Dataset Information

Ultrasmall Core-Shell Silica Nanoparticles for Precision Drug Delivery in a High-Grade Malignant Brain Tumor Model.

ABSTRACT:

Purpose

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.

Experimental design

Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with ?_v 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.

Results

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.

Conclusions

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.

SUBMITTER: Juthani R

PROVIDER: S-EPMC6942644 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Ultrasmall Core-Shell Silica Nanoparticles for Precision Drug Delivery in a High-Grade Malignant Brain Tumor Model.

Juthani Rupa R Madajewski Brian B Yoo Barney B Zhang Li L Chen Pei-Ming PM Chen Feng F Turker Melik Z MZ Ma Kai K Overholtzer Michael M Longo Valerie A VA Carlin Sean S Aragon-Sanabria Virginia V Huse Jason J Gonen Mithat M Zanzonico Pat P Rudin Charles M CM Wiesner Ulrich U Bradbury Michelle S MS Brennan Cameron W CW

Clinical cancer research : an official journal of the American Association for Cancer Research 20190912 1

<h4>Purpose</h4>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.<h4>E ...[more]

PMID: 31515460

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Project description:One of the challenges in designing a successful drug-delivery vehicle is the control over drug release. Toward this, a number of multifunctional nanoparticles with multiple triggers and complex chemistries have been developed. To achieve an efficient and maximum therapeutic effect, a trigger dependent drug-delivery system with sustained release is desirable. In this paper, we report the use of a combination of thermoresponsive gold core and polymeric shell nanoparticles that can provide a sustained, triggered release of doxorubicin, making the system more efficient compared to individual nanoparticles. The selection of the system was dependent on the best trigger applicable in biological systems and a component responsive to that trigger. Because of the best tissue penetration depth observed for radiofrequency (rf), we chose rf as a trigger. Whereas the gold nanoparticles (AuNPs) provided hyperthermia trigger on exposure to rf fields, the thermoresponsiveness was endowed by poly(N-isopropylacrylamide) (pNIPAm)-based polymer shells. AuNPs with three different compositions of shells, only pNIPAm and p(NIPAm-co-NIPMAm) with the ratio of NIPAm/N-(isopropylmethacrylamide) (NIPMAm) 1:1 (pNIPMAm50) and 1:3 (pNIPMAm75), were synthesized. We observed that the polymer coating on the AuNPs did not affect the heating efficiency of AuNPs by rf and exhibited a temperature-dependent release of the chemotherapeutic drug, doxorubicin. The nanoparticles were biocompatible, stable in biologically relevant media, and were able to show a burst as well as a sustained release, which was rf-dependent. Interestingly, we observed that when HeLa cells were treated with doxorubicin-loaded gold core-polymeric shell NPs and exposed to rf for varying times, the mixture of the two polymeric shell nanoparticles induced more cell death as compared to the cells treated with single nanoparticles, suggesting that such multi-nanoparticle systems can be more efficacious delivery systems instead of a single multicomponent system.

Dataset Information

Ultrasmall Core-Shell Silica Nanoparticles for Precision Drug Delivery in a High-Grade Malignant Brain Tumor Model.

Purpose

Experimental design

Results

Conclusions

Publications

Ultrasmall Core-Shell Silica Nanoparticles for Precision Drug Delivery in a High-Grade Malignant Brain Tumor Model.

Similar Datasets

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