Achieving successful delivery of oligonucleotides--From physico-chemical characterization to in vivo evaluation.
RNA interference is one of the most promising fields in modern medicine to treat several diseases, ranging from cancer to cardiac diseases, passing through viral infections and metabolic pathologies. Since the discovery of the potential therapeutic properties of non-self oligonucleotides, it was clear that it is important to develop delivery systems that are able to increase plasma stability and bestow membrane-crossing abilities to the oligonucleotides in order to reach their cytoplasmic targets. Polymer therapeutics, among other systems, are widely investigated as delivery systems for therapeutic agents, such as oligonucleotides. Physico-chemical characterization of the supramolecular polyplexes obtained upon charge interaction or covalent conjugation between the polymeric carrier and the oligonucleotides is critical. Appropriate characterization is fundamental in order to predict and understand the in vivo silencing efficacy and to avoid undesired side effects and toxicity profile. Shedding light on the physico-chemical and in vitro requirements of a polyplex leads to an efficient in vivo delivery system for RNAi therapeutics. In this review, we will present the most common techniques for characterization of obtained polymer/oligonucleotide polyplexes and an up-to-date state of the art in vivo preclinical and clinical studies. This is the first review to deal with the difficulties in appropriate characterization of small interfering RNA (siRNA) or microRNA (miRNA) polyplexes and conjugates which limit the clinical translation of this promising technology.
Department of Physiology and Pharmacology, Sackler School of Medicine, Room 607, Tel Aviv University, Tel Aviv 69978, Israel.
Anna
A
Scomparin
Department of Physiology and Pharmacology, Sackler School of Medicine, Room 607, Tel Aviv University, Tel Aviv 69978, Israel.
Dina
D
Polyak
Department of Physiology and Pharmacology, Sackler School of Medicine, Room 607, Tel Aviv University, Tel Aviv 69978, Israel.
Adva
A
Krivitsky
Department of Physiology and Pharmacology, Sackler School of Medicine, Room 607, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: ronitsf@post.tau.ac.il.
Ronit
R
Satchi-Fainaro
D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D006505:Hepatitis / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000008:administration & dosage; D008853:Microscopy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000235:genetics; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000737:chemistry* / Q000494:pharmacology; D034622:RNA Interference; D055672:Static Electricity
D050091:Dendrimers; D035683:MicroRNAs; D009841:Oligonucleotides; D000111:Acetylcysteine
Delivery systems; Nanoparticles; Polymer therapeutics; RNA interference