Data from Ultrasmall Nanoparticle Delivery of Doxorubicin Improves Therapeutic Index for High-Grade Glioma

Abstract

<div>AbstractPurpose:<p>Despite dramatic growth in the number of small-molecule 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 <i>ultrasmall</i> (<8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C′ dots), for the efficacious treatment of high-grade gliomas.</p>Experimental Design:<p>This work presents first-in-kind renally clearable <i>ultrasmall</i> (<8 nm) multimodal C′ dots with surface-conjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models.</p>Results:<p>Optimal drug-per-particle ratios of as-developed nanoparticle–drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The <i>in vivo</i> efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor–driven genetically engineered mouse model, and an EGF-expressing patient-derived xenograft (EGFR PDX) model.</p>Conclusions:<p>Ultrasmall C′ 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.</p></div>