RNA nanoparticle distribution and clearance in the eye after subconjunctival injection with and without thermosensitive hydrogels

Shi, Zhanquan; Li, S. Kevin; Charoenputtakun, Ponwanit; Liu, Chia-Yang; Jasinski, Daniel L.; Guo, Peixuan

doi:10.1016/j.jconrel.2017.11.028

Cited by 38 publications

(23 citation statements)

References 37 publications

(52 reference statements)

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“…This study utilized a commercialized thermosensitive hydrogel (AK097, PolySciTech, Lafayette, USA) composed of PLGA-PEG-PLGA copolymers (LA:GA = 15:1 by weight) and previously proven to be an effective controlled-release carrier [22]. Hydrogel was dissolved at a 1:4 (v/v) ratio in PBS or in PBS plus Atsttrin.…”

Section: Methodsmentioning

confidence: 99%

Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice

Wang

Zhang

Ndong

et al. 2019

J Neuroinflammation

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PurposeSpinal cord injury (SCI) often results in significant and catastrophic dysfunction and disability and imposes a huge economic burden on society. This study aimed to determine whether progranulin (PGRN) plays a role in the progressive damage following SCI and evaluate the potential for development of a PGRN derivative as a new therapeutic target in SCI.MethodsPGRN-deficient (Gr−/−) and wild-type (WT) littermate mice were subjected to SCI using a weight-drop technique. Local PGRN expression following injury was evaluated by Western blotting and immunofluorescence. Basso Mouse Scale (BMS), inclined grid walking test, and inclined plane test were conducted at indicated time points to assess neurological recovery. Inflammation and apoptosis were examined by histology (Hematoxylin and Eosin (H&E) staining and Nissl staining, TUNEL assays, and immunofluorescence), Western blotting (from whole tissue protein for iNOS/p-p65/Bax/Bcl-2), and ex vivo ELISA (for TNFα/IL-1β/IL-6/IL-10). To identify the prophylactic and therapeutic potential of targeting PGRN, a PGRN derived small protein, Atsttrin, was conjugated to PLGA-PEG-PLGA thermosensitive hydrogel and injected into intrathecal space prior to SCI. BMS was recorded for neurological recovery and Western blotting was applied to detect the inflammatory and apoptotic proteins.ResultsAfter SCI, PGRN was highly expressed in activated macrophage/microglia and peaked at day 7 post-injury. Grn−/− mice showed a delayed neurological recovery after SCI at day 21, 28, 35, and 42 post-injury relative to WT controls. Histology, TUNEL assay, immunofluorescence, Western blotting, and ELISA all indicated that Grn−/− mice manifested uncontrolled and expanded inflammation and apoptosis. Administration of control-released Atsttrin could improve the neurological recovery and the pro-inflammatory/pro-apoptotic effect of PGRN deficiency.ConclusionPGRN deficiency exacerbates SCI by promoting neuroinflammation and cellular apoptosis, which can be alleviated by Atsttrin. Collectively, our data provide novel evidence of using PGRN derivatives as a promising therapeutic approach to improve the functional recovery for patients with spinal cord injury.

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Section: Methodsmentioning

confidence: 99%

Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice

Wang

Zhang

Ndong

et al. 2019

J Neuroinflammation

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“…A clear trend was observed in terms of timing, where topically applied nanoparticles required more than 15 min after application to reach the peak concentration in these tissues but were mostly cleared within an hour (Figure 8). It was not surprising that the most signi cant decreases from 30 min to 1 h occurred in the episcleral tissue and choroid, as both of these tissues contain dense vasculature and are responsible for rapid elimination of drugs in the eye (Y. C. Kim et al, 2015;Shi et al, 2018). Only about 20% lutein was released after 1 day at 37°C, which appears to create an issue for the nanodelivery system's ability to delivery lutein within the effective time frame before clearance.…”

Section: Discussionmentioning

confidence: 99%

Stability and Ocular Biodistribution of Topically Administered PLGA Nanoparticles

Swetledge

Carter

Stout

et al. 2020

Preprint

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The spatiotemporal distribution profile of polymeric nanoparticles (NPs) in the eye is important as it will determine their effectiveness as topical ocular drug delivery systems for specific eye diseases. Physical stability of the nanoparticles in an ophthalmic formulation and thermal stability of the entrapped drug are critical as well to the applicability of polymeric nanoparticles as drug delivery to the eye. To investigate these characteristics, Cy5-labeled, poly(lactic-co-glycolic acid) (PLGA) NPs (ζ-potential: -14.1±1.5 mV, size: 241.7±0.6 nm) and lutein-loaded PLGA NPs (ζ-potential: -6.7±0.3 mV, size: 210.6±3.3 nm) were synthesized, and their stability and biodistribution were assessed. Lutein-loaded NPs were stable at 4°C without significant changes in size and morphology, without significant lutein degradation, and 26% release after 5 weeks in suspension. In contrast, lutein-loaded NPs stored at 25°C and 37°C experienced significant changes in size, likely due to aggregation and surfactant dissociation; these NPs showed signs of bulk degradation based on transmission electron microscopy (TEM), and had significant lutein degradation and over 40% release after 5 weeks. Lutein loaded in NPs was more resistant to photodegradation compared to a free lutein solution when exposed to UV for 6 h, degrading 5 times slower than free lutein. To test the performance of NP therapeutics in vivo, Cy5-labled NPs were applied topically to the eyes of rats and incubated for 15 min, 30 min, or 60 min. Exterior eye tissues including the cornea, episcleral tissue, and sclera showed the highest fluorescence intensity in animals that received fluorescent nanoparticles, while the choroid was the only inner eye tissue that was significantly higher in a treatment group compared to the control group. Additionally, decreases of fluorescence in all exterior eye tissues and the choroid at 1 h compared to 30 min, indicated rapid elimination of NPs from the eye.

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“…After the Tam-Gel hydrogel was injected into the tumor tissue, the drug was released by the dissolution of the gel into the tumor tissue, thereby achieving the sustained release of the drug in the tumor tissue. PLGA-PEG-PLGA is a novel organic polymer material with good safety and is fully biodegradable 45–47. It also has the chemistry of sol-gel conversion and could be used to prepare temperature-sensitive phase-change hydrogels.…”

Section: Discussionmentioning

confidence: 99%

<p>A temperature-sensitive phase-change hydrogel of tamoxifen achieves the long-acting antitumor activation on breast cancer cells</p>

Du¹,

Lei²,

Zheng³

et al. 2019

OTT

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Background: Breast cancer is one of the foremost threats to female health nowadays. Tamoxifen, an antagonist of estrogen receptor-α (ERα), is the first choice for endocrine-dependent breast cancer (ERα-positive breast cancer) treatment. However, ERα has an important function in the normal physical regulation of estrogen, and current oral administration of tamoxifen has potential side effects on normal endocrine secretion. In the present work, we aim to develop novel approaches to increase the antitumor effect of tamoxifen on breast cancer cells and decrease the potential side effects in the human body during treatment. Methods: A temperature-sensitive phase-change hydrogel for tamoxifen (Tam-Gel) was generated. After establishing subcutaneous tumors formed by MCF-7, an ERα-positive breast cancer cell line, in nude mice, an intratumoral injection of Tam-Gel was performed to examine whether Tam-Gel facilitated the slow-release or antitumor effect of tamoxifen. A metastatic breast cancer model was established using the intrahepatic growth of MCF-7 cells in immunodeficient rats. Results: Tam-Gel can transform from liquid to hydrogel at room temperature. An intratumoral injection of Tam-Gel facilitated the slow-release or antitumor effect of tamoxifen. Once Tam-Gel, but not Tam-Sol, was administered by intratumoral injection, it significantly decreased the uptake of radionuclide probes ( 18 F-fluoroestradiol or 18 F-fluorodeoxyglucose) by cells in rats’ livers and the intrahepatic growth of MCF-7 cells in rats’ livers. Conclusion: A novel slow-release system was successfully prepared to facilitate the long-term release of tamoxifen in breast cancer tissues, and achieved an antitumor effect in the long term.

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RNA nanoparticle distribution and clearance in the eye after subconjunctival injection with and without thermosensitive hydrogels

Cited by 38 publications

References 37 publications

Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice

Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice

Stability and Ocular Biodistribution of Topically Administered PLGA Nanoparticles

<p>A temperature-sensitive phase-change hydrogel of tamoxifen achieves the long-acting antitumor activation on breast cancer cells</p>

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