RT Journal Article
SR Electronic
T1 Development of Targetable Multi-Drug Nanoparticles for Glioblastoma Treatment and In Vitro Evaluation in Glioblastoma Stem Cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.08.373696
DO 10.1101/2020.11.08.373696
A1 Shelby B. Smiley
A1 Yeonhee Yun
A1 Pranav Ayyagari
A1 Harlan E. Shannon
A1 Karen E. Pollok
A1 Michael W. Vannier
A1 Sudip K. Das
A1 Michael C. Veronesi
YR 2020
UL http://biorxiv.org/content/early/2020/11/09/2020.11.08.373696.abstract
AB Glioblastoma (GBM) is a malignant brain tumor with a poor long-term prognosis. The current median survival is approximately fifteen to twenty months with the standard of care therapy which includes surgery, radiation, and chemotherapy. An important factor contributing to recurrence of GBM is high resistance of GBM cancer stem cells (CSCs) to several anticancer drugs, for which a systemically delivered single drug approach will be unlikely to produce a viable cure. Therefore, multidrug therapies have the potential to improve the survival time. Currently, only temozolomide (TMZ), which is a DNA alkylator, affects overall survival in GBM patients. CSCs regenerate rapidly and over-express a methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to drug resistance. Idasanutlin (RG7388, R05503781) is a potent, selective MDM2 antagonist that additively kills GBM CSCs when combined with TMZ. Nanotechnology is an emerging field that shows great promise in drug delivery and diagnostics. The ability to combine both therapy and imaging allows real time assessment of drug delivery in vivo for the field of theranostics.To develop a multi-drug therapy using multi-functional nanoparticles (NPs) that preferentially target the GBM CSC subpopulation and provide in vivo preclinical imaging capability. Polymer-micellar NPs composed of poly(styrene-b-ethylene oxide) (PS-b-PEO) and poly(lactic-co-glycolic) acid (PLGA) were developed investigating both single and double emulsion fabrication techniques as well as combinations of TMZ and RG7388. The NPs were covalently bound to a 15-base-pair CD133 aptamer in order to target the CD133 antigen expressed on the surface of GBM CSC subpopulation. For theranostic functionality, the NPs were also labelled with a radiotracer, Zirconium-89 (89Zr). The NPs maintained a small size of less than 100 nm, a low negative charge and exhibited the ability to effectively target and kill the CSC subpopulation. In addition, the conjugation of the CD133 aptamer was able to promote killing in CSCs leading to the justification of a targeted nanosystem to potentially improve localized therapy in future in vivo models. This work has provided a potentially therapeutic option for GBM specific for CSC targeting and theranostic imaging.Competing Interest StatementThe authors have declared no competing interest.