The scientists from the Korea Institute of Science and Technology (KIST) and led by Kwang-meyung Kim, Ph.D., say they have created a new therapy that could prevent drug resistance by conjugating a drug that inhibits resistance against anticancer drugs (SMAC) and an anticancer agent (Doxorubicin) .

The resulting drug remains inactive in the body until it encounters a cancer cell and reacts with cathepsin B that is overexpressed in cancer cells. The conjugate specifically releases the anticancer agent in cancer cells along with the drug-resistance inhibitor to effectively treat cancers without concern over drug resistance, according to the team. As a result, it can inhibit not only the inherent drug resistance of cancer cells but also the acquired drug resistance that cancer cells can develop during chemotherapy.

Also, cathepsin B is produced in relatively small amounts in normal cells. Thus, the drug-drug nanoparticles remain inactive and do not release the drugs in normal cells, which will reduce the side effects associated with conventional chemotherapy.

“The cancer-specific drug-drug nanoparticles effectively inhibit drug resistance that lead to treatment failures in conventional chemotherapy and at the same time reduce toxicity in normal cells, so it is expected that it’ll be possible to use it as a new anticancer agent that can prevent the drug resistance and adverse effects,” said Kim.

The team published its study, “Cancer-specific drug-drug nanoparticles of pro-apoptotic and cathepsin B-cleavable peptide-conjugated doxorubicin for drug-resistant cancer therapy,” in Biomaterials.

“Chemotherapy has shown remarkable therapeutic efficacy for various types of cancer. However, drug resistance reduces the effectiveness and sensitivity of chemotherapy, leading to treatment failure and cancer relapse in many clinical indications. Herein, we propose cancer-specific drug-drug nanoparticles (DD-NPs) that improve the therapeutic efficacy of chemotherapy against drug-resistant cancer,” the investigators wrote.

“Cancer-specific and pro-apoptotic drug-drug conjugate was prepared by conjugating the pro-apoptotic peptide drug (SMAC; Ala-Val-Pro-Ile-Ala-Gln, AVPIAQ) and cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly, FRRG) to a doxorubicin (DOX), resulting in SMAC-FRRG-DOX that allows self-assembled into nanoparticles. The resulting DD-NPs were specifically cleaved to pro-apoptotic SMAC and cytotoxic DOX only in cathepsin B-overexpressing cancer cells, inducing a synergy of the pro-apoptotic activity with the chemotherapy.

“In MCF-7 breast tumor-bearing mice, intravenously injected DD-NPs highly accumulated at targeted tumor tissues via enhanced permeability and retention (EPR) effect, releasing SMAC and DOX, which showed a synergetic pro-apoptotic/chemotherapy. Furthermore, DD-NPs greatly suppressed tumor growth and improved overall survival in a metastatic lung cancer model.

“Collectively, these cancer-specific drug-drug nanoparticles may be a promising strategy to treat drug-resistant cancers with high cancer cell-specificity.”