Monitoring and modulating drug delivery to tumors

Theek, Benjamin; Lammers, Twan (Thesis advisor); Jahnen-Dechent, Wilhelm (Thesis advisor)

Aachen (2020)
Dissertation / PhD Thesis

Dissertation, Rheinisch-Westfälische Technische Hochschule Aachen, 2020, kumulative Dissertation


Drug delivery systems are developed to improve the efficacy and reduce side-effects of (chemo-) therapeutic drugs. The tumor accumulation of drug delivery systems, which are nowadays typically referred to as nanomedicines, relies on the enhanced permeability and retention (EPR) effect. The pathophysiological phenomena underlying the EPR effect are poorly understood, and it is becoming increasingly apparent that EPR is highly heterogeneous in different tumors and patients. To improve nanomedicine-based anticancer therapy, imaging strategies are needed to identify patients which are more likely to respond. In addition, combination therapies need to be established to improve EPR-based tumor targeting. This thesis evaluates imageable tumor characteristics which influence the EPR effect and which may help to establish protocols for patient stratification. Furthermore, it describes a physical EPR modulation strategy, i.e. sonoporation, to improve the EPR-based accumulation of nanomedicine formulations in tumors. To visualize and quantify the accumulation of 10-20 nm-sized fluorophore-labeled polymeric drug carriers, fluorescence molecular tomography combined with computed tomography was performed in mice bearing CT26 colon carcinoma tumors. Depending on the analytical protocol, 5-18% of the injected dose (%ID) accumulated in tumors over time. In the same mice, the tumor vascularization was studies by 2D and 3D contrast-enhanced ultrasound, rendering relative blood volumes (rBV) ranging from 4% to 11%. A good correlation between tumor vascularization and tumor accumulation was observed (r²=0.82). To promote the accumulation and penetration of liposomes in tumors with low levels of EPR, a sonoporation study was performed in mice bearing A431 epidermoid and BxPC3 pancreatic cancer xenografts. Sonoporation refers to the combined use of ultrasound and microbubbles with the intention of enhancing vascular perfusion and permeability. At the macroscopic level, sonoporated tumors showed an up two-fold higher liposome accumulation. At the microscopic level, sonoporation strongly potentiated the ability of the liposomes to penetrate away from the blood vessels into the tumor interstitium. In summary, we show that monitoring and modulating the tumor vasculature helps to predict and promote nanomedicine-based drug delivery. These findings may help to stratify patients for more personalized anticancer nanotherapy, and they contribute to the development of combination therapies to achieve improved clinical outcomes.