenge, a group of scientists, led by a team at University of California, San Francisco (UCSF), have developed a drug carrier that physically anchors itself to cancer cell membrane, which helps to improve drug retention and effectiveness. Full details are published in a new ACS Central Science paper titled “A Prodrug Strategy to Conditionally Trap Therapeutic Payloads for Improved Tumor Retention.”
“Retaining drugs within tumors is an often-overlooked dimension of drug development that nevertheless greatly impacts the therapeutic window and outcomes,” said Michael Evans, PhD, a professor in the department of radiology and biomedical imaging at UCSF and a corresponding author on the study. In fact, approaches that deliver cancer therapeutics to tumors but lack dedicated mechanisms to ensure tumor retention often lose efficacy within a few days of drug administration.
Previously, Evans and others designed drug delivery systems called restricted interaction peptides or RIPs that can deliver diverse therapeutic cargos including cytotoxins and radioisotopes. They work by changing shape when processed by disease-associated enzymes. These allow them to embed in cell membranes, tethering their drug payloads in place, promoting cellular uptake and improving effectiveness. Building on that work, the scientists engineered RIPs to interact with fibroblast activation protein, a serine protease that is prevalent in solid tumors and fibrosis.
Imaging studies of cancer cell cultures showed that a fluorescently tagged RIP was rapidly taken up by the cells. Then when the scientists attached an anticancer drug, monomethyl auristatin E or MMAE, to the RIP, they found that the drug-peptide combination was as effective in killing cancer cells as the drug alone. Furthermore, when the drug-peptide combination was injected into mice with human cancers, it selectively targeted tumor tissue and was more effective at shrinking tumors than the unmodified drug with fewer side effects. The scientists observed similar results when they attached RIPs to radioactive copper isotopes which are commonly used in nuclear imaging and radiotherapy.
The scientists expect to initiate Phase I clinical imaging studies of the RIP-radioactive copper isotope pairing in human cancer patients later in 2026 in collaboration with a company that is developing RIPs into therapeutics.
