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10780432ccr191834-sup-223490_2_supp_5715828_pwc38j.pptx (616.22 kB)

Supplemental Figure 6 from Ultrasmall Core-Shell Silica Nanoparticles for Precision Drug Delivery in a High-Grade Malignant Brain Tumor Model

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posted on 2023-03-31, 21:26 authored by Rupa Juthani, Brian Madajewski, Barney Yoo, Li Zhang, Pei-Ming Chen, Feng Chen, Melik Z. Turker, Kai Ma, Michael Overholtzer, Valerie A. Longo, Sean Carlin, Virginia Aragon-Sanabria, Jason Huse, Mithat Gonen, Pat Zanzonico, Charles M. Rudin, Ulrich Wiesner, Michelle S. Bradbury, Cameron W. Brennan

Representative images of I-124-cRGD-C' dot uptake and distribution in primary human glioma; part of an ongoing Phase 1 trial

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ARTICLE ABSTRACT

Small-molecule inhibitors have revolutionized treatment of certain genomically defined solid cancers. Despite breakthroughs in treating systemic disease, central nervous system (CNS) metastatic progression is common, and advancements in treating CNS malignancies remain sparse. By improving drug penetration across a variably permeable blood–brain barrier and diffusion across intratumoral compartments, more uniform delivery and distribution can be achieved to enhance efficacy. Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with αv integrin-binding (cRGD), or nontargeting (cRAD) peptides, and PET labels (124I, 89Zr) to investigate the utility of dual-modality cRGD-C' dots for enhancing accumulation, distribution, and retention (ADR) in a genetically engineered mouse model of glioblastoma (mGBM). mGBMs were systemically treated with 124I-cRGD- or 124I-cRAD-C' dots and sacrificed at 3 and 96 hours, with concurrent intravital injections of FITC-dextran for mapping blood–brain barrier breakdown and the nuclear stain Hoechst. We further assessed target inhibition and ADR following attachment of dasatinib, creating nanoparticle–drug conjugates (Das-NDCs). Imaging findings were confirmed with ex vivo autoradiography, fluorescence microscopy, and p-S6RP IHC. Improvements in brain tumor delivery and penetration, as well as enhancement in the ADR, were observed following administration of integrin-targeted C' dots, as compared with a nontargeted control. Furthermore, attachment of the small-molecule inhibitor, dasatinib, led to its successful drug delivery throughout mGBM, demonstrated by downstream pathway inhibition. These results demonstrate that highly engineered C' dots are promising drug delivery vehicles capable of navigating the complex physiologic barriers observed in a clinically relevant brain tumor model.

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