Size Matters: Developing Design Rules to Engineer Nanoparticles for Solid Tumour Targeting

Nanotechnology enables the design of highly customizable platforms for producing minimally invasive and programmable strategies for cancer diagnosis and treatment. Advances in this field have demonstrated that nanoparticles can enhance specificity of anti-cancer agents, respond to tumour-specific cues, and direct the visualization of biological targets in vivo. Nanoparticles can be synthesized within the 1 to 100 nm range to achieve different electromagnetic properties and specifically interact with biological tissues by tuning their size, shape, and surface chemistry. However, it remains unclear which physicochemical parameters are critical for delivering nanomaterials to the tumour site. With less than 5% of administered nanoparticles reaching the tumour, engineering of nanoparticles for effective delivery to solid tumours remains a critical challenge to cancer nanomedicine. A more comprehensive understanding of the interplay between the nanomaterial physicochemical properties and biological systems is necessary to enhance the efficacy of nanoparticle tumour targeting. This thesis explores how nanoparticle size and functionalization with cancer cell specific agents impact nanoparticle delivery to tumours. Furthermore, this doctoral work (i) discusses how tumour structure evolves with growth, (ii) elucidates how such changes modulate nanoparticle accumulation, and (iii) identifies how the skin serves as a significant off-target site for nanoparticle uptake. This thesis also demonstrates the utility of empirically-derived parametric models, Monte Carlo simulations, and decision matrices for mechanistically understanding and predicting the impact of nanomaterial features and tumour biology on nanoparticle fate in vivo. These topics establish key design considerations to tailor nanoparticles for enhanced tumour targeting. Collectively, the concepts presented herein form a fundamental framework for the development of personalized nanomedicine and nano-diagnostic agents in the future.Ph.D