BIODEGRADABLE CATIONIC NANOPARTICLES AS A PUSH CHEMODRUG CARRIER AND A PULL CFDNA SCAVENGER AGAINST BREAST CANCER METASTASIS

Background: Breast cancer, particularly the metastatic form, continues to impose significant mortality on women. Cell-free nucleic acids (cfDNA) released by apoptotic and necrotic cancer cells, acting as damage-associated molecular patterns (DAMP) molecules, stimulate pro-invasive and pro-metastatic effects in breast cancer progression by activating the Toll-like receptors (TLRs), thereby providing an intriguing anti-metastasis target for breast cancer treatment. Blocking the cfDNA-TLR interactions may inhibit cancer progression. Previously, we reported the application of water-soluble nucleic acid binding cationic polymers (NABPs) to scavenge cfDNA for anti-inflammatory therapy. Recent studies also showed that NABPs could dramatically reduce liver metastasis in a murine model of pancreatic cancer by capturing cfDNA, but could not inhibit primary cancer growth. Ample literature has demonstrated that similar cationic polymers can be formulated into nanoparticles for chemodrug delivery to improve anti-cancer efficacy. We hypothesize that a synergistic effect can be achieved by integrating the dual push-pull functions of delivery and scavenging, and propose to develop a biocompatible nanoparticulate system with high chemodrug loading efficiency and strong cfDNA binding affinity.Overarching Challenges: Radiotherapy and chemotherapy are applicable to the therapy of metastatic breast cancer, but they lead to severe side effects and drug-resistant neoplasm recurrence. Thus, a significant challenge in breast cancer disease management and eradication is to develop new therapeutic strategies for metastatic breast cancer based on a different mechanism. Nanoparticles could offer advanced delivery functions for genes, proteins or small molecule drugs to tumor. Many types of nanomedicines against primary tumors have been developed, but the development of anti-metastasis nanomedicines and nanomedicine-based anti-metastatic strategies lags far behind. The overall challenge of this proposal is to improve chemodrug delivery with nanoparticles and reduce metastasis at the same time.Objective/Hypothesis: Hypothesizing that a combination of chemotherapy and scavenging of pathogenic cfDNA can impact both primary as well as metastatic breast cancer treatment, we aspire to achieve the following objectives: (1) treating breast cancer based on a new mechanism; (2) understanding the mechanism of cfDNA scavenging in breast cancer metastasis; and (3) defining the merits of integrative chemotherapy and cfDNA scavenging; (4) stimulating a new direction of anti-cancer nanomedicine research.Specific Aims: We propose to pursue three specific aims: (1) Synthesize and systematically optimize NABPs and NABP nanoparticles (NABNPs) with respect to cfDNA-scavenging ability, drug delivery efficiency, and low toxicity. (2) Evaluate the anti-metastatic effect of NABNP as cfDNA scavenger and drug carrier and investigate their anti-metastatic mechanism. (3) Evaluate therapeutic efficacy, safety, biodistribution, and anti-metastatic mechanism of NABNPs in relevant breast cancer models.Study Design: We will rationally synthesize and systematically characterize NABNPs using advanced bioengineering techniques. Next, we will evaluate the effects of nucleic acid scavenging and chemodrug delivery on tumor cell viability at the cellular level and will conduct mechanistic studies to elucidate their mode of action. Finally, we will elucidate the therapeutic efficacy, safety, biodistribution, and anti-metastatic mechanism of NABNPs for nucleic acid scavenging and drug delivery in relevant breast metastasis models, including patient-derived lines established from human triple-negative breast cancers. The experiment group will include untreated group, free drug treated group, blank NABP treated group, blank NABNP treated group, and drug loaded NABNP treated group.Impact: The proposed therapeutic approach, if successful, will help four types of patients: (1) Patients with early stage breast cancer but need chemotherapy; our nanomedicines will enhance the chemodrug therapy efficiency, decrease side effects, and also prohibit the metastasis risk that chemotherapy causes. (2) Patients with primary breast cancer and metastasis cancer at the same time; our nanomedicines can deliver chemodrug to decrease the tumor size of in situ and metastasis sites; nanomedicines will also capture the cfDNA in the blood and in tumor to suppress the metastasis cancer. (3) Patients with metastasis cancer and resistant to chemodrug. (4) Patients who already received surgery and chemo/radiotherapy for primary cancer therapy, but have metastasis after several months/years.