(119g) A Novel Nano-Carrier Engineered for High Payload and Efficient Delivery of Daunomycin

Byrne, M. E., Auburn University
Sundaram, P., Auburn University
Wower, J., Auburn University
Lipke, E. A., Auburn University
Pradhan, S., Auburn University
Kurniawan, H., Auburn University

Controlled delivery of therapeutics to target tissues constitutes a great challenge of modern medicine, especially in the field of cancer treatment. By exploiting the canonical mechanism of action of the anticancer drug daunomycin we have developed a bio-hybrid nano-carrier for controlled and extended release of daunomycin. In this nano-carrier, daunomycin is bound to DNA aptamers conjugated to 15 nm gold nanoparticle (AuNps) via single-stranded DNA anchors. Our results are the first to demonstrate that drug release can be exquisitely controlled and modulated by adjusting the strength of the molecular interactions between daunomycin and its aptamers.

We investigated the factors affecting the loading of DNA on AuNps. A maximum loading of 108 strands of anchor DNAs per AuNp was observed with 0.4M NaCl and 4µM DNA. On binding daunomycin to the aptamer-anchor DNA complex conjugated to AuNps we demonstrated a very high payload of 1157 ± 18 daunomycin molecules per AuNp. Such a large drug payload per AuNp has never been reported before. The in-vitro release of daunomycin at body temperature demonstrated controlled release of drug from the nano-carrier for an extended period of time. After 6 days of release only about 55% of the bound daunomycin was released from the nano-carrier which implies that the release can be extended much further. With this high drug payload and an ability to release it slowly for an extended period of time this nano-carrier can bring a revolution to the cancer treatments. To test the efficiency of the nano-carrier in delivering the drug to cells, we studied the cellular uptake of the nano-carrier and cell viability in MCF7 breast cancer cells. The nano-carrier displayed excellent cellular uptake, and the cell death was observed to be proportional to the concentration of the nano-carrier. At any tested concentration, cell death by the nano-carrier was significantly higher compared to the cell death by the corresponding concentration of free daunomycin. After 4 hours of incubation, the cell death by 100 nM nano-carriers was twice as much as cell death by same concentration of free daunomycin, proving that it is much more efficient in killing cancer cells compared to that of the free drug. Furthermore, to highlight the versatility of the nano-carrier, we modified the aptamers on the particles demonstrating excellent control over drug release using affinity modulation. One and two point mutants of the DNA aptamer displayed different drug binding affinity and thereby varied drug release profile. After 2 hrs of drug release, the strongest aptamer released just 20% of bound drug while the weakest released about 70%. Thus by having various combinations of two aptamers (weak and strong) on AuNps we were able to obtain any desired drug release profile. Such high variation in drug release with just one point mutation of the DNA is the ultimate control that could be achieve in a nano-scale system.

This nano-carrier with a very high payload and efficient drug delivery when equipped with molecules that allow for precise targeting of diseased cells and tissues will provide medical doctors with a powerful, yet flexible, tool for fighting cancer. Being versatile to be modified for any drug it is expected to impact a number of treatment strategies.