bm-2014-001229_0007The wealth of information being obtained from genomic, proteomic, and glycomic research is allowing researchers to unravel the intricate genetic and epigenetic mechanisms associated with human health and disease. Ubiquitous tools such as miRNA (microRNA), siRNA (small interfering RNA), oligodeoxynucleotide (ODN) transcription factor decoys, plasmid DNA, aptamers, genetic vaccines, and many other polynucleotide forms are transforming the methods of regulating gene expression and epigenetic mechanisms for understanding biological processes, disease pathways, and are undergoing extensive research and development as novel therapeutics.

Nucleic acids have exceptional affinity and specificity for their intracellular targets; yet, many complex factors dictate the accuracy, reproducibility, and relevance of utilizing polynucleotides as novel therapeutics. Delivery systems are needed to compact nucleic acids into nanostructures, termed polyplexes, that can enter cells, protect nucleic acids from enzymatic damage, and provide the possibility of targeting the delivery to specific tissue types and sites within the cell.

We strive to creatively design innovative polymeric vehicles for delivering gene regulatory nucleic acids and develop new experimental methods to gain a fundamental understanding of their interactions and pathways taken within living systems in a spatial and temporal manner. We have developed several novel carbohydrate-containing polymers that have shown outstanding affinity to form polyplexes and facilitate intracellular nucleic acid delivery efficiency with low toxicity. These systems are being carefully investigated to build fundamental structure-property relationships describing how polymers complex with nucleic acids and interact with its biological environment. Ultimately, we are concerned with the design, synthesis, and biological characterization, as well as with the examination of the mechanism of delivery of polymers.

Featured Projects

Yogesh TOC Interpolyelectrolyte complexes (polyplexes) prepared between cationic glycopolymers and nucleic acids play an important role in gene delivery. The goal of this project is to target the delivery of nucleic acids to specific cells and tissues by tailoring polymer properties. We have demonstrated this ability by specifically targeting hepatocytes in the liver, an ideal organ due to its ability to manufacture and secrete proteins into the blood, with N-acetyl-d-galactosamine (GalNAc)-based polyplexes. Reference: Y. Dhande, B. Wagh, B. Hall, D. Sprouse, P. Hackett, T. M. Reineke "N-Acetylgalactosamine Block-co-Polycations Form Stable Polyplexes with Plasmids and Promote Liver-Targeted Delivery", Biomacromolecules 2016, 17, 830–840.
Yaming_TOCUnderstanding the composition and structure of interpolyelectrolyte complexes is vital to the development of new therapeutics. Therefore, we have recently investigated the complexation of AB and ABC polymeric micelles with plasmid DNA to explore how the outer nonionic corona length affects various properties of these complexes. In this work, amphiphilic block polymers were prepared with or without an outer PEG block at various molecular weights. Micelleplex properties such as size, composition, and structure were found to correlate with the molecular weight of the PEG block. This work has provided a deep understanding how the tuning of specific parameters can influence the properties of micelleplexes. Reference: Y. Jiang, T. P. Lodge, T. M. Reineke "Packaging pDNA by Polymeric ABC Micelles Simultaneously Achieves Colloidal Stability and Structural Control", J. Am. Chem. Soc. 2018, 140, 11101–11111.