Inhaled Gold Nano‐Star Carriers for Targeted Delivery of Triple Suicide Gene Therapy and Therapeutic MicroRNAs to Lung Metastases: Development and Validation in a Small Animal Model

Liu, Yi; Sukumar, Uday Kumar; Jugniot, Natacha; Seetharam, Sumanth Mosale; Rengaramachandran, Adith; Sadeghipour, Negar; Mukherjee, Pinaki; Krishnan, Anandi; Massoud, Tarik F.; Paulmurugan, Ramasamy

doi:10.1002/adtp.202200018

Cited by 12 publications

(7 citation statements)

References 47 publications

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“… 101 Currently, non-surgical miRNA-based therapies are not being tested clinically, 102 but strategies such as nasal delivery of nanoparticle miRNAs are under development in the cancer therapeutics space. 103 To date, nasal administration of a long non-coding RNA was reported to regulate insulin signalling and reduce inflammation in aged mice in the absence of toxicity or adverse events. 104 Finally, an exciting new line of investigation involves identifying non-coding RNAs that regulate miRNA expression and activity, such as circular RNAs.…”

Section: Resultsmentioning

confidence: 99%

Micro-RNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders

Kelley,

Maloney,

Beck

et al. 2024

Brain Communications

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The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer’s disease. We recently performed RNA sequencing of postmortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an antemortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to Alzheimer’s disease pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak stages III/IV compared with stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small noncoding microRNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance, and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs significantly associated (rho > 0.38, p < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation, and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak stages I-II and 47 miRNAs were associated with higher Braak stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak stages I/II vs. Braak stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau, and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and postmortem neuropathological Alzheimer’s disease diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (preclinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Micro-RNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders

Kelley,

Maloney,

Beck

et al. 2024

Brain Communications

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“…We used a 3D-fluorescence imaging computed tomography technique to monitor the passage of Nic-SMEDDS in vivo in non-tumor bearing mice, using the vivoTag680 ® dye (Perkin Elmer LLC, Waltham, MA). 20 To prepare the dye stock solution, 10 mg of the dye was dissolved in 1 mL of dimethylsulfoxide (per the manufacturer’s protocol). For nine mice, we prepared the control dye mixture consisting of 405 µL of stock dye, 225 µL of buffer solution (50 mM NaHCO 3 ), and 720 µL of water.…”

Section: Methodsmentioning

confidence: 99%

Lipid-Based Self-Microemulsion of Niclosamide Achieved Enhanced Oral Delivery and Anti-Tumor Efficacy in Orthotopic Patient-Derived Xenograft of Hepatocellular Carcinoma in Mice

Liu,

Guerrero,

Lechuga-Ballesteros

et al. 2024

IJN

Self Cite

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Introduction We previously identified niclosamide as a promising repurposed drug candidate for hepatocellular carcinoma (HCC) treatment. However, it is poorly water soluble, limiting its tissue bioavailability and clinical application. To overcome these challenges, we developed an orally bioavailable self-microemulsifying drug delivery system encapsulating niclosamide (Nic-SMEDDS). Methods Nic-SMEDDS was synthesized and characterized for its physicochemical properties, in vivo pharmacokinetics and absorption mechanisms, and in vivo therapeutic efficacy in an orthotopic patient-derived xenograft (PDX)-HCC mouse model. Niclosamide ethanolamine salt (NEN), with superior water solubility, was used as a positive control. Results Nic-SMEDDS (5.6% drug load) displayed favorable physicochemical properties and drug release profiles in vitro. In vivo, Nic-SMEDDS displayed prolonged retention time and plasma release profile compared to niclosamide or NEN. Oral administration of Nic-SMEDDS to non-tumor bearing mice improved niclosamide bioavailability and C max by 4.1- and 1.8-fold, respectively, compared to oral niclosamide. Cycloheximide pre-treatment blocked niclosamide absorption from orally administered Nic-SMEDDS, suggesting that its absorption was facilitated through the chylomicron pathway. Nic-SMEDDS (100 mg/kg, bid) showed greater anti-tumor efficacy compared to NEN (200 mg/kg, qd); this correlated with higher levels ( p < 0.01) of niclosamide, increased caspase-3, and decreased Ki-67 in the harvested PDX tissues when Nic-SMEDDS was given. Biochemical analysis at the treatment end-point indicated that Nic-SMEDDS elevated lipid levels in treated mice. Conclusion We successfully developed an orally bioavailable formulation of niclosamide, which significantly enhanced oral bioavailability and anti-tumor efficacy in an HCC PDX mouse model. Our data support its clinical translation for the treatment of solid tumors.

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“…The intranasal administration of saline, GNPs (2.5 mg/L), curcumin (10 mg/kg) and GNPs-curcumin (2.5 mg/L) was performed with the aid of a micropipette in a volume of 14 μl (7 μl/nostril) at a 45 angle. The doses of GNPs were selected according to previous studies 7, [19][20][21][22][23] and curcumin. [24][25][26]…”

Section: Intranasal Administrationmentioning

confidence: 99%

Green synthesis of gold nanoparticles modulates lipopolysaccharide‐induced lung inflammation in Wistar rats

Casagrande

Porto

Colares

et al. 2023

Basic Clin Pharma Tox

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This study aimed to investigate the effect of intranasal treatment of gold nanoparticles (GNPs) and Curcumin (Cur) on the lipopolysaccharide (LPS)-induced acute pulmonary inflammatory response. A single intraperitoneal injection of LPS (0.5 mg/Kg) was performed, and the animals in the Sham group were injected with 0.9% saline. Treatment was daily intranasally with GNPs (2.5 mg/L), Cur (10 mg/kg) and GNP-Cur started 12 h after LPS administration and ended on the seventh day. The results show that the treatment performed with GNP-Cur was the most effective to attenuate the action of proinflammatory cytokines, and a lower leukocyte count in the bronchoalveolar lavage, in addition to positively regulating anti-inflammatory cytokines in relation to other groups. As a result, it promoted an oxirreductive balanced environment in the lung tissue, providing a histological outcome with a reduction in inflammatory cells and greater alveolar area. The group treated with GNPs-Cur was superior to the other groups, with better anti-inflammatory activity and reduced oxidative stress, resulting in less morphological damage to lung tissue. In conclusion, the use of reduced GNPs with curcumin demonstrates promising effects in the control of the acute inflammatory response, helping to protect the lung tissue at the biochemical and morphological levels.

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Inhaled Gold Nano‐Star Carriers for Targeted Delivery of Triple Suicide Gene Therapy and Therapeutic MicroRNAs to Lung Metastases: Development and Validation in a Small Animal Model

Cited by 12 publications

References 47 publications

Micro-RNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders

Micro-RNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders

Lipid-Based Self-Microemulsion of Niclosamide Achieved Enhanced Oral Delivery and Anti-Tumor Efficacy in Orthotopic Patient-Derived Xenograft of Hepatocellular Carcinoma in Mice

Green synthesis of gold nanoparticles modulates lipopolysaccharide‐induced lung inflammation in Wistar rats

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