TY - JOUR
T1 - Chitosan/Hyaluronic Acid Nanoparticles: Rational Design Revisited for RNA Delivery
AU - Lallana-Ozores, Enrique
AU - Ríos De La Rosa, Julio Manuel
AU - Tirella, Annalisa
AU - Pelliccia, Maria
AU - Gennari, Arianna
AU - Stratford, Ian
AU - Puri, Sanyogitta
AU - Ashford, Marianne
AU - Tirelli, Nicola
PY - 2017/7/3
Y1 - 2017/7/3
N2 - Chitosan/hyaluronic acid (HA) nanoparticles can be used to deliver an RNA/DNA cargo to cells overexpressing HA receptors such as CD44. For these systems, unequivocal links have not been established yet between chitosan macromolecular (molecular weight; degree of deacetylation, i.e., charge density) and nanoparticle variables (complexation strength, i.e., stability; nucleic acid protection; internalization rate) on one hand, and transfection efficiency on the other hand. Here, we have focused on the role of avidity on transfection efficiency in the CD44-expressing HCT-116 as a cellular model; we have employed two differently sized payloads (a large luciferase-encoding mRNA and a much smaller anti-Luc siRNA), and a small library of chitosans (variable molecular weight and degree of deactylation). The RNA avidity for chitosan showed—as expected—an inverse relationship: higher avidity–higher polyplex stability–lower transfection efficiency. The avidity of chitosan for RNA appears to lead to opposite effects: higher avidity–higher polyplex stability but also higher transfection efficiency. Surprisingly, the best transfecting particles were those with the lowest propensity for RNA release, although this might be a misleading relationship: for example, the same macromolecular parameters that increase avidity can also boost chitosan’s endosomolytic activity, with a strong enhancement in transfection. The performance of these nonviral vectors appears therefore difficult to predict simply on the basis of carrier- or payload-related variables, and a more holistic consideration of the journey of the nanoparticle, from cell uptake to cytosolic bioavailability of payload, is needed. It is also noteworthy that the nanoparticles used in this study showed optimal performance under slightly acidic conditions (pH 6.4), which is promising for applications in a tumoral extracellular environment. It is also worth pointing out that under these conditions we have for the first time successfully delivered mRNA with chitosan/HA nanoparticles.
AB - Chitosan/hyaluronic acid (HA) nanoparticles can be used to deliver an RNA/DNA cargo to cells overexpressing HA receptors such as CD44. For these systems, unequivocal links have not been established yet between chitosan macromolecular (molecular weight; degree of deacetylation, i.e., charge density) and nanoparticle variables (complexation strength, i.e., stability; nucleic acid protection; internalization rate) on one hand, and transfection efficiency on the other hand. Here, we have focused on the role of avidity on transfection efficiency in the CD44-expressing HCT-116 as a cellular model; we have employed two differently sized payloads (a large luciferase-encoding mRNA and a much smaller anti-Luc siRNA), and a small library of chitosans (variable molecular weight and degree of deactylation). The RNA avidity for chitosan showed—as expected—an inverse relationship: higher avidity–higher polyplex stability–lower transfection efficiency. The avidity of chitosan for RNA appears to lead to opposite effects: higher avidity–higher polyplex stability but also higher transfection efficiency. Surprisingly, the best transfecting particles were those with the lowest propensity for RNA release, although this might be a misleading relationship: for example, the same macromolecular parameters that increase avidity can also boost chitosan’s endosomolytic activity, with a strong enhancement in transfection. The performance of these nonviral vectors appears therefore difficult to predict simply on the basis of carrier- or payload-related variables, and a more holistic consideration of the journey of the nanoparticle, from cell uptake to cytosolic bioavailability of payload, is needed. It is also noteworthy that the nanoparticles used in this study showed optimal performance under slightly acidic conditions (pH 6.4), which is promising for applications in a tumoral extracellular environment. It is also worth pointing out that under these conditions we have for the first time successfully delivered mRNA with chitosan/HA nanoparticles.
KW - hyaluronan
KW - RNA
KW - chitosan
KW - targeting
KW - gene delivery
KW - HCT-116
U2 - 10.1021/acs.molpharmaceut.7b00320
DO - 10.1021/acs.molpharmaceut.7b00320
M3 - Article
SN - 1543-8384
VL - 14
SP - 2422
EP - 2436
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 7
ER -