Targeted Delivery of Albumin Nanoparticles to Bacterial Beacons in Tumors
Abstract
The systemic administration of chemotherapy does not restrict the toxic drug to the tumor and induces damage to healthy tissues, causing adverse side effects. We will create a new therapy that uses bacterial beacons to specifically target chemotherapy to breast cancer metastases. Salmonella has the inherent capacity to accumulate in high concentrations in solid tumors, but not in healthy tissue. We will engineer albumin nanoparticles coated with bacteria-specific antibodies to focus paclitaxel, the most commonly prescribed drug in late-stage breast cancer, specifically into the tumor, to reduce taxane-mediated side effects. Over the years, the administration of paclitaxel has changed to increase efficacy and reduce side effects. Due to its low solubility in water, several solvents, such as castor oil and ethanol, were used to increase dosage. Over time, these solvents have been shown to induce harmful effects, such as hypersensitivity, to the patients. To improve the solubility of paclitaxel, the compound was complexed with albumin nanoparticles (nab-paclitaxel). This provided safer administration, but did not mitigate taxane-mediated side effects in patients, such as sensory neuropathy, fatigue, nausea, and diarrhea. The proposed therapy will avoid distribution of toxic drug to healthy tissue by using bacterial beacons to target paclitaxel to the tumor. One of the major challenges in concentrating cancer therapy in tumors is developing a drug delivery vehicle that can distinguish cancer cells from other mammalian cells. The use of antibody targeting to tumor-associated antigens (TAAs) has increased the specificity of some therapies, but these TAAs are often also present on several healthy tissue types and are dependent on the genetic profile of the tumor. The use of bacteria as antibody beacons has several advantages. Salmonella can colonize tumors in ratios of 100,000 to 1 compared to healthy tissue, making it highly tumor specific. Bacteria (e.g., Salmonella) also possess unique cellular membrane chemistry compared to mammalian cells. The specific homing capabilities of Salmonella to metastases as small as five cell layers coupled with their distinct cellular chemistry render them ideal beacons for late-stage breast cancer and enable the early treatment of metastases. Our proposed therapy is based on pre-existing, Food and Drug Administration (FDA)-approved cancer therapies, but drastically alters traditionally used targeting mechanisms. Instead of targeting hard-to-distinguish cancer cells, our system introduces a distinct targeting beacon, i.e., Salmonella, and then administers chemotherapeutic nanoparticles specially engineered to target those beacons. The result is a drug delivery system that aggregates toxic drug into tumors, thereby creating a safe and efficacious treatment for breast cancer metastases. The research plan has three specific aims. Aim 1 will create a functionalized nanoparticle system that is capable of targeting tumor-associated bacteria. This will serve as the first proof-of-concept that our proposed delivery system provides significant targeting capabilities compared to conventional, non-targeted systems. Aim 2 will alter particle parameters to provide the optimal delivery of nanoparticles to tumor tissue. Aim 3 will demonstrate the efficacy of the functionalized nanoparticles loaded with paclitaxel. The functionalized chemotherapeutic particles will be tested against nab-paclitaxel to demonstrate the efficacy of our targeted drug delivery platform. This proposed system will offer late-stage cancer patients a promising and efficacious chemotherapeutic delivery platform that will not diminish quality of life during treatment. The proposed delivery system will be safe for treatment. The Salmonella strain used in this research proposal is attenuated and is 10,000-fold less virulent than wild-type Salmonella. When systemically administered to mice, dogs, pigs, and mo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910601
Entities
People
- John Klier
Organizations
- United States Army
- University of Massachusetts Amherst