Profiling target engagement and cellular uptake of cRGD-decorated clinical-stage core-crosslinked polymeric micelles

Polymeric micelles are increasingly explored for tumor-targeted drug delivery. CriPec® technology enables the generation of core-crosslinked polymeric micelles (CCPMs) based on thermosensitive (mPEG-b-pHPMAmLacn) block copolymers, with high drug loading capacity, tailorable size, and controlled drug release kinetics. In this study, we decorated clinical-stage CCPM with the αvβ3 integrin-targeted cyclic arginine-glycine-aspartic acid (cRGD) peptide, which is one of the most well-known active targeting ligands evaluated preclinically and clinically. Using a panel of cell lines with different expression levels of the αvβ3 integrin receptor and exploring both static and dynamic incubation conditions, we studied the benefit of decorating CCPM with different densities of cRGD. We show that incubation time and temperature, as well as the expression levels of αvβ3 integrin by target cells, positively influence cRGD-CCPM uptake, as demonstated by immunofluorescence staining and fluorescence microscopy. We demonstrate that even very low decoration densities (i.e., 1 mol % cRGD) result in increased engagement and uptake by target cells as compared to peptide-free control CCPM, and that high cRGD decoration densities do not result in a proportional increase in internalization. In this context, it should be kept in mind that a more extensive presence of targeting ligands on the surface of nanomedicines may affect their pharmacokinetic and biodistribution profile. Thus, we suggest a relatively low cRGD decoration density as most suitable for in vivo application

Cancer-associated fibroblasts: Origin, function, imaging, and therapeutic targeting

The tumor microenvironment (TME) is emerging as one of the primary barriers in cancer therapy. Cancer-associated fibroblasts (CAF) are a common inhabitant of the TME in several tumor types and play a critical role in tumor progression and drug resistance via different mechanisms such as desmoplasia, angiogenesis, immune modulation, and cancer metabolism. Due to their abundance and significance in pro-tumorigenic mechanisms, CAF are gaining attention as a diagnostic target as well as to improve the efficacy of cancer therapy by their modulation. In this review, we highlight existing imaging techniques that are used for the visualization of CAF and CAF-induced fibrosis and provide an overview of compounds that are known to modulate CAF activity. Subsequently, we also discuss CAF-targeted and CAF-modulating nanocarriers. Finally, our review addresses ongoing challenges and provides a glimpse into the prospects that can spearhead the transition of CAF-targeted therapies from opportunity to reality