Development and MPI tracking of novel hypoxia-targeted theranostic exosomes

Kyung Oh Jung; Hunho Jo; Jung Ho Yu; Sanjiv Sam Gambhir; Guillem Pratx

doi:10.1016/j.biomaterials.2018.05.048

Development and MPI tracking of novel hypoxia-targeted theranostic exosomes

Biomaterials. 2018 Sep:177:139-148. doi: 10.1016/j.biomaterials.2018.05.048. Epub 2018 May 29.

Authors

Kyung Oh Jung¹, Hunho Jo², Jung Ho Yu³, Sanjiv Sam Gambhir³, Guillem Pratx⁴

Affiliations

¹ Department of Radiation Oncology, Division of Medical Physics, Stanford University School of Medicine, Stanford University, Stanford, CA, USA; Molecular Imaging Program at Stanford (MIPS), School of Medicine, Stanford University, Stanford, CA, USA. Electronic address: blpg86@stanford.edu.
² Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA.
³ Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA; Molecular Imaging Program at Stanford (MIPS), School of Medicine, Stanford University, Stanford, CA, USA.
⁴ Department of Radiation Oncology, Division of Medical Physics, Stanford University School of Medicine, Stanford University, Stanford, CA, USA; Molecular Imaging Program at Stanford (MIPS), School of Medicine, Stanford University, Stanford, CA, USA. Electronic address: pratx@stanford.edu.

Abstract

Treating the hypoxic region of the tumor remains a significant challenge. The goals of this study are to develop an exosome platform that can target regions of tumor hypoxia and that can be monitored in vivo using magnetic particle imaging (MPI). Four types of exosomes (generated under hypoxic or normoxic conditions, and with or without exposure to X-ray radiation) were isolated from MDA-MB-231 human breast cancer cells. Exosomes were labeled by DiO, a fluorescent lipophilic tracer, to quantify their uptake by hypoxic cancer cells. Subsequently, the exosomes were modified to carry SPIO (superparamagnetic iron oxide) nanoparticles and Olaparib (PARP inhibitor). FACS and fluorescence microscopy showed that hypoxic cells preferentially take up exosomes released by hypoxic cells, compared with other exosome formulations. In addition, the distribution of SPIO-labeled exosomes was successively imaged in vivo using MPI. Finally, the therapeutic efficacy of Olaparib-loaded exosomes was demonstrated by increased apoptosis and slower tumor growth in vivo. Our novel theranostic platform could be used as an effective strategy to monitor exosomes in vivo and deliver therapeutics to hypoxic tumors.

Keywords: Cancer; Drug delivery; Exosomes; Hypoxia; Magnetic particle imaging (MPI).

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Breast Neoplasms / diagnostic imaging*
Breast Neoplasms / therapy*
Cell Line, Tumor
Drug Carriers / chemistry*
Drug Delivery Systems
Exosomes / chemistry*
Female
Flow Cytometry / methods
Fluorescent Dyes / chemistry
Humans
Magnetics / methods
Magnetite Nanoparticles / chemistry
Mice, Nude
Microscopy, Fluorescence / methods
Phthalazines / administration & dosage*
Phthalazines / therapeutic use
Piperazines / administration & dosage*
Piperazines / therapeutic use
Theranostic Nanomedicine / methods*
Tumor Hypoxia / drug effects

Substances

Antineoplastic Agents
Drug Carriers
Fluorescent Dyes
Magnetite Nanoparticles
Phthalazines
Piperazines
olaparib

Grants and funding

R01 CA186275/CA/NCI NIH HHS/United States