The limited transport of conventional chemotherapy within the tumor microenvironment (TME) is due to irregular vascularization, increased tumor interstitial pressure, and a dense extracellular matrix (ECM). The lack of selectivity of anticancer drugs often leads to systemic toxicity and damage to healthy tissues. Bacteria-based cancer therapy (BBCT) is a promising alternative, as tumor-targeting bacteria have been shown to preferentially colonize primary and metastatic tumors and induce anti-tumor effects. In this dissertation, we focus on several aspects of bacteria-nanoparticle conjugates, wherein BBCT is synergistically combined with nanomedicine to augment the efficacy of both treatment modalities. We explore biofabrication of our bacteria-nanoparticle conjugates called NanoBEADS (Nanoscale Bacteria Enabled Autonomous Drug Delivery Systems) and their interaction with the TME. Specifically, (1) we investigate the effects of two bacteria-NP conjugation chemistry and assembly process parameters of mixing method, volume, and duration, on NP attachment density and repeatability. We evaluate the influence of linkage chemistry and NP size on NP attachment density, viability, growth rate, and motility of NanoBEADS. (2) We investigate the effect of dense stroma and ECM production on the intratumoral penetration of bacteria with a mathematical model of bacterial intratumoral transport and growth. (3) We develop a microfluidic device with multicellular tumor spheroids to study the transport of tumor-targeting bacteria and support real-time imaging and long-term experiments. (4) We develop a new type of bacteria-based bio-hybrid drug delivery system using engineered cell surface display for enhancing the attachment of nanoparticles. / Doctor of Philosophy / Chemotherapy faces challenges in effectively reaching tumors due to factors like irregular blood vessel distribution, increased tumor pressure, and the presence of dense structures such as the extracellular matrix (ECM). This often results in collateral damage to healthy tissues. Bacteria-based cancer therapy (BBCT) offers a promising alternative, utilizing tumor-targeting bacteria to selectively attack tumors. This dissertation focuses on optimizing NanoBEADS (Nanoscale Bacteria Enabled Autonomous Drug Delivery Systems), which are chemotherapy encapsulating nanoparticle-bacteria assemblies to overcome these challenges and characterizing its behavior in tumors. Firstly, we investigated the optimization of bacteria-nanoparticle attachment, exploring various linkage chemistries and assembly processes to enhance attachment density, viability, and motility. Secondly, we examine how dense stroma and ECM affect bacterial penetration providing insights into intratumoral transport dynamics. Thirdly, we develop a microfluidic device integrated with multicellular tumor spheroids to enable real-time imaging and long-term experimentation on bacteria and drug transport. Lastly, we explore the potential of engineered cell surface display to enhance nanoparticle attachment in NanoBEADS, paving the way for self-propelled and highly targeted drug delivery systems. This dissertation strives to contribute to the transformation of current approaches to cancer treatment by refining drug delivery precision and efficacy while minimizing systemic toxicity.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/118972 |
| Date | 14 May 2024 |
| Creators | Zhan, Ying |
| Contributors | Mechanical Engineering, Behkam, Bahareh, Davis, Richey M., Paul, Mark R., Kale, Sohan, Robertson, John L. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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