Development of bubble and ligand-based targeted nanoparticles for solid tumor therapy
Abstract
The use of nanoparticles to enhance targeted chemotherapeutic delivery and efficacy against solid tumors is on the rise. Conventional chemotherapy can be associated with deleterious systemic side effects and limited efficacy, due in part to the insufficient drug delivery to the tumor site following systemic injections. Chemotherapy can also be limited by its adverse effects and tumor hypoxia that reduces the overall therapeutic outcomes and patient survival rates. To overcome these barriers, this project aimed to develop targeted nanoparticles (NPs) for systemic chemo-immunotherapy of both treated and untreated solid tumors. We hypothesize that combining in-situ delivered ligand- and bubble-based nanoparticles with high intensity focused ultrasound (HIFU) will enhance chemotherapy efficacy and induce immune-mediated clearance of untreated cancer cells, thereby significantly improving treatment outcomes. As model drugs, we chose doxorubicin (DOX) and mitoxantrone (MTX) from the anthracycline/anthraquinone class of chemotherapies for encapsulation into NPs. These chemotherapies are known inducers of immunogenic cell death (ICD). For bubble-based NP synthesis, polymeric NPs incorporating perfluoropentane, a known ultrasound contrast agent, and chemotherapies (i.e., DOX & MTX) were developed. Biophysical characterizations of the polymeric NPs showed controlled chemotherapy release in vitro and enhanced stability within serum with a targeted delivery in presence of HIFU via the 'micro/nanobubble' effect. This resulted in an enhanced chemotherapy effects and extended survival following in-situ therapy of murine colon tumor in vivo compared to controls. We also similarly generated ligand-based NPs targeting CXCR4 receptors. We demonstrated the successful synthesis of these NPs loaded with chemotherapies in thermally sensitive formulations. Future studies are under planning to utilize these to test their targeting capabilities and therapeutic efficacy in comparison to free drug controls. Our data suggests that targeted NPs in combination with HIFU may be an innovative chemo-immunotherapeutic treatment regimen to improve targeting of solid tumors.
Collections
- OSU Dissertations [11222]