Although it may appear that cells rely almost entirely on proteins to maintain their function, this is far from the case: DNA is not merely a repository of genetic information, nor is RNA a simple vehicle for transforming that information into the all-important proteins. Nucleic acids play direct and important roles in regulating cellular activity, and drugs based on their structure and function are potent agents for the treatment of a wide variety of diseases. Such drugs have one fatal flaw, however: Nucleic acids are not built to last outside the cell, and when administered into the bloodstream, nucleases and other hydrolytic enzymes make quick work of them. Successful application of nucleic acid-based drugs therefore requires a means of protecting them in the blood and delivering them exactly where they may work their magic – and a peptide amphiphile-based system, developed by the groups of Drs. Ayşe Begüm Tekinay and Mustafa Özgür Güler, now provides the capability to do both.
The delivery vesicle uses a combination of cell-penetrating polyarginine and membrane-targeting KRSR sequences – the highly cationic nature of arginine allows it to pass through the negatively-charged cell membrane, while the proteoglycan-binding KRSR sequence enhances the affinity of the peptide complex to cells. The positive charge of polyarginine is in fact a mixed blessing, as the same mechanism that allows it to penetrate cells also makes it highly cytotoxic – but this toxicity is mitigated when polyarginine is tempered with KRSR-PA, and the combination of both peptide molecules creates a highly effective delivery system that is minimally toxic to non-target cells. When loaded with an antisense oligonucleotide against a breast cancer gene, peptide vesicles were able to decrease the expression of their target with an efficiency comparable to lipofectamine, a cationic liposome system that is commercially provided as a transfection-enhancing agent.
Although breast cancer was the subject of the study, the authors believe that the system can be extended to the treatment of other diseases: Zahide Didem Mumcuoğlu, the lead author of the study, highlights the clinical failures faced by nucleic acid therapeutics and suggests that “[The present work is] only a small step for the development of effective oligonucleotide-based drugs”.
The research has been published in the journal ACS Molecular Pharmaceutics and can be accessed at the following address: