Ultrasmall nanoparticle delivery of doxorubicin improves therapeutic index for high-grade glioma Journal Article
| Authors: | Aragon-Sanabria, V.; Aditya, A.; Zhang, L.; Chen, F.; Yoo, B.; Cao, T.; Madajewski, B.; Lee, R.; Turker, M. Z.; Ma, K.; Monette, S.; Chen, P.; Wu, J.; Ruan, S.; Overholtzer, M.; Zanzonico, P.; Rudin, C. M.; Brennan, C.; Wiesner, U.; Bradbury, M. S. |
| Article Title: | Ultrasmall nanoparticle delivery of doxorubicin improves therapeutic index for high-grade glioma |
| Abstract: | Purpose: Despite dramatic growth in the number of smallmolecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents that appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall (<8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C0 dots), for the efficacious treatment of highgrade gliomas. Experimental Design: This work presents first-in-kind renally clearable ultrasmall (<8 nm) multimodal C0 dots with surfaceconjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant highgrade glioma models. Results: Optimal drug-per-particle ratios of as-developed nanoparticle- drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in plateletderived growth factor-driven genetically engineered mousemodel, and an EGF-expressing patient-derived xenograft (EGFR PDX) model. Conclusions: Ultrasmall C0 dot-drug conjugates showed great translational potential over DOX for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety. © 2022 The Authors. |
| Keywords: | doxorubicin; glioma; mouse; animal; animals; mice; cell line, tumor; drug delivery systems; tumor cell line; nanoparticles; nanoparticle; silicon dioxide; drug delivery system; procedures; therapeutic index; humans; human |
| Journal Title: | Clinical Cancer Research |
| Volume: | 28 |
| Issue: | 13 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-07-01 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-21-4053 |
| PUBMED: | 35499557 |
| PROVIDER: | scopus |
| PMCID: | PMC9250642 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
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