Combination treatment with theranostic nanoparticles for glioblastoma sensitization to TMZ.
OBJECTIVE
Tumor resistance to chemotherapeutic drugs is one of the major obstacles in the treatment of glioblastoma multiforme (GBM). In this study, we attempted to modulate tumor response to chemotherapy by combination treatment that included experimental (small interference RNA (siRNA), chlorotoxin) and conventional (temozolomide, TMZ) therapeutics.


METHODS
siRNA therapy was used to silence O(6)-methylguanine methyltransferase (MGMT), a key factor in brain tumor resistance to TMZ. For targeting of tumor cells, we used chlorotoxin (CTX), a peptide with antitumoral properties. siRNA and CTX were conjugated to iron oxide nanoparticles (NP) that served as the drug carrier and allowed the means to monitor the changes in tumor volume by magnetic resonance imaging (MRI).


RESULTS
Theranostic nanoparticles (termed CTX-NP-siMGMT) were internalized by T98G glioblastoma cells in vitro leading to enhancement of TMZ toxicity. Combination treatment of mice bearing orthotopic tumors with CTX-NP-siMGMT and TMZ led to significant retardation of tumor growth, which was monitored by MRI.


CONCLUSIONS
While our results demonstrate that siRNA delivery by targeted nanoparticles resulted in modulating tumor response to chemotherapy in GBM, they also point to a significant contribution of CTX to tumor cell death.
Molecular Imaging Laboratory, MGH/HST Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Building 75, 13th Street, Charlestown, MA, 02129, USA.
Byunghee
B
Yoo
Marytheresa A
MA
Ifediba
Subrata
S
Ghosh
Zdravka
Z
Medarova
Anna
A
Moore
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007501:Iron / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000627:therapeutic use*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012604:Scorpion Venoms / Q000494:pharmacology / Q000627:therapeutic use; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; D012604:Scorpion Venoms; C091539:Chlorotoxin; D003606:Dacarbazine; D007501:Iron; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide