Celastrol-loaded PEG-<i>b</i>-PPS nanocarriers as an anti-inflammatory treatment for atherosclerosis

Allen, Shannon A.; Liu, Yu-Gang; Kim, Taehyeung; Bobbala, Sharan; Yi, Sijia; Zhang, Xiaohan; Choi, Jaehyuk; Scott, Evan A.

doi:10.1039/c8bm01224e

Cited by 71 publications

(59 citation statements)

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“…After 2 hours of exposure to various doses of (+)MiNP and Free LatA, (+)MiNP treated macrophages remained highly viable at all tested concentrations, while free LatA treated macrophages demonstrated significant toxicity at doses of 0.5 μM and above (Figure 2e). This is consistent with our previous findings in which encapsulation of small molecule drug Celastrol reduced its cytotoxicity in vitro [20] .…”

Section: Resultssupporting

confidence: 94%

“…These micelles have also been previously shown to reduce the cytotoxicity of small molecule drugs such as celastrol. [20] Here, we employ macropinocytosis inhibitory nanoparticles (MiNP) to reduce non-specific nanoparticle uptake by the MPS and enhance their accumulation within target tissues. MiNP are comprised of PEG-b-PPS micelles containing Latrunculin A (LatA), a well-known and transient actin depolymerizing agent [21] .…”

Section: Introductionmentioning

confidence: 99%

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Co-administration of macropinocytosis inhibitory nanoparticles (MiNP) for enhanced nanoparticle circulation time and target tissue accumulation following subcutaneous injection

Stack¹,

Liu²,

Frey³

et al. 2020

Preprint

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A signficant barrier to the application of nanoparticles for precision medicine is the mononuclear phagocyte system (MPS), a diverse population of phagocytic cells primarily located within the liver, spleen and lymph nodes. The majority of nanoparticles are indiscriminantly cleared by the MPS via macropinocytosis before reaching their intended targets, resulting in side effects and decreased efficacy. This work demonstrates that the biodistribution and desired tissue accumulation of targeted nanoparticles can be significantly enhanced by co-injection with polymeric micelles containing the actin depolymerizing agent latrunculin A. These macropinocytosis inhibitory nanoparticles (MiNP) were found to selectively inhibit non-specific uptake of a second “effector” nanoparticle in vitro without impeding receptor-mediated endocytosis. In tumor bearing mice, co-injection with MiNP in a single multi-nanoparticle formulation significantly increased the accumulation of folate-receptor targeted nanoparticles within tumors. Furthermore, subcutaneous co-administration with MiNP allowed effector nanoparticles to achieve serum levels that rivaled a standard intravenous injection. This effect was only observed if the effector nanoparticles were injected within 24 h following MiNP administration, indicating a temporary avoidance of MPS cells. Co-injection with MiNP therefore allows reversible evasion of the MPS for targeted nanoparticles and presents a previously unexplored method of modulating and improving nanoparticle biodstribution following subcutaneous administration.Abstract FigureTOC Text: Polymeric macropinocytosis inhibiting nanoparticles reduce non-specific uptake of an “effector” nanoparticle by cells of the mononuclear phagocyte system. This macropinocytosis specific inhibition allows for greater accumulation and uptake of targeted nanoparticles in tissues of interest thereby increasing their efficacy and reducing side effects.

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Section: Resultssupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Co-administration of macropinocytosis inhibitory nanoparticles (MiNP) for enhanced nanoparticle circulation time and target tissue accumulation following subcutaneous injection

Stack¹,

Liu²,

Frey³

et al. 2020

Preprint

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“…As a natural product, celastrol was mainly extracted from Tripterygium wilfordii and listed as one of the five traditional natural medicinal compounds most likely to be developed as modern drugs (Corson & Crews, 2007). Celastrol revealed multiple activity on immunity (Dudics et al, 2018), diabetes (Pfuhlmann et al, 2019) and inflammatory (Allen et al, 2019) and tumor diseases (Li et al, 2019). To reduce its toxicity and optimize its pharmacological properties, many superior derivatives were generated as indicated in other reports.…”

Section: Discussionmentioning

confidence: 99%

Design and synthesis of novel celastrol derivative and its antitumor activity in hepatoma cells and antiangiogenic activity in zebrafish

Wang

Xiao

et al. 2019

Journal Cellular Physiology

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Two series of celastrol derivatives were designed and synthesized by modifying carboxylic acid at the 28th position with amino acid, and their intermediates with isobutyrate at the third position. All compounds were evaluated for their antiproliferation activity by four human cancer cell lines (SCG7901, HGC27, HepG2, and Bel7402) and one normal cell LO2. The most promising compound, compound 8, showed superior bioactivity and lower toxicity than others including celastrol. Further underlying tests illustrated that compound 8 induced apoptosis and cell arrest at G2/M and inhibited proliferation and mobility of human hepatoma cells by suppressing the signal transducer and activator of transcription‐3 signaling pathway. Besides these, a highly accurate and reproducible high performance liquid chromatography protocol was established to determine celastrol and compound 8 absorption in zebrafish, and results demonstrated that their concentration increased rapidly within 4 hr in a time‐dependent manner and the concentration of compound 8 was higher than that of celastrol. In addition, without detection at 12 hr, compound 8 was rapidly metabolized in vivo. These findings are very helpful for the structural modification of celastrol and other bioactive compounds to improve their bioactivity, toxicity, and absorption.

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“…[10] Targeted nanomaterials have been shown to lower the therapeutic threshold concentration for cer tain drugs after encapsulation as well as reduce cytotoxicity and other unwanted effects in many cell types including SC cells. [11][12][13] Latrunculin is a wellknown transient actin depolymerizing agent that mechanically softens cells [14] and has been shown to significantly reduce IOP in animal studies. [5,15] A phase I clinical trial, at concentrations previously found to be effective in primates, found a modest reduction of IOP with side effects that included mild redness, irritation, and a transient increase in central corneal thickness.…”

Section: Doi: 101002/smll202004205mentioning

confidence: 99%

Targeted Delivery of Cell Softening Micelles to Schlemm's Canal Endothelial Cells for Treatment of Glaucoma

Stack

Vincent

Vahabikashi

et al. 2020

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Increased stiffness of the Schlemm's canal (SC) endothelium in the aqueous humor outflow pathways has been associated with elevated intraocular pressure (IOP) in glaucoma. Novel treatments that relax this endothelium, such as actin depolymerizers and rho kinase inhibitors, are in development. Unfortunately, these treatments have undesirable off‐target effects and a lower than desired potency. To address these issues, a targeted PEG‐b‐PPS micelle loaded with actin depolymerizer latrunculin A (tLatA‐MC) is developed. Targeting of SC cells is achieved by modifying the micelle surface with a high affinity peptide that binds the VEGFR3/FLT4 receptor, a lymphatic lineage marker found to be highly expressed by SC cells relative to other ocular cells. During in vitro optimization, increasing the peptide surface density increased micellar uptake in SC cells while unexpectedly decreasing uptake by human umbilical vein endothelial cells (HUVEC). The functional efficacy of tLatA‐MC, as measured by decreased SC cell stiffness compared to non‐targeted micelles (ntLatA‐MC) or targeted blank micelles (tBL‐MC), is verified using atomic force microscopy. tLatA‐MC reduced IOP in an in vivo mouse model by 30–50%. The results validate the use of a cell‐softening nanotherapy to selectively modulate stiffness of SC cells for therapeutic reduction of IOP and treatment of glaucoma.

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Celastrol-loaded PEG-b-PPS nanocarriers as an anti-inflammatory treatment for atherosclerosis

Abstract: Encapsulation within poly(ethylene glycol)-b-poly(propylene sulfide) micelles reduces the toxicity of celastrol and enhances its anti-inflammatory effect during treatment of atherosclerosis.

Cited by 71 publications

References 71 publications

Co-administration of macropinocytosis inhibitory nanoparticles (MiNP) for enhanced nanoparticle circulation time and target tissue accumulation following subcutaneous injection

Co-administration of macropinocytosis inhibitory nanoparticles (MiNP) for enhanced nanoparticle circulation time and target tissue accumulation following subcutaneous injection

Design and synthesis of novel celastrol derivative and its antitumor activity in hepatoma cells and antiangiogenic activity in zebrafish

Targeted Delivery of Cell Softening Micelles to Schlemm's Canal Endothelial Cells for Treatment of Glaucoma

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