Biodegradable Cationic Nanoparticles as a Push Chemodrug Carrier and a Pull cfDNA Scavenger Against Breast Cancer Metastasis
Abstract
The goal of this project is to develop a novel therapeutic approach for the prevention of breast cancer metastasis, by using nucleic acid binding nanoparticles (NABNPs) designed to deliver high payloads of cytotoxic drugs to tumor tissues, while simultaneously scavenging the pro-inflammatory cell-free DNA (cfDNA) that is released in the blood circulation as a result of tumor progression and/or destruction by chemotherapy. It is well established that cfDNA released by apoptotic and necrotic cancer cells acts as damage-associated molecular pattern (DAMP) molecule, and displays pro-invasive and pro-metastatic activity on breast cancer cells by activating Toll-like receptors (TLRs), therefore representing a promising pharmacological target for the development of anti-tumor treatments against breast cancer. In this study, we propose to develop bio-compatible NABNPs that can bind and sequester cfDNA with high affinity and that, at the same time, can be "loaded" with high amounts of cytotoxic drugs used in conventional chemotherapy (taxanes, doxorubicin) and then used to preferentially deliver such drugs to tumor sites. The goal is to inhibit tumor progression at primary tumor sites by delivering high payloads of conventional chemotherapy in a selective and sustained manner, while, at the same time, inhibiting metastatic dissemination of cancer cells by scavenging cf DNA released by dying cells. The project is structured into three specific aims: 1) to synthesize and optimize NABNPs with respect to cfDNA-scavenging ability, drug delivery efficiency, and low toxicity; 2) to evaluate the anti-metastatic activity of NABNPs and investigate the cellular mechanisms that underpin it; 3) to evaluate the safety, biodistribution and therapeutic efficacy against both primary tumors and metastases of drug-loaded NABNPs in relevant in vivo breast cancer models, including patient-derived xenografts (PDX) from triple-negative breast carcinomas (TNBCs).
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2022
- Accession Number
- AD1190854
Entities
People
- Piero Dalerba
Organizations
- Columbia University