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Eur J Pharm Biopharm. 2019 Jun 17. pii: S0939-6411(19)30487-4. doi: 10.1016/j.ejpb.2019.06.013. [Epub ahead of print]

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

Author information

1
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
2
Institut Galien Paris-Sud, UMR 8612, CNRS, Université Paris-Sud, Université Paris-Saclay, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry cedex, France.
3
Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
4
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland. Electronic address: jleroux@ethz.ch.

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 gene-based 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 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.

KEYWORDS:

Nanoparticles; bisphosphonates; calcium phosphate; gene delivery; pH-sensitive; transfection

PMID:
31220571
DOI:
10.1016/j.ejpb.2019.06.013

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