NC State is seeking an industry partner to further develop and commercialize a novel anticancer drug delivery nanoclew
Self-assembled DNA nanostructures have been developed with precisely controlled size and architecture. Upon DNA’s intrinsic biocompatibility and degradability, DNA nanostructures hold tremendous promise for drug delivery. Numerous cargos including small molecule drugs, small interfering RNA (siRNA), immuno-stimulatory oligonucleotide CpG, photosensitizer and protein were successfully delivered intracellularly by DNA nanocarriers. Moreover, DNA-based carriers can be readily functionalized either by hybridizing a targeting moiety onto the nanostructure or programming a targeting aptamer into the DNA chain for targeted drug delivery. Despite these, strategies utilizing DNA scaffolds for on-demand drug delivery in a stimuli-responsive fashioninstead of passive release still remain elusive.
Researchers at NC State have developed a Herein, we describe a bio-inspired drug delivery carrier by integrating a cocoon-like DNA nano-composite with “caged worm”-deoxyribonuclease (DNAse) to achieve self-degradation for promoting drug release inside cells. The DNA structure is based on a “nanoclew” (designated as NCl), “weaved” by the rolling circle amplification, the product of which is often applied in biodetection. Multiple GC-pair sequences were integrated in the NCl for enhancing loading capacity of DOX. To facilitate self-assembly, a palindromic sequence is incorporated into the template. To enable degradation of NCl, DNAse I is encapsulated into a single-protein based nanocapsule (designated as NCa) with a positively charged thin polymeric shell, cross-linked by acid-degradable linkers using interfacial polymerization. Furthermore, to achieve a tumor-targeting delivery of DOX folic acid (FA) is conjugated to an NCl complementary DNA oligo followed by hybridization into the DNA NCl. The positively charged NCa can be embedded into the NCl via electrostatic interaction to form the DOX-loaded self-degradable NA scaffold (designated as DOX/FA-NCl/NCa). The polymeric capsule cages the activity of DNAse I under the physiological pH, which retains DOX in the NCl. When DOX/FA-NCl/NCa is internalized by the cancer cells and enters the acidic endo-lysosome, the polymeric shell of NCa degrades and sheds from DNAse I. This results in the immediate rejuvenation of DNAse I, thereby rapidly degrading NCl and subsequently releasing the encapsulated DOX for enhanced anticancer efficacy. This formulation represents a novel stimuli-responsive drug delivery sys-tem, the trigger of which is preloaded with the delivery vehicle and can be activated by cellular environment.
- Highly biocompatible
- Very high drug loading capacity
- Assembly of DNAse and DNA via electrostatic interaction
- Caged DNAse was used as a trigger
- Targets anticancer drug to cancer cells nucleus in a rapid fashion
- Easy functionalization of DNA nanoclew with targeting ligand lead
Related Patent Information
- Patent Application Filed
About the Inventors
Dr. Zhen Gu is an Assistant Professor in the Joint Department of Biomedical Engineering at North Carolina State University and the University of North Carolina-Chapel Hill. He received a B.S. in Chemistry and a M.S. in Polymer Chemistry and Physics from Nanjing University, China, and a Ph.D. in Chemical and Biomolecular Engineering from UCLA. His research focuses on exploiting novel strategies that apply stimuli-responsive systems for precisely delivering therapeutics in dose-, spatial-, and temporal-controlled fashions for therapeutics and diagnostics.