Gene Therapy for Advanced Melanoma: Selective Targeting and Therapeutic Nucleic Acids
Advantages and limitations in nucleic acid nanosystems delivery. Particular advantages of nucleic acid therapies are (1) the ability to include tissue specific targeting (or transcriptional targeting) and (2) the possibility to systemically deliver genes encoding for proteins with toxic properties. Moreover, as macromolecules, nucleic acids can overcome resistance mechanisms such as that supported by p-glycoprotein. However, nucleic acids are vulnerable in blood circulation, and hence they must be protected against enzyme degradation and condensed in the form of polyplexes. Physiological barriers, such as reticulo-endothelial system, still present a threat for nanosystems, and these must be armed against possible interactions with blood cells that can result in opsonization or undesired blood vessel adhesion. Decoration of nanocarriers with PEG or HPMA can provide shielding effect, while decoration with ligands that can bind receptors overexpressed in tumors can assist in cellular targeting and internalization. TNF: tumor necrosis factor; DTA: Diphteria toxin A; HPMA: N-(2-hydroxypropyl)methacrylamide; PEG: polyethylene glycol; HES: hydroxyethyl starch.