Abstract
Despite advancements in the development of high generation cationic-dendrimer systems for delivery of nucleic acid-based therapeutics, commercially available chemical agents suffer from major drawbacks such as cytotoxicity while being laborious and costly to synthesize. To overcome the aforementioned limitations, low-generation cationic peptide asymmetric dendrimers with side arm lipid (cholic and decanoic acid) conjugation were designed, synthesized and systematically screened for their ability to self-assemble into micelles using dynamic light scattering. Cytotoxicity profiling revealed that our entire asymmetric peptide dendrimer library when trialled alone, or as asymmetric dendrimer micelle-nucleic acid complexes, were non-cytotoxic across a broad concentration range. Further, the delivery efficiency of asymmetric peptide dendrimers in H-4-II-E (rat hepatoma), H2K (mdx mouse myoblast), and DAOY (human medulloblastoma) cells demonstrated that cholic acid-conjugated asymmetric dendrimers possess far superior delivery efficiency when compared to the commercial standards, Lipofectamine 2000 or Lipofectin®.
Highlights
Dendrimers by virtue of their structure possess flexible surface functionality, which influences their capacity to complex and/or conjugate therapeutic agents, making them attractive as carriers for drugs/genes[1]
High generation spherical dendrimers have been the center of attention, they are invariably cytotoxic due to their high charge, and are rapidly cleared, which limits their applicability in vivo[3,4]
The focus of this research was to address each of these shortfalls, which has led to the development of biocompatible, low generation, asymmetric peptide dendrimers prepared by solid phase peptide synthesis (SPPS)[6], which serve as promising substitutes to commercially available spherical dendrimers
Summary
Dendrimers by virtue of their structure possess flexible surface functionality, which influences their capacity to complex and/or conjugate therapeutic agents, making them attractive as carriers for drugs/genes[1]. Lipids can serve as targeting ligands enhancing cell-specific recognition, binding and cargo internalization[19,20] Such hybrid systems are purported to promote self-assembly into secondary structures, such as micelles (Fig. 1), which provide added protection to therapeutics, such as nucleic acids from the abundance of exo- and endonucleases[21]. Keeping the aforementioned features firmly in mind, our goal was to synthesize appropriately functionalized low-generation asymmetric peptide dendrimers with various lipid scaffolds that would serve to enhance targeting, cell membrane delivery and partitioning, and lastly facilitate transfection of the nucleic acid cargo. To enhance nucleic acid delivery in vitro a subset of asymmetric dendrimers were prepared with side arm cholic acid or decanoic acid conjugation
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