Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance

Yongheng Wang; Yuhang Jiang; Dengshuai Wei; Priya Singh; Yingjie Yu; Teresa Lee; Lingpu Zhang; Hanna K Mandl; Alexandra S Piotrowski-Daspit; Xinyuan Chen; Fan Li; Xing Li; Yiyu Cheng; Alexander Josowitz; Fan Yang; Yao Zhao; Fuyi Wang; Zhenwen Zhao; Anita Huttner; Ranjit S Bindra; Haihua Xiao; W Mark Saltzman

doi:10.1038/s41551-021-00728-7

Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance

Nat Biomed Eng. 2021 Sep;5(9):1048-1058. doi: 10.1038/s41551-021-00728-7. Epub 2021 May 27.

Authors

Yongheng Wang^{1

2}, Yuhang Jiang², Dengshuai Wei^{1

3}, Priya Singh², Yingjie Yu⁴, Teresa Lee², Lingpu Zhang⁵, Hanna K Mandl², Alexandra S Piotrowski-Daspit², Xinyuan Chen⁶, Fan Li^{6

7}, Xing Li^{3

8}, Yiyu Cheng^{8

9}, Alexander Josowitz², Fan Yang², Yao Zhao⁸, Fuyi Wang^{3

8}, Zhenwen Zhao^{3

8}, Anita Huttner¹⁰, Ranjit S Bindra^{10

11}, Haihua Xiao^{12

13}, W Mark Saltzman^{14

15

16}

Affiliations

¹ Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.
² Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
³ University of Chinese Academy of Sciences, Beijing, China.
⁴ Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
⁵ College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
⁶ Department of Statistics and Data Science, Yale University, New Haven, CT, USA.
⁷ Center for Methods in Implementation and Prevention Science, Yale University, New Haven, CT, USA.
⁸ National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.
⁹ Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, China.
¹⁰ Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
¹¹ Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.
¹² Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China. [email protected].
¹³ University of Chinese Academy of Sciences, Beijing, China. [email protected].
¹⁴ Department of Biomedical Engineering, Yale University, New Haven, CT, USA. [email protected].
¹⁵ Department of Chemical and Environmental Engineering, Yale University, New Haven, CT, USA. [email protected].
¹⁶ Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA. [email protected].

Abstract

In patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. Here we show that the convection-enhanced delivery of nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumour) and encapsulating an oxaliplatin prodrug and a cationic DNA intercalator inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human glioblastoma tumours in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signalling and metabolic pathways altered by each drug. Our findings suggest that the combination of anticancer drugs with distinct mechanisms of action with selective drug release and convection-enhanced delivery may represent a translational strategy for the treatment of TMZ-resistant gliomas.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Brain Neoplasms* / drug therapy
Cell Line, Tumor
Convection
DNA
Glioma* / drug therapy
Humans
Intercalating Agents
Mice
Nanoparticles*
Temozolomide
Xenograft Model Antitumor Assays

Substances

Intercalating Agents
DNA
Temozolomide

Abstract

Publication types

MeSH terms

Substances

Grants and funding