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Development of CD133 Targeting Multi-Drug Polymer Micellar Nanoparticles for Glioblastoma - In Vitro Evaluation in Glioblastoma Stem Cells

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Abstract

Purpose

Glioblastoma (GBM) is a malignant brain tumor with a poor long-term prognosis due to recurrence from highly resistant GBM cancer stem cells (CSCs), for which the current standard of treatment with temozolomide (TMZ) alone will unlikely produce a viable cure. In addition, CSCs regenerate rapidly and overexpress methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to resistance. The objective of this research was to apply the concepts of nanotechnology to develop a multi-drug therapy, TMZ and idasanutlin (RG7388, a potent mouse double minute 2 (MDM2) antagonist), loaded in functionalized nanoparticles (NPs) that target the GBM CSC subpopulation, reduce the cell viability and provide possibility of in vivo preclinical imaging.

Methods

Polymer-micellar NPs composed of poly(styrene-b-ethylene oxide) (PS-b-PEO) and poly(lactic-co-glycolic) acid (PLGA) were developed by a double emulsion technique loading TMZ and/or RG7388. The NPs were covalently bound to a 15-nucleotide base-pair CD133 aptamer to target the CD133 antigen expressed on the surfaces of GBM CSCs. For diagnostic functionality, the NPs were labelled with radiotracer Zirconium-89 (89Zr).

Results

NPs maintained size range less than 100 nm, a low negative charge and exhibited the ability to target and kill the CSC subpopulation when TMZ and RG7388 were used in combination. The targeting function of CD133 aptamer promoted killing in GBM CSCs providing impetus for further development of targeted nanosystems for localized therapy in future in vivo models.

Conclusions

This work has provided a potential clinical application for targeting GBM CSCs with simultaneous diagnostic imaging.

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Data Availability

N/A

Abbreviations

ACN:

Acetonitrile

BBB:

Blood brain barrier

DCM:

Dichloromethane

DDR:

DNA damage response

DFOM:

Deferoxamine mesylate

EMSA:

Electrophoretic mobility shift assay

FAM:

Fluorescein amidite

GBM:

Glioblastoma multiforme

MDM2:

Mouse double minute 2

NP:

Nanoparticles

PLGA:

Poly(lactic-co-glycolic) acid

PS-b-PEO:

Poly(styrene-b-ethylene oxide)

TMZ:

Temozolomide

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to acknowledge Dr. Daniel Minner of IUPUI Integrated Nanosystems Development Institute, Dr. Anne Shanahan of IUPUI Department of Chemistry & Chemical Biology, Ms. Caroline Miller of IU School of Medicine Electron Microscopy Core, and Ms. Barbara Bailey of the IU Simon Cancer Center In Vivo Therapeutics Core.

Funding

This publication was made possible by an award from the Indiana University School of Medicine (Indiana University School of Medicine Biomedical Research Grant). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Indiana University School of Medicine.

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Authors and Affiliations

  1. Department of Radiology and Imaging, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Shelby B. Smiley, Yeonhee Yun, Pranav Ayyagari & Michael C. Veronesi

  2. Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Harlan E. Shannon

  3. Department of Pediatrics, Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Karen E. Pollok

  4. Department of Radiology, University of Chicago School of Medicine, Chicago, Illinois, USA

    Michael W. Vannier

  5. Department of Pharmaceutical Sciences, Butler University, Indianapolis, Indiana, USA

    Sudip K. Das

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  1. Shelby B. Smiley
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  8. Michael C. Veronesi
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Contributions

A part of this research constitute the MS thesis of SBS. The PI of the research project is MCV. All coauthors participated in intellectual contribution.

Corresponding author

Correspondence to Michael C. Veronesi.

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Smiley, S.B., Yun, Y., Ayyagari, P. et al. Development of CD133 Targeting Multi-Drug Polymer Micellar Nanoparticles for Glioblastoma - In Vitro Evaluation in Glioblastoma Stem Cells. Pharm Res 38, 1067–1079 (2021). https://doi.org/10.1007/s11095-021-03050-8

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  • DOI: https://doi.org/10.1007/s11095-021-03050-8

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