E-Thesis 378 views
Chemically programming redox-active nanovaccines and theranostic nanoparticles for combination cancer immunotherapy / Marc Bilbao-Asensio
Swansea University Author: Marc Bilbao-Asensio
DOI (Published version): 10.23889/SUthesis.60304
Abstract
Cancer immunotherapies have established their relevance in the clinic in recent years. These therapies have increased patient survival rates with few toxic side-effects. However, they still suffer from low patient response rates. With the progression of the disease, tumors become increasingly hetero...
| Published: |
Swansea
2022
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| Institution: | Swansea University |
| Degree level: | Doctoral |
| Degree name: | Ph.D |
| Supervisor: | Mareque-Rivas, Juan |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa60304 |
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| Abstract: |
Cancer immunotherapies have established their relevance in the clinic in recent years. These therapies have increased patient survival rates with few toxic side-effects. However, they still suffer from low patient response rates. With the progression of the disease, tumors become increasingly heterogeneous, which poses limits to the development of universal, “off the shelf” cures. Nanotechnology allows insight over novel therapy strategies to better suit the specificities and uniqueness of each patient’s cancer. In this work, a chemistry and material science approach enabled the development of iron oxide nanoparticle-filled nanovaccines (IONVs) to exploit the biochemical features of the tumor microenvironment for cancer immunotherapy and combination therapy. A systematic nanoparticle engineering rationale is stablished to “programme” IONVs for: (i) cancer cell sensitization to oxidative damage and ferroptosis; (ii) pH-catalysed disassembly and drug release; (iii) macrophage repolarization towards tumor-suppressing phenotypes; (iv) optimization of tumor-antigen processing and cross-presentation; (v) optimization of platinum-based prodrug delivery for chemotherapy and chemoimmunotherapy; (vi) integration of directing ligands for active targeted drug delivery; (vii) monitorable therapy biodistribution; and (viii) synergy with state-of-the-art antibody-based immunotherapies.Systematic IONV engineering provided control over distinguishable device properties such as size, charge, stability, chemical reactivity, bioactive molecule loading and particle surface functionalization. The device integrated iron catalysis for cancer-cell specific activation of ferroptosis, immunostimulatory redox stress and site-specific disassembly for targeted drug release. IONVs were visualized to accumulate into the tumor tissue as well as immune cell-rich tissues such as spleen and lymph nodes. Their high biocompatibility enabled immune cell activation for multipronged antitumor action. The results show how IONVs can unite and improve concurrently effective anticancer strategies, resulting in complete elimination of established aggressive tumors and acquisition of protective long-term immunity. Overall, this work demonstrates the suitability of programmable IONVs to act as generalizable platforms for cancer immunotherapy enhancement. |
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| Item Description: |
ORCiD identifier: https://orcid.org/0000-0002-2862-403X |
| Keywords: |
Chemistry, Immunotherapy, Oncology, Nanomedicine |
| College: |
Faculty of Science and Engineering |