Ratiometric Combination Nanoprodrug Strategy Under Study in Triple-Negative Breast Cancer

By: Victoria Kuhr, BA
Posted: Monday, July 11, 2022

Xiangrui Liu, MD, of Zhejiang University, Hangzhou, China, and colleagues may have discovered a polymeric prodrug–based co-delivery therapeutic strategy that may overcome some of the limitations of traditional small-molecule drug combinations in the treatment of triple-negative breast cancer. The researchers observed that autophagy inhibitor hydroxychloroquine (HCQ) enhanced the response of tumor cells to 7-ethyl-10-hydroxycamptothecin (SN38) by impairing DNA damage repair. Additionally, the drugs obtained the range of synergistic HCQ/SN38 molar ratios in triple-negative breast cancer cells. These findings were published in the journal Biomaterials.

“The combination nanoparticle not only significantly improves the pharmacokinetics and tumor distribution of both drugs, but also achieves the designed ratiometric delivery, resulting in superior antitumor activity versus the free drug combination regimen in metastatic triple-negative breast cancer mice,” said the study authors.

In April 2020, the U.S. Food and Drug Administration approved the topoisomerase inhibitor SN38-based antibody-drug conjugate sacituzumab govitecan-hziy. The study authors used this agent in 30 BALB/c mice and ICR mice injected with human breast cancer cells. The tumor-bearing mice received the combination nanoparticle treatment. The study authors further developed a nanoprodrug strategy for implementing the ratiometric combination of SN38 and HCQ for the mice.

The use of SN38 or HCQ was linked to an amphiphilic polymer through a disulfide bond. This bond was split under high levels of glutathione in tumor cells to release the parent drugs. This split helped to avoid the unselective release of the parent drugs into normal tissues. The two polymeric prodrugs were ratiometrically coassembled into nanoparticles at the optimized synergistic molar ratio. The autophagy inhibitor HCQ and SN38 exhibited synergistic effects when the molar ratio reached 5:1. In the triple-negative breast cancer cells treated with the combination nanoparticle, HCQ-mediated autophagy blockage enhanced the DNA damage and apoptotic effect of SN38, manifesting synergistically cytotoxic effects.

Disclosure: The study authors reported no conflicts of interest.

Biomaterials

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