Dual delivery of nucleic acids and PEGylated-bisphosphonates via calcium phosphate nanoparticles

Abstract

Despite many years of research and a few success stories with gene therapeutics, efficient and safe DNA delivery remains a major bottleneck for the clinical translation of genebased therapies. Gene transfection with calcium phosphate (CaP) nanoparticles brings the advantages of low toxicity, high DNA entrapment efficiency and good endosomal escape properties. The macroscale aggregation of CaP nanoparticles can be easily prevented through surface coating with bisphosphonate conjugates. Bisphosphonates, such as alendronate, recently showed promising anticancer effects. However, their poor cellular permeability and preferential bone accumulation hamper their full application in chemotherapy. Here, we investigated the dual delivery of plasmid DNA and alendronate using CaP nanoparticles, with the goal to facilitate cellular internalization of both 2 compounds and potentially achieve a combined pharmacological effect on the same or different cell lines. A pH-sensitive poly(ethylene glycol)-alendronate conjugate was synthetized and used to formulate stable plasmid DNA-loaded CaP nanoparticles. These particles displayed good transfection efficiency in cancer cells and a strong cytotoxic effect on macrophages. The in vivo transfection efficiency, however, remained low, calling for an improvement of the system, possibly with respect to the extent of particle uptake and their physical stability.

A Ternary Synergistic eNOS Gene Delivery System Based on Calcium Ion and L-Arginine for Accelerating Angiogenesis by Maximizing NO Production

“…CaP is a promising transfection agent as it is an important component of tissues such as bones and teeth and can be progressively degraded by the acidic environment in the endo/lysosomes and release plasmid DNA (pDNA) upon completion of pDNA loading and cellular uptake. 19,20 Co-precipitation is the simplest and most classical method for the preparation of CaP/pDNA nanocomplexes, including preparation in the aqueous-phase or microemulsion. 21 There are many processes to prepare CaP/pDNA nanocomplexes.…”