Intracellular Trafficking Considerations in the Development of Natural Ligand-Drug Molecular Conjugates for Cancer

Overexpressed receptors, characteristic of many cancers, have been targeted by various researchers to achieve a more specific treatment for cancer. A common approach is to use the natural ligand for the overexpressed receptor as a cancer-targeting agent which can deliver a chemically or genetically conjugated toxic molecule. However, it has been found that the therapeutic efficacy of such ligand-drug molecular conjugates can be limited, since they naturally follow the intracellular trafficking pathways of the endogenous ligands. Therefore, a thorough understanding of the intracellular trafficking properties of these ligands can lead to novel design criteria for engineering ligands to be more effective drug carriers. This review presents a few commonly used ligand/receptor systems where intracellular trafficking considerations can potentially improve the therapeutic efficacy of the ligand-drug molecular conjugates

Folate-Decorated Polyamidoamine Dendrimer Nanoparticles for Head and Neck Cancer Gene Therapy

Gene delivery systems have been developed on the basis of dendrimers and many other types of nanoparticle carriers, but few have been developed for head and neck squamous cell carcinomas (HNSCC). Herein, we describe the design and synthesis of fluorescently labeled, folic acid-decorated polyamidoamine (PAMAM) generation 4 (G4) dendrimer conjugates for HNSCC-targeted gene delivery. This delivery system comprises a dendrimer as the carrier that is conjugated with folic acid (FA) as HNSCC targeting moiety and imaging agents fluorescein isothiocyanate (FITC) or IRDye 800CW (NIR) for in vitro trafficking or bioimaging, respectively. By complexing with plasmid or siRNA, G4-FA/plasmid (or siRNA) significantly enhances gene transfection or knockdown efficiency in HNSCC cells. In a mouse xenograft model of HNSCC, this versatile G4-FA vector shows high biocompatibility, tumor targeting, high uptake, and sustained retention, making it a suitable platform for HNSCC gene therapy