Abstract 18238: Cardiomyocyte-specific Bag3+ Mutation P209L Induces Mitochondrial Fragmentation, Increased Apoptosis, and Activates p38 Signaling in vivo

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Megan T Quintana ◽  
Samuel C Eaton ◽  
Cecelia C Yates ◽  
Shinichi Takayama ◽  
Monte S Willis
Keyword(s):  
Mitochondrial Dynamics ◽  
Systolic Function ◽  
Cardiac Complications ◽  
Autophagic Flux ◽  
Mitochondrial Fragmentation ◽  
Downstream Signaling ◽  
Transmission Electron ◽  
Confocal Immunofluorescence ◽  
Amyloid Oligomers

Introduction: There are 6 members of the Bcl2-related anthanogene (BAG) protein family, which act as co-chaperones expressed at high levels in skeletal and cardiac muscle. BAG3 is involved in chaperone-assisted selective autophagy (CASA). Mutations in the Z-disc protein BAG3 have recently been found to cause myofibrillar myopathy (MFM) with cardiac complications (dilated cardiomyopathy). The missense mutation Pro209Leu (P209L) is one of ten BAG3 mutations identified in human disease to date. Hypothesis: Cardiac BAG3 P209L expression inhibits CASA, evidenced by less autophagic flux of misfolded proteins. Methods: Cardiac specific transgenic mice with alphaMHC-driven human Bag3P209L were created and analyzed functionally over 12 months. Histological analysis of apoptosis (TUNEL), pre-amyloid oligomers (PAO), and fibroblasts were performed in parallel with transmission electron microscopy (TEM) and molecular analysis of autophagy and mitochondrial dynamics. Results: Starting at 8 months, Bag3 P209L Tg+ hearts had significantly depressed systolic function. By 12 months, significant deficits in both diastolic and systolic function were identified, along with increased number of fragmented mitochondria and significant alterations in genes regulating mitochondrial fusion (Opa1) and Fission (Drp1). Immunofluorescence analysis revealed no differences in apoptosis (TUNEL) or autophagic flux (LC3II). But increased levels of cardiomyocyte pre-amyloid oligomers (PAO) were identified by confocal immunofluorescence. As PAO proteotoxic intermediates found in neurodegenerative diseases reportedly activate p38 MAPK, we assayed BAG3 P209L Tg+ hearts and found a significant ~50% increase in phospho-p38/p38. Conclusion: As increased activated p38 activity has negative inotropic and restrictive diastolic effects in vivo, we conclude that inhibiting p38 activity in BAG3 P209L patients may attenuate and/or delay the onset of heart failure. Studies are underway testing this hypothesis using specific inhibitors of P38 and downstream signaling pathways in vivo.

scholarly journals Mfn2 Overexpression Attenuates MPTP Neurotoxicity In Vivo

2021 ◽  
Vol 22 (2) ◽  
pp. 601
Author(s):  
Fanpeng Zhao ◽  
Quillan Austria ◽  
Wenzhang Wang ◽  
Xiongwei Zhu
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Dynamics ◽  
Significant Loss ◽  
Critical Event ◽  
Mitochondrial Fragmentation ◽  
Wild Type Littermate ◽  
Littermate Control ◽  
Mptp Administration

Mitochondrial dysfunction represents a critical event in the pathogenesis of Parkinson’s disease (PD). Increasing evidence demonstrates that disturbed mitochondrial dynamics and quality control play an important role in mitochondrial dysfunction in PD. Our previous study demonstrated that MPP+ induces mitochondrial fragmentation in vitro. In this study, we aimed to assess whether blocking MPTP-induced mitochondrial fragmentation by overexpressing Mfn2 affords neuroprotection in vivo. We found that the significant loss of dopaminergic neurons in the substantia nigra (SN) induced by MPTP treatment, as seen in wild-type littermate control mice, was almost completely blocked in mice overexpressing Mfn2 (hMfn2 mice). The dramatic reduction in dopamine neuronal fibers and dopamine levels in the striatum caused by MPTP administration was also partially inhibited in hMfn2 mice. MPTP-induced oxidative stress and inflammatory response in the SN and striatum were significantly alleviated in hMfn2 mice. The impairment of motor function caused by MPTP was also blocked in hMfn2 mice. Overall, our work demonstrates that restoration of mitochondrial dynamics by Mfn2 overexpression protects against neuronal toxicity in an MPTP-based PD mouse model, which supports the modulation of mitochondrial dynamics as a potential therapeutic target for PD treatment.

Abstract 14412: Activation of Autophagic Flux Maintains Mitochondrial Homeostasis During Cardiac Ischemia/reperfusion Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jing Yang ◽  
Geoffrey W CHO ◽  
Lihao He ◽  
Yuxin Chu ◽  
Jin He ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Border Zone ◽  
Autophagic Flux ◽  
Hdac Inhibition ◽  
Infarct Border Zone ◽  
Infarct Border

Background and Hypothesis: Reperfusion injury accounts for ~50% of myocardial infarct size, and clinically efficacious therapies are lacking. Histone deacetylase (HDAC) inhibition enhances cardiomyocyte autophagic activity, mitochondria biogenesis, and blunts ischemia/reperfusion (I/R) injury when given at the time of reperfusion. However, as HDAC inhibition has pleiotropic effects, we will test whether augmentation of autophagic flux using a specific autophagy-inducing peptide, Tat-Beclin (TB), is cardioprotective. Methods: 8-12-week-old, wild-type, C57BL6 mice were randomized into three groups: vehicle control, Tat-Scrambled (TS) peptide, or Tat-Beclin (TB) peptide. Each group was subjected to I/R surgery (45min ischemia, 24h reperfusion). Infarct size, systolic function, and mitochondrial dynamics were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were used to test for cardiomyocyte specificity. Conditional cardiomyocyte ATG7 knockout (ATG7 KO) mice and ATG7 knockdown by siRNA in NRVMs were used to evaluate the role of autophagy. Results: TB treatment at reperfusion reduced infarct size by 20.1±6.3% (n=23, p<0.02) and improved systolic function. Increased autophagic flux and reduced reactive oxygen species (ROS) were observed in the infarct border zone. The cardioprotective effects of TB were abolished in ATG7 KO mice. TB increased mtDNA content in the border zone significantly. In NRVMs subjected to I/R, TB reduced cell death by 41±6% (n=12, p<0.001), decreased ROS, and increased mtDNA content significantly by ~50%. Moreover, TB promoted expression of PGC1α (a major driver of mitochondrial biogenesis) both in the infarct border zone and NRVMs subjected to I/R by ~40%, and increased levels of mitochondrial dynamics gene transcripts Drp1, Fis1, and MFN1 / 2. Conversely, ATG7 knockdown in NRVMs and cardiac ATG7 KO abolished the beneficial effects of TB on mitochondria DNA content. Conclusions: Autophagic flux is an essential process to mitigate myocardial reperfusion injury acting, at least in part, by inducing PGC1α-mediated mitochondrial biogenesis. Augmentation of autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in myocardial infarction.

scholarly journals Hepatitis C Virus Non-Structural Protein 5A (NS5A) Disrupts Mitochondrial Dynamics and Induces Mitophagy

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 290 ◽  
Author(s):  
Alagie Jassey ◽  
Ching-Hsuan Liu ◽  
Chun Changou ◽  
Christopher Richardson ◽  
Hsue-Yin Hsu ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Underlying Mechanism ◽  
Effector Protein ◽  
Autophagic Flux ◽  
Oxygen Species ◽  
Structural Protein ◽  
Mitochondrial Fragmentation ◽  
Lysosomal Degradation ◽  
Subgenomic Replicon ◽  
Important Regulator

Mitophagy is a selective form of autophagy, targeting damaged mitochondria for lysosomal degradation. Although HCV infection has been shown to induce mitophagy, the precise underlying mechanism and the effector protein responsible remain unclear. Herein, we demonstrated that the HCV non-structural protein 5A (NS5A) plays a key role in regulating cellular mitophagy. Specifically, the expression of HCV NS5A in the hepatoma cells triggered hallmarks of mitophagy including mitochondrial fragmentation, loss of mitochondrial membrane potential, and Parkin translocation to the mitochondria. Furthermore, mitophagy induction through the expression of NS5A led to an increase in autophagic flux as demonstrated by an accumulation of LC3II in the presence of bafilomycin and a time-dependent decrease in p62 protein level. Intriguingly, the expression of NS5A concomitantly enhanced reactive oxygen species (ROS) production, and treatment with an antioxidant attenuated the NS5A-induced mitophagy event. These phenomena are similarly recapitulated in the NS5A-expressing HCV subgenomic replicon cells. Finally, we demonstrated that expression of HCV core, which has been documented to inhibit mitophagy, blocked the mitophagy induction both in cells harboring HCV replicating subgenomes or expressing NS5A alone. Our results, therefore, identified a new role for NS5A as an important regulator of HCV-induced mitophagy and have implications to broadening our understanding of the HCV-mitophagy interplay.

scholarly journals The Drosophila effector caspase Dcp-1 regulates mitochondrial dynamics and autophagic flux via SesB

2014 ◽  
Vol 205 (4) ◽  
pp. 477-492 ◽  
Author(s):  
Lindsay DeVorkin ◽  
Nancy Erro Go ◽  
Ying-Chen Claire Hou ◽  
Annie Moradian ◽  
Gregg B. Morin ◽  
...  
Keyword(s):  
Adenine Nucleotide ◽  
Mitochondrial Dynamics ◽  
Negative Regulator ◽  
Mitochondrial Morphology ◽  
Autophagic Flux ◽  
Loss Of Function ◽  
Effector Caspase ◽  
Apoptosis Pathways ◽  
Mitochondrial Elongation

Increasing evidence reveals that a subset of proteins participates in both the autophagy and apoptosis pathways, and this intersection is important in normal physiological contexts and in pathological settings. In this paper, we show that the Drosophila effector caspase, Drosophila caspase 1 (Dcp-1), localizes within mitochondria and regulates mitochondrial morphology and autophagic flux. Loss of Dcp-1 led to mitochondrial elongation, increased levels of the mitochondrial adenine nucleotide translocase stress-sensitive B (SesB), increased adenosine triphosphate (ATP), and a reduction in autophagic flux. Moreover, we find that SesB suppresses autophagic flux during midoogenesis, identifying a novel negative regulator of autophagy. Reduced SesB activity or depletion of ATP by oligomycin A could rescue the autophagic defect in Dcp-1 loss-of-function flies, demonstrating that Dcp-1 promotes autophagy by negatively regulating SesB and ATP levels. Furthermore, we find that pro–Dcp-1 interacts with SesB in a nonproteolytic manner to regulate its stability. These data reveal a new mitochondrial-associated molecular link between nonapoptotic caspase function and autophagy regulation in vivo.

scholarly journals CMTM7 as a novel molecule of ATG14L-Beclin1-VPS34 complex enhances autophagy by Rab5 to regulate tumorigenicity

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Baocai Liu ◽  
Yinliang Lu ◽  
Tingting Zhang ◽  
Xinyue Yu ◽  
Qian Wang ◽  
...  
Keyword(s):  
Early Stage ◽  
Xenograft Model ◽  
Vital Role ◽  
Autophagic Flux ◽  
In Vivo Experiments ◽  
Transmission Electron ◽  
Autophagy Induction

Abstract Background CMTM7 is a tumor suppressor that positively regulates EGFR degradation by promoting Rab5 activation, and plays a vital role in tumor progression. Rab5 forms complexes with Beclin1 and VPS34, and acts in the early stage of autophagy. However, the affects of CMTM7 on autophagy and its mechanism are still unclear. Methods The effect of CMTM7 on autophagy induction was confirmed by western blotting, confocal microscopy and transmission electron microscopy. Co-immunoprecipitation was used to analyse the interaction of CMTM7 with autophagy initiation complex and Rab5. The xenograft model in nude mice was used to elucidate the function of CMTM7 in tumorigenicity and autophagy in vivo. Results In this study, we first demonstrated that CMTM7 facilitated the initiation of autophagosome formation, which consequently promoted the subsequent multistage process of autophagic flux, i.e. from autophagosome assembly till autolysosome formation and degradation. Confocal and co-immunoprecipitation showed that CMTM7 interacted with Rab5, VPS34, Beclin1, and ATG14L, but not with ULK1, UVRAG and LC3B. CMTM7 also increased the activity of ATG14L-linked VPS34 complex and its association with Rab5. Both in vitro and in vivo experiments demonstrated that knockdown of CMTM7 enhanced tumor growth by impairing autophagy. Conclusion These findings highlighted the role of CMTM7 in the regulation of autophagy and tumorigenicity, revealing it as a novel molecule that is associated with the interaction of Rab5 and ATG14L-Beclin1-VPS34 complex.

Mitochondrial Fusion Suppresses Tau Pathology-Induced Neurodegeneration and Cognitive Decline

2021 ◽  
pp. 1-13
Author(s):  
Luwen Wang ◽  
Mengyu Liu ◽  
Ju Gao ◽  
Amber M. Smith ◽  
Hisashi Fujioka ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Loss ◽  
Mitochondrial Fusion ◽  
Barnes Maze ◽  
Mitochondrial Fragmentation ◽  
Tau Pathology ◽  
Marked Suppression

Background: Abnormalities of mitochondrial fission and fusion, dynamic processes known to be essential for various aspects of mitochondrial function, have repeatedly been reported to be altered in Alzheimer’s disease (AD). Neurofibrillary tangles are known as a hallmark feature of AD and are commonly considered a likely cause of neurodegeneration in this devastating disease. Objective: To understand the pathological role of mitochondrial dynamics in the context of tauopathy. Methods: The widely used P301S transgenic mice of tauopathy (P301S mice) were crossed with transgenic TMFN mice with the forced expression of Mfn2 specifically in neurons to obtain double transgenic P301S/TMFN mice. Brain tissues from 11-month-old non-transgenic (NTG), TMFN, P301S, and P301S/TMFN mice were analyzed by electron microscopy, confocal microscopy, immunoblot, histological staining, and immunostaining for mitochondria, tau pathology, and tau pathology-induced neurodegeneration and gliosis. The cognitive function was assessed by the Barnes maze. Results: P301S mice exhibited mitochondrial fragmentation and a consistent decrease in Mfn2 compared to age-matched NTG mice. When P301S mice were crossed with TMFN mice (P301S/TMFN mice), neuronal loss, as well as mitochondria fragmentation were significantly attenuated. Greatly alleviated tau hyperphosphorylation, filamentous aggregates, and thioflavin-S positive tangles were also noted in P301S/TMFN mice. Furthermore, P301S/TMFN mice showed marked suppression of neuroinflammation and improved cognitive performance in contrast to P301S mice. Conclusion: These in vivo findings suggest that promoted mitochondrial fusion suppresses toxic tau accumulation and associated neurodegeneration, which may protect against the progression of AD and related tauopathies.

scholarly journals Aberrant mitochondrial fission in neurons induced by protein kinase Cδ under oxidative stress conditions in vivo

2011 ◽  
Vol 22 (2) ◽  
pp. 256-265 ◽  
Author(s):  
Xin Qi ◽  
Marie-Helene Disatnik ◽  
Ning Shen ◽  
Raymond A. Sobel ◽  
Daria Mochly-Rosen
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Mitochondrial Fragmentation ◽  
Neurological Pathology ◽  
Protein Kinase Cδ

Neuronal cell death in a number of neurological disorders is associated with aberrant mitochondrial dynamics and mitochondrial degeneration. However, the triggers for this mitochondrial dysregulation are not known. Here we show excessive mitochondrial fission and mitochondrial structural disarray in brains of hypertensive rats with hypertension-induced brain injury (encephalopathy). We found that activation of protein kinase Cδ (PKCδ) induced aberrant mitochondrial fragmentation and impaired mitochondrial function in cultured SH-SY5Y neuronal cells and in this rat model of hypertension-induced encephalopathy. Immunoprecipitation studies indicate that PKCδ binds Drp1, a major mitochondrial fission protein, and phosphorylates Drp1 at Ser 579, thus increasing mitochondrial fragmentation. Further, we found that Drp1 Ser 579 phosphorylation by PKCδ is associated with Drp1 translocation to the mitochondria under oxidative stress. Importantly, inhibition of PKCδ, using a selective PKCδ peptide inhibitor (δV1-1), reduced mitochondrial fission and fragmentation and conferred neuronal protection in vivo and in culture. Our study suggests that PKCδ activation dysregulates the mitochondrial fission machinery and induces aberrant mitochondrial fission, thus contributing to neurological pathology.

scholarly journals Dependence of Leydig Cell’s Mitochondrial Physiology on Luteinizing Hormone Signaling

Life ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 19
Author(s):  
Marija L. J. Medar ◽  
Dijana Z. Marinkovic ◽  
Zvezdana Kojic ◽  
Alisa P. Becin ◽  
Isidora M. Starovlah ◽  
...  
Keyword(s):  
Leydig Cells ◽  
Ex Vivo ◽  
Mitochondrial Dynamics ◽  
Experimental Models ◽  
Atp Production ◽  
Transmission Electron ◽  
Important Regulator ◽  
Steroidogenic Cells ◽  
And Function

Knowledge about the relationship between steroidogenesis and the regulation of the mitochondrial bioenergetics and dynamics, in steroidogenic cells, is not completely elucidated. Here we employed in vivo and ex vivo experimental models to analyze mitochondrial physiology in Leydig cells depending on the different LH-cAMP environments. Activation of LH-receptor in rat Leydig cells ex and in vivo triggered cAMP, increased oxygen consumption, mitoenergetic and steroidogenic activities. Increased mitoenergetic activity i.e., ATP production is achieved through augmented glycolytic ATP production and a small part of oxidative phosphorylation (OXPHOS). Transcription of major genes responsible for mitochondrial dynamics was upregulated for Ppargc1a (regulator of mitogenesis and function) and downregulated for Drp1 (main fission marker), Prkn, Pink1 and Tfeb (mitophagy markers). Leydig cells from gonadotropin-treated rats show increased mitogenesis confirmed by increased mitochondrial mass, increased mtDNA, more frequent mitochondria observed by a transmission electron microscope and increased expression of subunits of respiratory proteins Cytc/CYTC and COX4. Opposite, Leydig cells from hypogonadotropic-hypogonadal rats characterized by low LH-cAMP, testosterone, and ATP production, reduced markers of mitogenesis and mitofusion (Mfn1/2, Opa1) associated with reduced mtDNA content. Altogether results underline LH-cAMP signaling as an important regulator of mitochondrial physiology arranging mitochondrial dynamics, bioenergetic and steroidogenic function in Leydig cells.

Abstract 283: SGK1-Dependent Sirt3 Phosphorylation Regulates Mitochondrial Dynamics

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Dallas Ellis ◽  
Takara Scott ◽  
Wei Zhong ◽  
Oguljahan Babayeva ◽  
Sharon C Francis
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Ectopic Expression ◽  
Mitochondrial Fragmentation ◽  
Proteomic Screen ◽  
Protein Levels ◽  
Stimulation Of

Mitochondrial dynamics (i.e. fusion and fission) is impaired in models of obesity and can result in target organ dysfunction. However, the mechanisms that regulate mitochondrial dynamics in the setting of obesity are not completely understood. The objectives of this study are to examine a role for and determine the molecular mechanisms of serum and glucocorticoid-inducible kinase 1 (SGK1) in obesity-related mitochondrial dynamics in the vasculature. We recently reported that aortic expression of SGK1 is elevated in a model of diet-induced obesity (DIO) in vivo and by resistin; a fat-derived adipokine, in human aortic smooth muscle cells (SMC) in vitro . To directly examine the effects of SMC-derived SGK1 on mitochondrial dynamics, wildtype and SMC-specific SGK1 knockout mice were subjected to DIO for eight weeks. Our results indicate that SMC-specific deletion of SGK1 induced a fused, elongated mitochondrial phenotype in aortic SMC in vivo and attenuated obesity-mediated arterial mitochondrial fragmentation suggesting a role for SGK1 in stimulation of mitochondrial fission. To determine the molecular mechanism for this effect, we performed a proteomic screen for novel SGK1 substrates and identified the mitochondrial deacetylase SIRT3 as a novel SGK1 target. Mass spectrometry indicates SGK1 phosphorylates SIRT3 on serine103. Increasing doses of resistin augmented SIRT3-S103 phosphorylation and caused a concomitant decrease in total SIRT3 in rat aortic SMC in vitro . To examine whether SGK1-dependent SIRT3 phosphorylation regulates the mitochondrial fission protein machinery; we evaluated total and activated levels of Drp1, the mitochondrial fission regulator, in response to ectopic expression of SIRT3 wildtype, phospho-memetic (S103D) and phospho-deficient (S103A) mutants. SIRT3-S103D increased total Drp1 and activated Drp1 protein levels an effect inhibited by SIRT3-S103A. These findings implicate elevated resistin observed during obesity in stimulation of SGK1 and subsequent phosphorylation of SIRT3 leading to activation of Drp1 and stimulation of arterial mitochondrial fragmentation.

Pharmacokinetic Evaluation of 99mTc-radiolabeled Solid Lipid Nanoparticles and Chitosan Coated Solid Lipid Nanoparticles

2020 ◽  
Vol 20 (13) ◽  
pp. 1044-1052
Author(s):  
Nasrin Abbasi Gharibkandi ◽  
Sajjad Molavipordanjani ◽  
Jafar Akbari ◽  
Seyed Jalal Hosseinimehr
Keyword(s):  
Solid Lipid Nanoparticles ◽  
Lipid Nanoparticles ◽  
High Resistivity ◽  
Scanning Calorimetry ◽  
Liver Uptake ◽  
Solid Lipid ◽  
Transmission Electron ◽  
Main Portion ◽  
Pharmacokinetic Behavior

Background: Solid Lipid Nanoparticles (SLNs) possess unique in vivo features such as high resistivity, bioavailability, and habitation at the target site. Coating nanoparticles with polymers such as chitosan greatly affects their pharmacokinetic behavior, stability, tissue uptake, and controlled drug delivery. The aim of this study was to prepare and evaluate the biodistribution of 99mTc-labeled SLNs and chitosan modified SLNs in mice. Methods: 99mTc-oxine was prepared and utilized to radiolabel pre-papered SLNs or chitosan coated SLNs. After purification of radiolabeled SLNs (99mTc-SLNs) and radiolabeled chitosan-coated SLNs (99mTc-Chi-SLNs) using Amicon filter, they were injected into BALB/c mice to evaluate their biodistribution patterns. In addition, nanoparticles were characterized using Transmission Electron Microscopy (TEM), Fourier-transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRD) and Dynamic Light Scattering (DLS). Results: 99mTc-oxine with high radiochemical purity (RCP~100%) and stability (RCP > 97% at 24 h) was used to provide 99mTc-SLNs and 99mTc-Chi-SLNs with high initial RCP (100%). TEM image and DLS data suggest 99mTc- SLNs susceptibility to aggregation. To that end, the main portion of 99mTc-SLNs radioactivity accumulates in the liver and intestines, while 99mTc-Chi-SLNs sequesters in the liver, intestines and kidneys. The blood radioactivity of 99mTc-Chi-SLNs was higher than that of 99mTc-SLNs by 7.5, 3.17 and 3.5 folds at 1, 4 and 8 h post-injection. 99mTc- Chi-SLNs uptake in the kidneys in comparison with 99mTc-SLNs was higher by 37.48, 5.84 and 11 folds at 1, 4 and 8h. Conclusion: The chitosan layer on the surface of 99mTc-Chi-SLNs reduces lipophilicity in comparison with 99mTc- SLNs. Therefore, 99mTc-Chi-SLNs are less susceptible to aggregation, which leads to their lower liver uptake and higher kidney uptake and blood concentration.

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