Biodegradable Cationic Nanoparticles as a Push Chemodrug Carrier and a Pull cfDNA Scavenger Against Breast Cancer Metastasis

Breast cancer is the most commonly diagnosed cancer in women. Although treatment has continued to improve over the years, over 40,000 women still die of breast cancer each year. For early diagnosed breast cancers, surgical resection plus radiation is the potentially curative treatment option. Still, 50% of patients who receive surgery ultimately suffer from recurrence with distant metastases. Metastatic breast cancer is much more malignant, and patients are often left with only months of survival time. Currently radiotherapy and chemotherapy are applicable to the therapy of metastatic breast cancer, but they cause severe side effects and drug-resistant neoplasm recurrence. Thus, we need new treatment strategies to combat metastatic breast cancer.

Chemotherapy can shrink the primary tumor. Unfortunately, it may also increase the risk of metastasis. Breast cancer cells, including healthy cells, release their contents into the body when killed by chemotherapy. These contents include fragmented DNA that may stimulate the immune cells to promote metastasis. These pathogenic, cell-free DNA (cfDNA) molecules are negatively charged. We propose to develop positively charged nanoparticles to scavenge these pathogenic cfDNA to inhibit metastasis. At the same time, these nanoparticles can also be used to deliver chemodrug in a sustained and local manner to increase efficacy by improving its pharmacokinetics and reducing the dose-related toxicity. We hypothesize that a synergistic effect can be achieved by integrating the dual push-pull functions of delivery and scavenging with biocompatible nanoparticles. This nanomedicine with a combination of chemotherapy and scavenging of pathogenic cfDNA can impact both primary as well as metastatic breast cancer treatment.

This proposal addresses two overarching challenges: (1) developing novel therapeutic strategies to treat metastatic breast cancer based on insights gained from recent research in the field and (2) improving chemodrug delivery with nanoparticles and reducing metastasis at the same time. If this proposed approach is successful, it will help: (1) patients with early stage breast cancer but need chemotherapy, because the proposed nanomedicine can enhance the chemodrug therapeutic efficiency by decreasing the side effects and at the same time reducing the risk of metastasis caused by chemotherapy and (2) patients who have primary breast cancer that has also spread to other organs, because the proposed nanomedicine can deliver chemodrug to decrease the tumor size in situ and capture the pathogenic cfDNA in systemic circulation to arrest metastasis. It may also help patients with metastatic breast cancer but resistant to other treatment modalities such as chemotherapy and radiotherapy.