Drug-resistant breast tumors' defenses lowered by stealth nanoparticles

Some of the most dangerous cancers are those that can outmaneuver the very drugs designed to defeat them, but researchers are now reporting a new Trojan-horse approach. In a preliminary study in the journal ACS Nano focusing on a type of breast cancer that is highly resistant to current therapies, they describe a way to sneak small particles into tumor cells, lower their defenses and attack them with drugs, potentially making the therapy much more effective.

Paula T. Hammond and colleagues at the Koch Institute of Integrative Cancer Research at MIT note that triple-negative breast cancer (TNBC) is an aggressive disease that is difficult to treat with standard-of-care therapy, and patients' prognoses are poor. These cancer cells evade treatment by ramping up the production of certain proteins that protect tumors from chemotherapy drugs. Interfering with this process could give anticancer drugs a better chance at killing resistant tumors. Recent research into molecules called small interfering RNAs, or siRNAs, is opening doors into possible new treatments using this approach. These molecules can halt the production of particular proteins, so they are ideal candidates for dialing down the levels of protective proteins in tumors. But there are challenges to using siRNAs as part of a cancer therapy, so Hammond's team set out to address them with novel molecular engineering approaches.

They designed a two-stage, "stealth" drug delivery system to attack TNBC cells in mice, often used as stand-ins for humans in research. They created "layer-by-layer" nanoparticles through assembly of components in a certain order around a nano-sized core. An anticancer drug is loaded into the core of the particle, which is then wrapped in a layer of negatively charged siRNA, alternating with positively charged polypeptides, then coated on the outside with a stealthy tumor-targeting shell layer. That layer helps keep the particles in the body long enough for therapy to work. It also allows the particles to specifically bind to TNBC tumor cells. When tested in mice, the nanoparticles targeted the tumors and reduced the levels of protective proteins by nearly 80 percent. With the cancer cells rendered vulnerable, the nanoparticles' anticancer drug payload showed significantly enhanced therapeutic effects and shrunk tumors by 8-fold. The scientists state, "In summary, the results here provide a potential strategy to treat an aggressive and recurrent form of TNBC, as well as a means of adapting this platform to a broad range of controlled multi-drug therapies customizable to the cancer type in a singular nanoparticle delivery system." They also say that the "layer-by-layer" nanoparticle components are biocompatible and biodegradable, which will allow rapid translation into potential clinical benefits.