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Systemically administered collagen-targeted gold nanoparticles bind to arterial injury following vascular interventions.

ABSTRACT: Surgical and endovascular therapies for severe atherosclerosis often fail due to the development of neointimal hyperplasia and arterial restenosis. Our objective was to synthesize, characterize, and evaluate the targeting specificity and biocompatibility of a novel systemically injected nanoparticle. We hypothesize that surface-functionalization of gold nanoparticles (AuNPs) with a collagen-targeting peptide will be biocompatible and target specifically to vascular injury. 13 nm AuNPs were surface functionalized with a peptide-molecular fluorophore and targeted to collagen (T-AuNP) or a scrambled peptide sequence (S-AuNP). After rat carotid artery balloon injury and systemic injection of T-AuNP or S-AuNP, arteries and organs were harvested and assessed for binding specificity and biocompatibility. The T-AuNP bound with specificity to vascular injury for a minimum of 24 h. No significant inflammation was evident locally at arterial injury or systemically in major organs. The T-AuNP did not impact endothelial cell viability or induce apoptosis at the site of injury in vivo. No major changes were evident in hepatic or renal blood chemistry profiles. Herein, we synthesized a biocompatible nanoparticle that targets to vascular injury following systemic administration. These studies demonstrate proof-of-principle and serve as the foundation for further T-AuNP optimization to realize systemic, targeted delivery of therapeutics to the sites of vascular injury.

SUBMITTER: Meyers MW

PROVIDER: S-EPMC5328771 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Systemically administered collagen-targeted gold nanoparticles bind to arterial injury following vascular interventions.

Meyers Molly Wasserman MW Rink Jonathan S JS Jiang Qun Q Kelly Megan E ME Vercammen Janet M JM Thaxton Colby S CS Kibbe Melina R MR

Physiological reports 20170227 4

Surgical and endovascular therapies for severe atherosclerosis often fail due to the development of neointimal hyperplasia and arterial restenosis. Our objective was to synthesize, characterize, and evaluate the targeting specificity and biocompatibility of a novel systemically injected nanoparticle. We hypothesize that surface-functionalization of gold nanoparticles (AuNPs) with a collagen-targeting peptide will be biocompatible and target specifically to vascular injury. 13 nm AuNPs were surfa ...[more]

PMID: 28242820

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Project description:Tumor suppressor gene TUSC2/FUS1 (TUSC2) is frequently inactivated early in lung cancer development. TUSC2 mediates apoptosis in cancer cells but not normal cells by upregulation of the intrinsic apoptotic pathway. No drug strategies currently exist targeting loss-of-function genetic abnormalities. We report the first in-human systemic gene therapy clinical trial of tumor suppressor gene TUSC2.Patients with recurrent and/or metastatic lung cancer previously treated with platinum-based chemotherapy were treated with escalating doses of intravenous N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP):cholesterol nanoparticles encapsulating a TUSC2 expression plasmid (DOTAP:chol-TUSC2) every 3 weeks.Thirty-one patients were treated at 6 dose levels (range 0.01 to 0.09 milligrams per kilogram). The MTD was determined to be 0.06 mg/kg. Five patients achieved stable disease (2.6-10.8 months, including 2 minor responses). One patient had a metabolic response on positron emission tomography (PET) imaging. RT-PCR analysis detected TUSC2 plasmid expression in 7 of 8 post-treatment tumor specimens but not in pretreatment specimens and peripheral blood lymphocyte controls. Proximity ligation assay, performed on paired biopsies from 3 patients, demonstrated low background TUSC2 protein staining in pretreatment tissues compared with intense (10-25 fold increase) TUSC2 protein staining in post-treatment tissues. RT-PCR gene expression profiling analysis of apoptotic pathway genes in two patients with high post-treatment levels of TUSC2 mRNA and protein showed significant post-treatment changes in the intrinsic apoptotic pathway. Twenty-nine genes of the 82 tested in the apoptosis array were identified by Igenuity Pathway Analysis to be significantly altered post-treatment in both patients (Pearson correlation coefficient 0.519; p<0.01).DOTAP:chol-TUSC2 can be safely administered intravenously in lung cancer patients and results in uptake of the gene by human primary and metastatic tumors, transgene and gene product expression, specific alterations in TUSC2-regulated pathways, and anti-tumor effects (to our knowledge for the first time for systemic DOTAP:cholesterol nanoparticle gene therapy).ClinicalTrials.gov NCT00059605.

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Systemically administered collagen-targeted gold nanoparticles bind to arterial injury following vascular interventions.

Publications

Systemically administered collagen-targeted gold nanoparticles bind to arterial injury following vascular interventions.

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