ssDNA nanotubes for selective targeting of glioblastoma and delivery of doxorubicin for enhanced survival

Michael A Harris; Huihui Kuang; Zachary Schneiderman; Maple L Shiao; Andrew T Crane; Matthew R Chrostek; Alexandru-Flaviu Tăbăran; Thomas Pengo; Kevin Liaw; Beibei Xu; Lucy Lin; Clark C Chen; M Gerard O'Sullivan; Rangaramanujam M Kannan; Walter C Low; Efrosini Kokkoli

doi:10.1126/sciadv.abl5872

ssDNA nanotubes for selective targeting of glioblastoma and delivery of doxorubicin for enhanced survival

Sci Adv. 2021 Dec 3;7(49):eabl5872. doi: 10.1126/sciadv.abl5872. Epub 2021 Dec 1.

Authors

Michael A Harris¹, Huihui Kuang², Zachary Schneiderman^{2

3}, Maple L Shiao⁴, Andrew T Crane⁴, Matthew R Chrostek⁴, Alexandru-Flaviu Tăbăran⁵, Thomas Pengo⁶, Kevin Liaw^{3

7}, Beibei Xu⁴, Lucy Lin^{2

3}, Clark C Chen⁴, M Gerard O'Sullivan⁵, Rangaramanujam M Kannan^{3

7}, Walter C Low⁴, Efrosini Kokkoli^{2

3}

Affiliations

¹ Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455, USA.
² Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
³ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
⁴ Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
⁵ Comparative Pathology Shared Resource, Masonic Cancer Center, University of Minnesota, Saint Paul, MN 55108, USA.
⁶ University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, MN 55455, USA.
⁷ Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Abstract

Effective treatment of glioblastoma remains a daunting challenge. One of the major hurdles in the development of therapeutics is their inability to cross the blood-brain tumor barrier (BBTB). Local delivery is an alternative approach that can still suffer from toxicity in the absence of target selectivity. Here, we show that nanotubes formed from self-assembly of ssDNA-amphiphiles are stable in serum and nucleases. After bilateral brain injections, nanotubes show preferential retention by tumors compared to normal brain and are taken up by glioblastoma cells through scavenger receptor binding and macropinocytosis. After intravenous injection, they cross the BBTB and internalize in glioblastoma cells. In a minimal residual disease model, local delivery of doxorubicin showed signs of toxicity in the spleen and liver. In contrast, delivery of doxorubicin by the nanotubes resulted in no systemic toxicity and enhanced mouse survival. Our results demonstrate that ssDNA nanotubes are a promising drug delivery vehicle to glioblastoma.