Cancer drug delivery paradigm crumbles as research exposes EPR effect's limitations
A landmark review challenges the 20-year-old foundation of tumor-targeting nanoparticle design, showing the widely-used EPR effect doesn't work as expected. Using live-cell microscopy, researchers identified superior delivery pathways—targeting blood vessel linings and exploiting immune cells—that could unlock billions in stalled oncology drug programs and reshape development timelines for precision medicines.
Originaltitel: Beyond the EPR effect: Intravital microscopy analysis of nanoparticle drug delivery to tumors
<p>Delivery of nanoparticles (NPs) to solid tumors has long relied on enhanced permeability and retention (EPR) effect, involving permeation of NPs through a leaky vasculature with prolonged retention by reduced lymphatic drainage in tumor. Recent research studies and clinical data challenge EPR concept, revealing alternative pathways and approaches of NP delivery. The area was significantly impacted by the implementation of intravital optical microscopy, unraveling delivery mechanisms at cellular level <em>in vivo</em>. This review presents analysis of the reasons for EPR heterogeneity in tumors and describes non-EPR based concepts for drug delivery, which can supplement the current paradigm. One of the approaches is targeting tumor endothelium by NPs with subsequent intravascular drug release and gradient-driven drug transport to tumor interstitium. Others exploit various immune cells for tumor infiltration and breaking endothelial barriers. Finally, we discuss the involvement active transcytosis through endothelial cells in NP delivery. This review aims to inspire further understanding the process of NP extravasation in tumors and provide insights for developing next-generation nanomedicines with improved delivery.</p>