Lipidoid nanoparticles (LNPs) are the delivery platform in Onpattro, the first FDA-approved siRNA drug. LNPs are also the carriers in the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines. While these applications have demonstrated that LNPs effectively deliver nucleic acids to hepatic and muscle cells, it is unclear if LNPs could be used for delivery of siRNA to neural cells, which are notoriously challenging delivery targets. Therefore, the purpose of this study was to determine if LNPs could efficiently deliver siRNA to neurons. Because of their potential delivery utility in either applications for the central nervous system and the peripheral nervous system, we used both cortical neurons and sensory neurons. We prepared siRNA-LNPs using C12-200, a benchmark ionizable cationic lipidoid along with helper lipids. We demonstrated using dynamic light scattering that the inclusion of both siRNA and PEG-lipid provided a stabilizing effect to the LNP particle diameters and polydispersity indices by minimizing aggregation. We found that siRNA-LNPs were safely tolerated by primary dorsal root ganglion neurons. Flow cytometry analysis revealed that Cy5 siRNA delivered via LNPs into rat primary cortical neurons showed uptake levels similar to Lipofectamine RNAiMAX—the gold standard commercial transfection agent. However, LNPs demonstrated a superior safety profile, whereas the Lipofectamine-mediated uptake was concomitant with significant toxicity. Fluorescence microscopy demonstrated a time-dependent increase in the uptake of LNP-delivered Cy5 siRNA in a human cortical neuron cell line. Overall, our results suggest that LNPs are a viable platform that can be optimized for delivery of therapeutic siRNAs to neural cells. Supplementary Information The online version contains supplementary material available at 10.1208/s12248-021-00653-2.

No abstract

Lipidoid nanoparticles (LNPs) are the delivery platform in Onpattro, the first FDA-approved siRNA drug. LNPs are also the carriers in the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines. While these applications have demonstrated that LNPs effectively deliver nucleic acids to hepatic and muscle cells, it is unclear if LNPs could be used for delivery of siRNA to neural cells, which are notoriously challenging delivery targets. Therefore, the purpose of this study was to determine if LNPs could efficiently deliver siRNA to neurons. Because of their potential utility in either applications in the central nervous system and the peripheral nervous system, we used both cortical neurons and sensory neurons. We prepared siRNA-LNPs using C12-200, a benchmark ionizable cationic lipidoid along with helper lipids. We demonstrated using dynamic light scattering that the inclusion of both siRNA and PEG-lipid provided a stabilizing effect to the LNP particle diameters and polydispersity indices by minimizing aggregation. We found that siRNA-LNPs were safely tolerated by primary dorsal root ganglion neurons. Flow cytometry analysis revealed that Cy5 siRNA delivered via LNPs into rat primary cortical neurons showed uptake levels similar to Lipofectamine RNAiMAX, the gold standard commercial transfection agent. However, LNPs demonstrated a superior safety profile whereas the Lipofectamine-mediated uptake was concomitant with significant toxicity. Fluorescence microscopy demonstrated a time-dependent increase in the uptake of LNP-delivered Cy5 siRNA in a human cortical neuron cell line. Overall, our results suggest that LNPs are a viable platform that can be optimized for delivery of therapeutic siRNAs to neural cells.

No abstract

The formulation and delivery of highly hydrophobic drugs in an optimized dosage form is challenging to formulation scientists. Posaconazole has shown promising action in case studies against fungal keratitis. Biological macromolecules like gellan gum would aid in enhancing the availability of such drugs by increasing the contact time of the formulation. Herein, we propose a transmucosal ocular delivery system of Posaconazole by developing a gellan gum–based in situ gelling nanosuspension. The HPLC method for Posaconazole was developed and validated as per ICH guidelines. The nanosuspension was prepared by microfluidization and optimized by Quality by Design. The gellan gum concentration selected was 0.4% w/v based on the viscosity and mucoadhesion measurements. A greater zone of inhibition of ~ 15 mm was observed for the prepared nanosuspension as compared to ~ 11 mm for the marketed itraconazole nanosuspension. A potential irritancy score of 0.85, considered to be non-irritant, was observed for the developed nanosuspension. Higher drug release of ~ 35% was noted for the nanosuspension compared to about ~ 10% for the coarse suspension. Ex vivo corneal retention studies on excised goat cornea demonstrated ~ 70% drug retention in the tissue. Graphical abstract Graphical abstract depicting the central hypothesis of the work. Supplementary information The online version contains supplementary material available at 10.1007/s13346-022-01155-0.