Overcoming biophysical barriers with innovative therapeutic delivery approaches

Cancer is often conceptualized as principally a cellular process, one initiated by genetic mutations in a progenitor cell that result in dysregulated cell proliferation. Accordingly, investigations into mechanisms of treatment resistance to cancer therapies often revolve around the biologic barriers to the therapies. However, there is a growing appreciation for the unique biomechanical properties for tumors and the role they play in treatment resistance for conventional, molecularly targeted, and immune-mediated cancer therapies. This understanding has inspired the development of pharmacologic and interventional approaches to overcome these barriers. Of particular promise are perfusion-enhanced drug delivery (PEDD) approaches that potentially allow for comprehensive tumor coverage with increased delivery pressure and prevention of reflux to drive therapeutics into the tumor parenchyma. In this review, we summarize the key features of the tumor microenvironment that drive tumor progression and impose barriers to anti-cancer therapies. We highlight the rationale and application of pharmacologic approaches and interventional drug delivery devices designed to overcome these impediments. We additionally contextualize these concepts by illustrating their application to the treatment of uveal melanoma liver metastases.