Dataset Information

Targeted Delivery of DNA Topoisomerase Inhibitor SN38 to Intracranial Tumors of Glioblastoma Using Sub-5 Ultrafine Iron Oxide Nanoparticles.

ABSTRACT: Effectively delivering therapeutics for treating brain tumors is hindered by the physical and biological barriers in the brain. Even with the compromised blood-brain barrier and highly angiogenic blood-tumor barrier seen in glioblastoma (GBM), most drugs, including nanomaterial-based formulations, hardly reach intracranial tumors. This work investigates sub-5 nm ultrafine iron oxide nanoparticles (uIONP) with 3.5 nm core diameter as a carrier for delivering DNA topoisomerase inhibitor 7-ethyl-10-hydroxyl camptothecin (SN38) to treat GBM. Given a higher surface-to-volume ratio, uIONP shows one- or three-folds higher SN38 loading efficiency (48.3 ± 6.1%, mg/mg Fe) than those with core sizes of 10 or 20 nm. SN38 encapsulated in the coating polymer exhibits pH sensitive release with <10% over 48 h at pH 7.4, but 86% at pH 5, thus being protected from converting to inactive glucuronide by UDP-glucuronosyltransferase 1A1. Conjugating α_v β₃ -integrin-targeted cyclo(Arg-Gly-Asp-D-Phe-Cys) (RGD) as ligands, RGD-uIONP/SN38 demonstrates targeted cytotoxicity to α_v β₃ -integrin-overexpressed U87MG GBM cells with a half-maximal inhibitory concentration (IC₅₀ ) of 30.9 ± 2.2 nm. The efficacy study using an orthotopic mouse model of GBM reveals tumor-specific delivery of 11.5% injected RGD-uIONP/SN38 (10 mg Fe kg^-1 ), significantly prolonging the survival in mice by 41%, comparing to those treated with SN38 alone (p < 0.001).

SUBMITTER: Li Y

PROVIDER: S-EPMC9308697 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Targeted Delivery of DNA Topoisomerase Inhibitor SN38 to Intracranial Tumors of Glioblastoma Using Sub-5 Ultrafine Iron Oxide Nanoparticles.

Li Yuancheng Y Xie Manman M Jones Joshua B JB Zhang Zhaobin Z Wang Zi Z Dang Tu T Wang Xinyu X Lipowska Malgorzata M Mao Hui H

Advanced healthcare materials 20220506 14

Effectively delivering therapeutics for treating brain tumors is hindered by the physical and biological barriers in the brain. Even with the compromised blood-brain barrier and highly angiogenic blood-tumor barrier seen in glioblastoma (GBM), most drugs, including nanomaterial-based formulations, hardly reach intracranial tumors. This work investigates sub-5 nm ultrafine iron oxide nanoparticles (uIONP) with 3.5 nm core diameter as a carrier for delivering DNA topoisomerase inhibitor 7-ethyl-10 ...[more]

PMID: 35481625

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Project description:Rationale: "Active targeting" based on the ligand-target affinity is a common strategy to precisely deliver nanoparticle (NP) imaging probes or drug carriers to the diseased tissue. However, such ligand-mediated active targeting inevitably takes place with prerequisite "passive targeting", driven by the enhanced permeability and retention (EPR) effect. Thus, the efficiency of active targeting in relation to off-targeted unbound NPs is of great importance in quantitative imaging of tumor biomarkers and delivery. With the notion that easy clearance of off-targeted uIONPs may lead to enhanced active targeting and tumor accumulation, we examined the NP size effect on "active targeting" of the transferrin receptor (TfR) using transferrin (Tf)-conjugated sub-5 nm (3 nm core) ultrafine iron oxide NPs (uIONPs) and larger IONPs (30 nm core). Methods: Green fluorescent dye (FITC)-labeled active targeting uIONPs (FITC-Tf-uIONPs) and red fluorescent dye (TRITC)-labeled passive targeting uIONPs (TRITC-uIONPs) were prepared. FITC-Tf-IONPs and TRITC-IONPs were used as comparison for the NP size effect. Multiphoton imaging, confocal fluorescence imaging, histological staining and computational analysis were applied to track different types of NPs in tumors at 1, 3 and 24 hours after co-injection of equal amounts of paired NPs, e.g., active targeting FITC-Tf-uIONPs and non-targeting TRITC-uIONPs, or FITC-Tf-IONPs and TRITC-IONPs into the same mice bearing 4T1 mouse mammary tumors. Results: Active targeting uIONPs exhibited an almost 6-fold higher level of tumor retention with deeper penetration comparing to non-targeting uIONPs at 24 hours after co-injection. However, accumulation of active targeting IONPs with a 30-nm core is only about 1.15-fold higher than non-targeting IONPs. The enhanced active targeting by uIONPs can be attributed to the size dependent clearance of unbound off-targeted NPs, as majority off-targeted uIONPs were readily cleared from the tumor by intravasation back into tumor blood vessels likely due to high interstitial pressure, even though they are not favorable for macrophage uptake. Conclusion: Ligand-mediated active targeting improves the delivery and accumulation of the sub-5 nm NPs. The improvement on active targeting is size-dependent and facilitated by NPs with sub-5 nm core sizes. Thus, sub-5 nm NPs may serve as favorable platforms for development of NP-based molecular imaging probes and targeted drug carriers.

Project description:The prognosis for glioblastoma (GBM) remains depressingly low. The biological barriers of the brain present a major challenge to achieving adequate drug concentrations for GBM therapy. To address this, we explore the potential of the nose-to-brain direct transport pathway to bypass the blood-brain barrier, and to enable targeted delivery of theranostic polyfunctional gold-iron oxide nanoparticles (polyGIONs) surface loaded with therapeutic miRNAs (miR-100 and antimiR-21) to GBMs in mice. These nanoformulations would thus allow presensitization of GBM cells to the systemically delivered chemotherapy drug temozolomide (TMZ), as well as in vivo multimodality molecular and anatomic imaging of nanoparticle delivery, trafficking, and treatment effects. First, we synthesized GIONs coated with β-cyclodextrin-chitosan (CD-CS) hybrid polymer, and co-loaded with miR-100 and antimiR-21. Then we decorated their surface with PEG-T7 peptide using CD-adamantane host-guest chemistry. The resultant polyGIONs showed efficient miRNA loading with enhanced serum stability. We characterized them for particle size, PDI, polymer functionalization, charge and release using dynamic light scattering analysis, TEM and qRT-PCR. For in vivo intranasal delivery, we used U87-MG GBM cell-derived orthotopic xenograft models in mice. Intranasal delivery resulted in efficient accumulation of Cy5-miRNAs in mice treated with T7-targeted polyGIONs, as demonstrated by in vivo optical fluorescence and MR imaging. We measured the therapeutic response of these FLUC-EGFP labelled U87-MG GBMs using bioluminescence imaging. Overall, there was a significant increase in survival of mice co-treated with T7-polyGIONs loaded with miR-100/antimiR-21 plus systemic TMZ, compared to the untreated control group, or the animals receiving non-targeted polyGIONs-miR-100/antimiR-21, or TMZ alone. Once translated clinically, this novel theranostic nanoformulation and its associated intranasal delivery strategy will have a strong potential to potentiate the effects of TMZ treatment in GBM patients.

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Dataset Information

Targeted Delivery of DNA Topoisomerase Inhibitor SN38 to Intracranial Tumors of Glioblastoma Using Sub-5 Ultrafine Iron Oxide Nanoparticles.

Publications

Targeted Delivery of DNA Topoisomerase Inhibitor SN38 to Intracranial Tumors of Glioblastoma Using Sub-5 Ultrafine Iron Oxide Nanoparticles.

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