Zhu, Yonglian; (2025) Nanoparticles Targeting Tumour Associated Macrophages. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text Zhu_10204159_Thesis.pdf Download (17MB) | Preview

Abstract

This thesis explores the application of macrophage polarization in cancer immunotherapy through the development of a paclitaxel-loaded, pro-tumour M2 macrophage-targeting drug formulation. Despite substantial progress, the precise mechanisms underlying M2 macrophage repolarization, as well as the efficacy of M2 repolarization in suppressing tumour growth in vivo, remain unresolved, thereby limiting the further development of this drug formulation in disease models and its potential clinical applications. The primary objective of this research is to develop a drug delivery system that targets M2 macrophages and is loaded with paclitaxel to induce the polarization of M2 macrophages to M1 macrophages. Specifically, the aim is to enhance the cellular uptake of the paclitaxel-loaded GCMP formulation in M2 macrophages via mannose-mannose receptor recognition, thereby repolarizing pro-tumour M2 macrophages into anti-tumour M1 macrophages to inhibit tumour progression. To achieve these objectives, RAW264.7 cells (M0) were polarized into M2 macrophages using IL-4 and IL-13 cytokines to increase the expression of the mannose receptor (CD206), a key biomarker of M2 macrophages. The cellular uptake of GCMP (a mannose-decorated M2-targeting vehicle) was then evaluated in these polarized M2 macrophages. Additionally, the ability of the PTX-GCMP formulation to repolarize M2 macrophages into M1 macrophages was assessed. The research involved the synthesis of GCMP nanoparticles inspired by GCPQ nanoparticles, the loading of paclitaxel into GCMP, the development of a method for polarizing RAW264.7 cells into M2 macrophages, and the investigation of cellular interactions between GCMP/PTX-GCMP and the RAW264.7 cell line. The results demonstrate that the PTX-GCMP formulation successfully repolarized M2 macrophages back into M1 macrophages, as determined by flow cytometry. After PTX-GCMP treatment, the expression levels of M1 biomarkers increased twofold, while the expression levels of M2 biomarkers were reduced to one-third of their original levels. These findings provide new insights into the application of paclitaxel for M2 macrophage repolarization. Additionally, IL-4 and IL-13 cytokines effectively polarized RAW264.7 cells into M2 macrophages, leading to a sixfold increase in mannose receptor expression. The mannose-decorated GCMP nanoparticles specifically targeted M2 macrophages, as evidenced by enhanced cellular uptake, which was sensitive to the presence and blockade of the mannose receptor. These findings have significant implications for cancer immunotherapy, suggesting that the mannose-mannose receptor recognition mechanism is a reliable approach for targeting M2 macrophages. Moreover, this research is the first to combine the concepts of M2 targeting and paclitaxel-mediated M2 repolarization, leading to the development of the PTX-GCMP formulation that specifically targets M2 macrophages and achieves effective repolarization. This work contributes to the field of M2 macrophage targeting and repolarization and broaden avenues for the development of immunotherapy drug formulations. In conclusion, this thesis advances our understanding of macrophage polarization in cancer treatment and provides a foundation for future research in the development of targeted immunotherapies for malignancies.

Downloads since deposit

Loading...

16Downloads

Download activity - last month

Export as XMLCSVJSON

Loading...

Download activity - last 12 months

Export as JSONCSVXML

Loading...

Downloads by country - last 12 months

Export as XMLJSONCSV

Loading...

Archive Staff Only

View Item