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Development of CD133 Targeting Multi-Drug Polymer Micellar Nanoparticles for Glioblastoma - In Vitro Evaluation in
Shelby B Smiley1, Yeonhee Yun1, Pranav Ayyagari1
1Department of Radiology and Imaging, Indiana University School of Medicine, Indianapolis, Indiana, USA.
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.
Insights
Nanoparticles loaded with temozolomide and idasanutlin target glioblastoma cancer stem cells. This dual-drug therapy shows potential for treating resistant brain tumors and offers diagnostic imaging capabilities.
Area of Science:
- Nanotechnology
- Oncology
- Biomedical Engineering
Background:
- Glioblastoma (GBM) is a lethal brain tumor with poor prognosis due to drug-resistant cancer stem cells (CSCs).
- Current treatments, including temozolomide (TMZ), are often ineffective against CSCs due to rapid regeneration and methyltransferase overexpression.
- Targeting GBM CSCs is crucial for developing effective glioblastoma therapies.
Purpose of the Study:
- To develop functionalized nanoparticles (NPs) for targeted multi-drug therapy against GBM CSCs.
- To combine temozolomide (TMZ) and idasanutlin (RG7388), an MDM2 antagonist, within NPs.
- To incorporate diagnostic imaging capabilities into the NPs for preclinical assessment.
Main Methods:
- Polymer-micellar NPs (PS-b-PEO and PLGA) were fabricated using a double emulsion technique.
- NPs were loaded with TMZ and/or RG7388 and functionalized with CD133 aptamers for GBM CSC targeting.
- Nanoparticles were labeled with 89Zr for diagnostic imaging.
Main Results:
- Developed NPs were sub-100 nm with low negative charge.
- Combined TMZ and RG7388 in NPs effectively targeted and reduced GBM CSC viability.
- CD133 aptamer-mediated targeting enhanced CSC killing, demonstrating the potential of this nanosystem.
Conclusions:
- This research presents a nanotechnology-based approach for simultaneously targeting GBM CSCs and enabling diagnostic imaging.
- The developed dual-drug loaded, aptamer-functionalized NPs show promise for future in vivo glioblastoma therapy.
- This study offers a potential clinical application for localized glioblastoma treatment and imaging.
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