Microenvironment-triggered multimodal precision diagnostics

Liangliang Hao; Nazanin Rohani; Renee T Zhao; Emilia M Pulver; Howard Mak; Olivia J Kelada; Henry Ko; Heather E Fleming; Frank B Gertler; Sangeeta N Bhatia

doi:10.1038/s41563-021-01042-y

Microenvironment-triggered multimodal precision diagnostics

Nat Mater. 2021 Oct;20(10):1440-1448. doi: 10.1038/s41563-021-01042-y. Epub 2021 Jul 15.

Authors

Liangliang Hao^{1

2}, Nazanin Rohani¹, Renee T Zhao², Emilia M Pulver², Howard Mak¹, Olivia J Kelada³, Henry Ko^{1

2}, Heather E Fleming^{1

4}, Frank B Gertler^{1

5}, Sangeeta N Bhatia^{6

7

8

9

10

11

12}

Affiliations

¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Preclinical Imaging, PerkinElmer, Hopkinton, MA, USA.
⁴ Howard Hughes Medical Institute, Cambridge, MA, USA.
⁵ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. sbhatia@mit.edu.
⁷ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. sbhatia@mit.edu.
⁸ Howard Hughes Medical Institute, Cambridge, MA, USA. sbhatia@mit.edu.
⁹ Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA. sbhatia@mit.edu.
¹⁰ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. sbhatia@mit.edu.
¹¹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. sbhatia@mit.edu.
¹² Ludwig Center at Massachusetts Institute of Technology's Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. sbhatia@mit.edu.

PMID: 34267368
DOI: 10.1038/s41563-021-01042-y

Abstract

Therapeutic outcomes in oncology may be aided by precision diagnostics that offer early detection, localization and the opportunity to monitor response to therapy. Here, we report a multimodal nanosensor engineered to target tumours through acidosis, respond to proteases in the microenvironment to release urinary reporters and (optionally) carry positron emission tomography probes to enable localization of primary and metastatic cancers in mouse models of colorectal cancer. We present a paradigm wherein this multimodal sensor can be employed longitudinally to assess burden of disease non-invasively, including tumour progression and response to chemotherapy. Specifically, we showed that acidosis-mediated tumour insertion enhanced on-target release of matrix metalloproteinase-responsive reporters in urine. Subsequent on-demand loading of the radiotracer ⁶⁴Cu allowed pH-dependent tumour visualization, enabling enriched microenvironmental characterization when compared with the conventional metabolic tracer ¹⁸F-fluorodeoxyglucose. Through tailored target specificities, this modular platform has the capacity to be engineered as a pan-cancer test that may guide treatment decisions for numerous tumour types.

Publication types

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

MeSH terms

Acidosis / complications
Acidosis / diagnosis*
Animals
Colorectal Neoplasms / complications
Colorectal Neoplasms / diagnosis*
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / pathology
Disease Progression
Female
Fluorodeoxyglucose F18
Mice
Mice, Inbred BALB C
Multimodal Imaging*
Positron-Emission Tomography
Precision Medicine*
Tumor Microenvironment*

Substances

Fluorodeoxyglucose F18

Abstract

Publication types

MeSH terms

Substances

Grants and funding