Molecular grappling hooks improve cancer drug targeting and effectiveness

Medications are designed to treat diseased tissues while sparing healthy ones, often by attaching the drug to something that helps guide it directly to its target. But drugs also need time to work, which means they need to stay near the diseased tissues long enough. Now, scientists reporting in ACS Central Science have developed a drug carrier that physically anchors itself to cancer cell membranes, improving drug retention and thereby effectiveness in animal trials. 

“This technology should maximize tumor delivery of drug while sparing normal tissues and result in safer and more effective therapies.” – Michael Evans

“Retaining drugs within tumors is an often-overlooked dimension of drug development that nevertheless greatly impacts the therapeutic window and outcomes,” says Michael Evans, a corresponding author of the study. 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, he adds. 

In previous research, Evans, Charles Craik and colleagues designed drug delivery systems called restricted interaction peptides (RIPs). RIPs change shape when processed by disease-associated enzymes, which allow the peptides to then embed themselves in cell membranes. This effectively tethers the drug to the cell, promoting cellular uptake and improving the drug treatment’s effectiveness. 

In the new study, the researchers designed RIPs to interact with fibroblast activation protein, a proteolytic enzyme prevalent in solid tumors. Imaging studies showed that a fluorescently tagged RIP was rapidly taken up by cancer cells in culture. They then attached an anticancer drug (monomethyl auristatin E) to the RIP and found that the drug-peptide combination was as effective at killing cancer cells in culture as the drug alone. When injected into mice carrying human cancers, the combination selectively targeted tumor tissue, shrinking tumors more effectively and with fewer side effects than the unmodified drug. 

Replacing the anticancer drug attached to the RIP with radioactive copper isotopes, which are commonly used in nuclear imaging and radiotherapy, showed similar results to the drug-RIP combo in mice for tumor targeting and shrinkage. This opens the door to perform disease diagnosis and treatment with the same molecule. The researchers expect to initiate Phase 1 clinical imaging studies of the RIP-copper pairing in human cancer patients later in 2026 in collaboration with a company developing RIPs into therapeutics. 

“This technology should maximize tumor delivery of drug while sparing normal tissues and result in safer and more effective therapies,” Evans concludes. 

The authors acknowledge funding from the Advanced Research Projects Agency for Health, the U.S. Department of Energy, the National Institutes of Health, the Benioff Institute for Prostate Cancer Research at the University of California San Francisco, and the Weill Cancer Hub West. 

Some of the study’s authors are co-founders of TheraPaint, Inc., a company spun out of the University of California San Francisco that is developing radiopharmaceuticals for cancer theranostics. 

The paper’s abstract will be available on May 13 at 8 a.m. Eastern time here: http://pubs.acs.org/doi/abs/10.1021/acscentsci.6c00185 

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