A Facile and Promising Delivery Platform for siRNA to Solid Tumors.

Over 20 years have passed since siRNA was brought to the public's attention. Silencing genes with siRNA has been used for various purposes, from creating pest-resistant plants to treating human diseases. In the last six years, several siRNA therapies have been approved by the FDA, which solely target disease-inducing proteins in the liver.

pH modification of gel mobility shift improves polyplex selection In Vivo.

Cationic polymers that bind with the plasmids to form polyplexes protect the DNA from enzymatic degradation and improve cellular and tissue uptake. Complete or near complete gel retardation of the polyplex is an important assay to determine the optimal polymer: plasmid ratio for in vitro and in vivo studies. Nevertheless, despite minimal to moderate gel retardation of histidine-lysine (HK) polyplexes formed with low peptide: plasmid DNA ratios (1:2 and 1:4; w:w), the polyplexes effectively targeted the tumor in vivo.

Delivery of mRNA with Histidine-Lysine Peptides.

Transfection with mRNA has been considered superior to that with plasmids since the mRNA can be translated to a protein in the cytosol without entering the nucleus. One disadvantage of using mRNA is its susceptibility to enzymatic biodegradability, and consequently, significant research has occurred to determine nonviral carriers that will sufficiently stabilize this nucleic acid for cellular transport. Histidine-lysine peptides (HK) are one such class of mRNA carriers, which we think serves as a model for other peptides and polymeric carrier systems.

pH-Dependent Non-Covalent Release of Chemotherapy from Carriers.

Although Warburg discovered pH discrepancies between tumor and normal tissues nearly 100 years ago, developing therapies to take advantage of this concept was relatively slow for the first 70 years. During the last 30 years, there has been an exponential increase in the use of pH-dependent strategies for both low molecular weight drugs and nanoparticles. Two frequently discussed approaches are the chemotherapy's release from pH-sensitive covalent linkages of macromolecules or from pH-dependent disruption of charged polymeric nanoparticles.

Exploring the outer limits of polyplexes.

Histidine-containing polymers show promise in their transport of nucleic acids in vitro and in vivo. In addition to the pH-buffering histidine component, the polymer often contains a protonated component at physiological pH, such as lysine. These polyplexes usually accumulate in the tumor by enhanced permeability and retention, which has proved disappointing in clinical trials.