Abstract
The sequence-dependent cellular uptake of spherical nucleic acid nanoparticle conjugates (SNAs) is investigated. This process occurs by interaction with class A scavenger receptors (SR-A) and caveolae-mediated endocytosis. It is known that linear poly(guanine) (poly G) is a natural ligand for SR-A, and it has been proposed that interaction of poly G with SR-A is dependent on the formation of G-quadruplexes. Since G-rich oligonucleotides are known to interact strongly with SR-A, it is hypothesized that SNAs with higher G contents would be able to enter cells in larger amounts than SNAs composed of other nucleotides, and as such, cellular internalization of SNAs is measured as a function of constituent oligonucleotide sequence. Indeed, SNAs with enriched G content show the highest cellular uptake. Using this hypothesis, a small molecule (camptothecin) is chemically conjugated with SNAs to create drug-SNA conjugates and it is observed that poly G SNAs deliver the most camptothecin to cells and have the highest cytotoxicity in cancer cells. Our data elucidate important design considerations for enhancing the intracellular delivery of spherical nucleic acids.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4173-4182 |
| Number of pages | 10 |
| Journal | Small |
| Volume | 11 |
| Issue number | 33 |
| DOIs | |
| State | Published - Sep 1 2015 |
Funding
S.P.N. and C.H.J.C contributed equally to this work. This material is based upon work supported by the following awards: Center for Cancer Nanotechnology Excellence (CCNE) initiative of the National Institutes of Health (NIH) under Award No. U54 CA151880, Air Force Office of Scientific Research (AFOSR) under Award No. FA9550‐11‐1‐0275, Department of Defense National Security Science and Engineering Faculty Fellowship (NSSEFF) Award N00014‐15‐1‐0043. C.H.J.C. acknowledges a postdoctoral research fellowship from The Croucher Foundation. S.P.N. and E.A. acknowledge the DoD, Air Force Office of Scientific Research, National Defense Science and Engineering Graduate (NDSEG) Fellowship, 32 CFR 168a. L.H. acknowledges a Howard Hughes Medical Institute (HHMI) International Student Research Fellowship. O.J.G.M.G. acknowledges the Institute for Complex Molecular Systems, Eindhoven, The Netherlands. ICP‐MS measurements and confocal microscopy were performed at the Quantitative Bioelemental Imaging Center (QBIC) at Northwestern University. TEM imaging was performed both at the Biological Imaging Facility (BIF) and at the Electron Probe Instrumentation Center of the NU Atomic and Nanoscale Characterization Experimental Center (NUANCE) at Northwestern University. Circular dichroism spectroscopy was performed at the Keck Biophysics Facility at Northwestern University. The authors thank C. Wilke from the BIF for assistance in ultramicrotomy. , , ,
Keywords
- cellular uptake
- guanine
- nanoparticles
- sequence-specific
- spherical nucleic acids
ASJC Scopus subject areas
- General Chemistry
- Engineering (miscellaneous)
- Biotechnology
- General Materials Science
- Biomaterials
