Modulating and monitoring the microenvironment in cancer and renal fibrosis
- Modulation und Monitoring der Mikroumgebung in Krebs und Nierenfibrose
Baues, Maike; Lammers, Twan (Thesis advisor); Boor, Peter (Thesis advisor)
Dissertation / PhD Thesis
Dissertation, Rheinisch-Westfälische Technische Hochschule Aachen, 2020
The dysregulation of microenvironmental homeostasis, particularly of the extracellular matrix (ECM), is a common driving force in various diseases, including renal fibrosis and cancer. A pathological microenvironment, together with an abnormal vascular network and dysfunctional lymphatic system, form the basis for the enhanced permeability and retention (EPR) effect, which is the underlying mechanism for passive tumor targeting with nanomedicine formulations. The EPR effect, however, is a highly variable phenomenon, in animal models and in patients. In this thesis, pharmacological and physical strategies to modulate EPR based nanomedicine delivery to tumors are assessed, including vascular normalization and sonopermeation (i.e. the combination of ultrasound (US) and microbubbles (MB)). Elevated expression of the histidine rich glycoprotein (HRG) polarizes tumor associated macrophages toward an anti tumor M1 like phenotype, thereby inducing vascular normalization and enhancing the EPR effect. Hard- and soft shelled MB formulations are used in this thesis to study the impact of sonopermeation on the EPR mediated accumulation and penetration of liposomes into highly cellular A431 and highly stromal BxPC 3 carcinoma xenografts. Our work demonstrates that both vascular normalization and sonopermeation improve the tumor accumulation, tumor penetration and the intra tumoral distribution of nanomedicine based drug delivery systems. Excessive ECM deposition in the kidney impairs renal function, contributing to incidence and severity of chronic kidney disease (CKD). As an alternative to needle based biopsies, collagen and elastin specific molecular imaging were explored in this thesis for non invasively diagnosing and staging renal fibrosis. The collagen binding protein CNA35 accumulated significantly stronger in fibrotic kidneys, and specifically detected collagen types I and III on murine and human sections. Elastin was found to be de novo overexpressed in fibrotic renal tissues of mice, rats and patients. The elastin specific molecular imaging agent ESMA captured fibrotic areas in human kidney samples. Fibrosis progression and anti fibrotic therapy responses were visualized and quantified by means of ESMA MRI. Taken together, these findings indicate that the modulation of the microenvironment improves EPR mediated tumor targeting and demonstrate that ECM monitoring enables specific and repetitive assessment of renal fibrosis. Nanomedicines and molecular imaging hold the potential to substantially transform the diagnosis and treatment of cancer and CKD.