Editors' ChoiceCancer Nanotechnology

Baited nanotraps for safer chemotherapy

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Science Translational Medicine  06 Jun 2018:
Vol. 10, Issue 444, eaau0465
DOI: 10.1126/scitranslmed.aau0465

Abstract

Gold nanocage-oligonucleotide composites sequester cytoplasmic doxorubicin to protect noncancerous liver cells from chemotherapy-induced cytotoxicity.

Chemotherapy regimens used to treat cancer are often themselves life-threatening because of severe toxicity to noncancerous tissues. Many tumor-homing modifications have been designed to overcome the nonspecific nature of these medicines. However, recent work by Zhao et al. uses a different tactic to prevent off-target cytotoxicity: baiting chemotherapy drugs into cleverly designed intracellular nanotraps.

Chemotherapy drugs such as doxorubicin (DOX) inhibit cancer cell division by binding to DNA. In previous work, DOX’s high affinity for DNA has been exploited using GC-rich oligonucleotides (ODNs) that scavenge DOX away from healthy cells. The use of ODNs in vivo, however, is hampered by their susceptibility to rapid degradation by nucleases. To overcome this, the group shielded thiolated-ODNs by conjugating them to gold nanocages. In vitro, these Au-ODN composite “nanotraps” resisted degradation by DNase I, spontaneously implanted themselves into the cytoplasm of L02 normal human liver cells, inhibited the translocation of DOX into nuclei, and prevented DOX-induced cytotoxicity. In mice bearing HeLa tumors, systemically injected Au-ODNs concentrated in the liver and prevented DOX-induced weight loss—a common measure of systemic chemotoxicity—without significantly inhibiting the antitumor effectiveness of DOX over 24 days. The selective action of these nanocomposites is likely related to their preferential distribution to the liver, which resulted in a 5.5-fold greater concentration of cytoplasmic Au-ODNs in healthy hepatocytes versus tumor cells.

The fate of bound “prey” molecules captured by the nanotrap strategy is currently unclear. More development likely needs to be done before cytoplasmic nanotraps are safe and effective for reducing the toxicity of chemotherapy regimens that can last up to 12 months, since methods of eliminating loaded nanotraps or metabolizing captured drugs into nontoxic products are currently lacking. Another challenge is to design nanocomposites that more effectively partition away from tumors and into the numerous healthy organs adversely affected by chemotherapy. If these issues can be addressed, we may be on the path to bioengineered “supercells” capable of programmable resilience to the drugs and toxins of the future.

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