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A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes.

ABSTRACT: Monocyte-derived myeloid cells play vital roles in inflammation-related autoimmune/inflammatory diseases and cancers. Here, we report that exosomes can deliver anti-inflammatory agents, such as curcumin, to activated myeloid cells in vivo. This technology provides a means for anti-inflammatory drugs, such as curcumin, to target the inflammatory cells as well as to overcome unwanted off-target effects that limit their utility. Using exosomes as a delivery vehicle, we provide evidence that curcumin delivered by exosomes is more stable and more highly concentrated in the blood. We show that the target specificity is determined by exosomes, and the improvement of curcumin activity is achieved by directing curcumin to inflammatory cells associated with therapeutic, but not toxic, effects. Furthermore, we validate the therapeutic relevance of this technique in a lipopolysaccharide (LPS)-induced septic shock mouse model. We further show that exosomes, but not lipid alone, are required for the enhanced anti-inflammatory activity of curcumin. The specificity of using exosomes as a drug carrier creates opportunities for treatments of many inflammation-related diseases without significant side effects due to innocent bystander or off-target effects.

SUBMITTER: Sun D

PROVIDER: S-EPMC2956928 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Curcumin encapsulated zeolitic imidazolate frameworks as stimuli responsive drug delivery system and their interaction with biomimetic environment.

Project description:Metal organic frameworks (MOFs) exhibit unique features of finely tunable pore structures, excellent chemical stability and flexible surface structural functionality, making them advantageous for a wide range of applications including energy storage, compound separation, catalysis, and drug delivery. The present work enlightens a novel approach of single step fabrication of CCM-ZIF-8 as a drug carrier and its application as stimuli responsive drug delivery systems via external stimuli involving change in pH and in presence of biomimetic cell membrane like environment using liposomes and SDS micelles. The methodology is devoid of any post synthesis drug loading steps. The synthesized curcumin encapsulated ZIF-8 frameworks demonstrate ultrahigh drug encapsulation efficiency (ca. 83.33%) and good chemical stability. In vitro drug release of curcumin was three times higher in acidic medium than in physiological pH. Cytotoxicity results demonstrated enhanced therapeutic effect of CCM-ZIF-8 than free curcumin. Confocal microscopy results confirmed the easy cellular internalization of CCM-ZIF-8 in HeLa cells. Intracellular distribution studies at various incubation times confirmed the clathrin-mediated endocytosis to lysosomal pathway of CCM-ZIF-8, but without mitochondria being an intracellular fate. The results signify that CCM-ZIF-8 is an efficient drug carrier for passive tumor therapy in future for cancer treatments.

| S-EPMC5626696 | biostudies-literature

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2023-03-11 | PXD033512 | Pride

Thermally responsive nanoparticle-encapsulated curcumin and its combination with mild hyperthermia for enhanced cancer cell destruction.

Project description:In this study, thermally responsive polymeric nanoparticle-encapsulated curcumin (nCCM) was prepared and characterized. The nCCM is ? 22 and 300 nm in diameter at 37 and 22 °C, respectively. The smaller size of the nCCM at 37 °C was found to significantly facilitate its uptake in vitro by human prostate adenocarcinoma PC-3 cancer cells. However, the intracellular nCCM decreases rapidly (rather than plateaus) after reaching its peak at ? 1.5 h during a 3-day incubation of the PC-3 cells with nCCM. Moreover, a mild hyperthermia (with negligible cytotoxicity alone) at 43 °C applied between 1 and 1.5 h during the 3-day incubation not only increases the peak uptake but also alters intracellular distribution of nCCM (facilitating its delivery into cell nuclei), which helps to retain a significantly much higher level of intracellular curcumin. These effects of mild hyperthermia could be due in part to the thermal responsiveness of the nCCM: they are more positively charged at 43 °C and can be more easily attracted to the negatively charged nuclear membrane to enter nuclei as a result of electrostatic interaction. Ultimately, a combination of the thermally responsive nCCM and mild hyperthermia significantly enhances the anticancer capability of nCCM, resulting in a more than 7-fold decrease in its inhibitory concentration to reduce cell viability to 50% (IC50). Further mechanistic studies suggest injury pathways associated with heat shock proteins 27 and 70 should contribute to the enhanced cancer cell destruction by inducing cell apoptosis and necrosis. Overall, this study demonstrates the potential of combining mild hyperthermia and thermally responsive nanodrugs such as nCCM for augmented cancer therapy.

| S-EPMC4136765 | biostudies-literature

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| S-EPMC8116217 | biostudies-literature

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| S-EPMC6619690 | biostudies-literature

Boosting Intracellular Delivery of Lipid Nanoparticle-Encapsulated mRNA.

Project description:Intracellular delivery of mRNA holds great potential for vaccine1-3 and therapeutic4 discovery and development. Despite increasing recognition of the utility of lipid-based nanoparticles (LNPs) for intracellular delivery of mRNA, particle engineering is hindered by insufficient understanding of endosomal escape, which is believed to be a main limiter of cytosolic availability and activity of the nucleic acid inside the cell. Using a series of CRISPR-based genetic perturbations of the lysosomal pathway, we have identified that late endosome/lysosome (LE/Ly) formation is essential for functional delivery of exogenously presented mRNA. Lysosomes provide a spatiotemporal hub to orchestrate mTOR signaling and are known to control cell proliferation, nutrient sensing, ribosomal biogenesis, and mRNA translation. Through modulation of the mTOR pathway we were able to enhance or inhibit LNP-mediated mRNA delivery. To further boost intracellular delivery of mRNA, we screened 212 bioactive lipid-like molecules that are either enriched in vesicular compartments or modulate cell signaling. Surprisingly, we have discovered that leukotriene-antagonists, clinically approved for treatment of asthma and other lung diseases, enhance intracellular mRNA delivery in vitro (over 3-fold, p < 0.005) and in vivo (over 2-fold, p < 0.005). Understanding LNP-mediated intracellular delivery will inspire the next generation of RNA therapeutics that have high potency and limited toxicity.

| S-EPMC5623340 | biostudies-literature

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