NRP1 transport of cancer therapeutics mediated by tumor-penetrating peptides

Whereas uptake of low-molecular-weight agents is generally inhibited in tumors due to high interstitial pressure, tumor uptake of macromolecules is increased due to enhanced permeability and retention. Small-molecule drugs alone or incorporated in nanoparticles (NPs) have largely been dependent on such physical tumor uptake (passive) for therapeutic activity. Although passively targeted NPs such as Stealth liposomal doxorubicin (Doxil) are effective with improved safety, drug delivery to tumors is still significantly limited. To improve tumor delivery and efficacy, tumor-penetrating peptides (TPP), which contain sequences that target the tumor and activate the neuropilin-1 receptor (NRP1), have either been coadministered with or conjugated to both small and large therapeutic molecules. In this review, we will discuss TPP-mediated therapeutics which target the NRP1 transport system of tumors.