The value of AI-based analysis of fractional flow reserve of volume computed tomographically detected coronary artery stenosis with regard to their hemodynamic relevance. / Die Bedeutung KI-basierter Analyse fraktioneller Flussreserven computertomografisch nachgewiesener Coronararterienstenosen im Hinblick auf deren hämodynamische Relevanz.

The aim of our work was to demonstrate the importance of artificial intelligence-based analysis of fractional flow reserves of computed tomographically detected coronary artery stenosis with regard to their hemodynamic relevance in patients with unclear chest pain and suspected stable coronary heart disease with a low to medium pre-test probability.The collective of our retrospective analysis includes 63 patients in whom coronary artery stenosis was detected by volume computed tomographic examination in "one beat, whole heart" mode in the period from March to October 2022. In these patients, the fractional flow reserve was also determined by computed tomography, which was modulated by the use of artificial intelligence.The calculated values of the fractional flow reserve and the degrees of stenosis determined by computed tomography showed a moderate and significant negative correlation for all three coronary vascular territories (LAD/CX/RCA) (correlation coefficient rho = 0.54/0.54/0.6; p < 0.01 respectively). In just over a third (37.6 %) of all stenoses classified as high-grade by computed tomography, the assessment of hemodynamic relevance by calculating the fractional flow reserve deviated from the severity of the stenosis diagnosed by computed tomography, while the results in the peripheral areas "no stenosis/vascular occlusion" were 100 % consistent in each case.The present results of this work illustrate that the calculation of the fractional flow reserve based on artificial intelligence as a supplement to volume computed tomography of the heart can make a decisive contribution to further therapy planning by increasing the specificity of the purely morphological method by the physiological aspect. · Calculation of fractional flow reserve is a useful addition to computed tomography of the heart.. · It provides possibility to dispense with unnecessary further diagnostics by increasing specificity.. · The combination of both procedures leads to therapy optimization for patients.. · Noblé H, Mühlbauer N, Ehling J et al. The value of AI-based analysis of fractional flow reserve of volume computed tomographically detected coronary artery stenosis with regard to their hemodynamic relevance. Fortschr Röntgenstr 2024; DOI: 10.1055/a-2271-0887.

CCL2 chemokine inhibition primes the tumor vasculature for improved nanomedicine delivery and efficacy.

Blood vessel functionality is crucial for efficient tumor-targeted drug delivery. Heterogeneous distribution and perfusion of angiogenic blood vessels contribute to suboptimal accumulation of (nano-) therapeutics in tumors and metastases. To attenuate pathological angiogenesis, an L-RNA aptamer inhibiting the CC motif chemokine ligand 2 (CCL2) was administered to mice bearing orthotopic 4T1 triple-negative breast cancer tumors. The effect of CCL2 inhibition on tumor blood vessel functionality and tumor-targeted drug delivery was evaluated via multimodal and multiscale optical imaging, employing fluorophore-labeled polymeric (10 nm) and liposomal (100 nm) nanocarriers. Anti-CCL2 treatment induced a dose-dependent anti-angiogenic effect, reflected by a decreased relative blood volume, increased blood vessel maturity and functionality, and reduced macrophage infiltration, accompanied by a shift in the polarization of tumor-associated macrophages (TAM) towards a less M2-like and more M1-like phenotype. In line with this, CCL2 inhibitor treatment improved the delivery of polymers and liposomes to tumors, and enhanced the antitumor efficacy of free and liposomal doxorubicin. Together, these findings demonstrate that blocking the CCL2-CCR2 axis modulates TAM infiltration and polarization, resulting in vascular normalization and improved tumor-targeted drug delivery.

ITIH5-Derived Polypeptides Covering the VIT Domain Suppress the Growth of Human Cancer Cells In Vitro.

Oncogenic drivers such as mutated EGFR are the preferred targets in modern drug development. However, restoring the lost function of tumor suppressor proteins could also be a valid approach to combatting cancer. ITIH5 has been revealed as a potent metastasis suppressor in both breast and pancreatic cancer. Here, we show that ITIH5 overexpression in MDA-MB-231 breast cancer cells can also locally suppress tumor growth by 85%, when transplanted into the mammary fat pad of nude mice. For a potential drug development approach, we further aimed to define downsized ITIH5 polypeptides that still are capable of mediating growth inhibitory effects. By cloning truncated and His-tagged ITIH5 fragments, we synthesized two recombinant N-terminal polypeptides (ITIH5681aa and ITIH5161aa), both covering the ITI heavy chain specific "vault protein inter-alpha-trypsin" (VIT) domain. Truncated ITIH5 variants caused dose-dependent cell growth inhibition by up to 50% when applied to various cancer cell lines (e.g., MDA-MB-231, SCaBER, A549) reflecting breast, bladder and lung cancer in vitro. Thus, our data suggest the substantial role of the ITIH5-specific VIT domain in ITIH5-mediated suppression of tumor cell proliferation. As extracellularly administered ITIH5 peptides mimic the growth-inhibitory effects of the full-length ITIH5 tumor suppressor protein, they may constitute the basis for developing anticancer drugs in the future.

Incidental Finding Prevalences in 3-Tesla Brain and Spine MRI of Military Pilot Applicants.

INTRODUCTION: Incidental findings in brain and spine MRI are common. In aerospace medicine, pilot selection may be affected by improved sensitivity of modern MRI devices. We investigated the occurrence of medically unfit rates caused by incidental findings in military pilot applicants using a 3-Tesla scanner as compared to the outcomes of a lower field strength 1-Tesla device based on similar screening protocols.METHODS: A total of 3315 military pilot applicants were assessed by a standardized German Air Force Imaging Screening Protocol and retrospectively subdivided into two cohorts, one of which was assessed by 1-Tesla MRI (2012-2015; N 1782), while in the second cohort (2016-2019; N 1808), a 3-Tesla MRI was used. Cohorts were statistically analyzed relating to three entities of incidental findings: 1) intervertebral disc displacements, 2) intracerebral vessel malformations, and 3) other abnormal findings in the brain.RESULTS: Pooled prevalences of incidental findings in medically unfit applicants significantly increased by use of 3-Tesla MRI as compared to lower resolution 1-Tesla MRI. Regarding the spine, prevalences more than doubled (1.46 vs. 4.99%; P < 0.05) for intervertebral disc displacements. Similarly, prevalences of cerebral vessel malformations as well as other abnormal CNS incidental findings considerably increased by use of 3-Tesla MRI (0.28 vs. 1.67%; P < 0.05, and 5.12 vs. 9.80%; P < 0.05). Effect sizes and correlations were substantial in all conditions analyzed (Cohens d > 0.8; Pearsons r > 0.75).CONCLUSIONS: Our data suggest a strong dependency of incidental cerebrospinal findings on image resolution and sensitivity of MRI devices used for screening, which is enhanced by refined imaging protocols and followed by increased medical unfit rates in prospective aviators. Adjusted strategies in the assessment of such lesions are needed to redefine their natural history and physiological impact, and to optimize screening protocols for future pilot selection.Snksen S-E, Khn SR, Nobl H-J, Knopf H, Ehling J, Jakobs FM, Frischmuth J, Weber F. Incidental finding prevalences in 3-Tesla brain and spine MRI of military pilot applicants. Aerosp Med Hum Perform. 2021; 92(3):146152.

A collagen-binding protein enables molecular imaging of kidney fibrosis in vivo.

Pathological deposition of collagen is a hallmark of kidney fibrosis. To illustrate this process we employed multimodal optical imaging to visualize and quantify collagen deposition in murine models of kidney fibrosis (ischemia-reperfusion or unilateral ureteral obstruction) using the collagen-binding adhesion protein CNA35. For in vivo imaging, we used hybrid computed tomography-fluorescence molecular tomography and CNA35 labeled with the near-infrared fluorophore Cy7. Upon intravenous injection, CNA35-Cy7 accumulation was significantly higher in fibrotic compared to non-fibrotic kidneys. This difference was not detected for a non-specific scrambled version of CNA35-Cy7. Ex vivo, on kidney sections of mice and patients with renal fibrosis, CNA35-FITC co-localized with fibrotic collagen type I and III, but not with the basement membrane collagen type IV. Following intravenous injection, CNA35-FITC bound to both interstitial and perivascular fibrotic areas. In line with this perivascular accumulation, we observed significant perivascular fibrosis in the mouse models and in biopsy sections from patients with chronic kidney disease using computer-based morphometry quantification. Thus, molecular imaging of collagen using CNA35 enabled specific non-invasive quantification of kidney fibrosis. Collagen imaging revealed significant perivascular fibrosis as a consistent component next to the more commonly assessed interstitial fibrosis. Our results lay the basis for further probe and protocol optimization towards the clinical translation of molecular imaging of kidney fibrosis.

Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis.

Fibrosis is the common endpoint and currently the best predictor of progression of chronic kidney diseases (CKDs). Despite several drawbacks, biopsies remain the only available means to specifically assess the extent of renal fibrosis. Here, we show that molecular imaging of the extracellular matrix protein elastin allows for noninvasive staging and longitudinal monitoring of renal fibrosis. Elastin was hardly expressed in healthy mouse, rat, and human kidneys, whereas it was highly up-regulated in cortical, medullar, and perivascular regions in progressive CKD. Compared to a clinically relevant control contrast agent, the elastin-specific magnetic resonance imaging agent ESMA specifically detected elastin expression in multiple mouse models of renal fibrosis and also in fibrotic human kidneys. Elastin imaging allowed for repetitive and reproducible assessment of renal fibrosis, and it enabled longitudinal monitoring of therapeutic interventions, accurately capturing anti-fibrotic therapy effects. Last, in a model of reversible renal injury, elastin imaging detected ensuing fibrosis not identifiable via routine assessment of kidney function. Elastin imaging thus has the potential to become a noninvasive, specific imaging method to assess renal fibrosis.

Fibrosis imaging: Current concepts and future directions.

Fibrosis plays an important role in many different pathologies. It results from tissue injury, chronic inflammation, autoimmune reactions and genetic alterations, and it is characterized by the excessive deposition of extracellular matrix components. Biopsies are routinely employed for fibrosis diagnosis, but they suffer from several drawbacks, including their invasive nature, sampling variability and limited spatial information. To overcome these limitations, multiple different imaging tools and technologies have been evaluated over the years, including X-ray imaging, computed tomography (CT), ultrasound (US), magnetic resonance imaging (MRI), positron emission tomography (PET) and single-photon emission computed tomography (SPECT). These modalities can provide anatomical, functional and molecular imaging information which is useful for fibrosis diagnosis and staging, and they may also hold potential for the longitudinal assessment of therapy responses. Here, we summarize the use of non-invasive imaging techniques for monitoring fibrosis in systemic autoimmune diseases, in parenchymal organs (such as liver, kidney, lung and heart), and in desmoplastic cancers. We also discuss how imaging biomarkers can be integrated in (pre-) clinical research to individualize and improve anti-fibrotic therapies.

ITIH5 mediates epigenetic reprogramming of breast cancer cells.

BACKGROUND: Extracellular matrix (ECM) is known to maintain epithelial integrity. In carcinogenesis ECM degradation triggers metastasis by controlling migration and differentiation including cancer stem cell (CSC) characteristics. The ECM-modulator inter- α-trypsin inhibitor heavy chain family member five (ITIH5) was recently identified as tumor suppressor potentially involved in impairing breast cancer progression but molecular mechanisms underlying its function are still elusive. METHODS: ITIH5 expression was analyzed using the public TCGA portal. ITIH5-overexpressing single-cell clones were established based on T47D and MDA-MB-231 cell lines. Colony formation, growth, apoptosis, migration, matrix adhesion, traction force analyses and polarization of tumor cells were studied in vitro. Tumor-initiating characteristics were analyzed by generating a metastasis mouse model. To identify ITIH5-affected pathways we utilized genome wide gene expression and DNA methylation profiles. RNA-interference targeting the ITIH5-downstream regulated gene DAPK1 was used to confirm functional involvement. RESULTS: ITIH5 loss was pronounced in breast cancer subtypes with unfavorable prognosis like basal-type tumors. Functionally, cell and colony formation was impaired after ITIH5 re-expression in both cell lines. In a metastasis mouse model, ITIH5 expressing MDA-MB-231 cells almost completely failed to initiate lung metastases. In these metastatic cells ITIH5 modulated cell-matrix adhesion dynamics and altered biomechanical cues. The profile of integrin receptors was shifted towards ß1-integrin accompanied by decreased Rac1 and increased RhoA activity in ITIH5-expressing clones while cell polarization and single-cell migration was impaired. Instead ITIH5 expression triggered the formation of epithelial-like cell clusters that underwent an epigenetic reprogramming. 214 promoter regions potentially marked with either H3K4 and /or H3K27 methylation showed a hyper- or hypomethylated DNA configuration due to ITIH5 expression finally leading to re-expression of the tumor suppressor DAPK1. In turn, RNAi-mediated knockdown of DAPK1 in ITIH5-expressing MDA-MB-231 single-cell clones clearly restored cell motility. CONCLUSIONS: Our results provide evidence that ITIH5 triggers a reprogramming of breast cancer cells with known stem CSC properties towards an epithelial-like phenotype through global epigenetic changes effecting known tumor suppressor genes like DAPK1. Therewith, ITIH5 may represent an ECM modulator in epithelial breast tissue mediating suppression of tumor initiating cancer cell characteristics which are thought being responsible for the metastasis of breast cancer.

Contrast-enhanced CT imaging in patients with chronic kidney disease.

Renal microvascular rarefaction characterizes chronic kidney disease (CKD). In murine models of CKD, micro-CT imaging reflected capillary rarefaction using quantification of renal relative blood volume (rBV). In addition, micro-CT imaging revealed morphological alterations of the intrarenal vasculature including reduced vascular branching and lumen diameter. Here, we retrospectively quantified rBV in contrast-enhanced CT angiography in patients and found that, compared to non-CKD patients, those with CKD and renal fibrosis had significantly reduced rBV in the renal cortex. rBV values closely mirrored capillary rarefaction in the corresponding nephrectomy specimens. In patients with follow-up CT angiography, reduction of renal function was paralleled by a decline in rBV. Using virtual autopsy, i.e., postmortem CT angiography, morphometry of intrarenal arteries in 3D-rendered CT images revealed significantly reduced arterial diameter and branching in CKD compared to non-CKD cases. In conclusion, in CKD patients, contrast-enhanced CT imaging with quantification of rBV correlates with functional renal vasculature, whereas virtual autopsy allows morphometric analyses of macrovascular changes. Importantly, the observed vascular alterations in CKD patients mirror those in animals with progressive CKD, suggesting a high relevance of animal models for studying vascular alterations in CKD and renal fibrosis.

The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance.

Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a form of programmed cell death that promotes inflammation in various pathological conditions, suggesting that it might be a privileged pharmacological target. However, its function in glucose homeostasis and obesity has been unknown. Here we show that RIPK3 is over expressed in the white adipose tissue (WAT) of obese mice fed with a choline-deficient high-fat diet. Genetic inactivation of Ripk3 promotes increased Caspase-8-dependent adipocyte apoptosis and WAT inflammation, associated with impaired insulin signalling in WAT as the basis for glucose intolerance. Similarly to mice, in visceral WAT of obese humans, RIPK3 is overexpressed and correlates with the body mass index and metabolic serum markers. Together, these findings provide evidence that RIPK3 in WAT maintains tissue homeostasis and suppresses inflammation and adipocyte apoptosis, suggesting that systemic targeting of necroptosis might be associated with the risk of promoting insulin resistance in obese patients.

In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization.

Vascular endothelial growth factor receptor 2 (VEGFR-2) and α v ß 3 integrin are the most frequently addressed targets in molecular imaging of tumor angiogenesis. In preclinical studies, molecular imaging of angiogenesis has shown potential to detect and differentiate benign and malignant lesions of the breast. Thus, in this retrospective clinical study employing patient tissues, the diagnostic value of VEGFR-2, α v ß 3 integrin and vascular area fraction for the diagnosis and differentiation of breast neoplasia was evaluated. To this end, tissue sections of breast cancer (n = 40), pre-invasive ductal carcinoma in situ (DCIS; n = 8), fibroadenoma (n = 40), radial scar (n = 6) and normal breast tissue (n = 40) were used to quantify (1) endothelial VEGFR-2, (2) endothelial α v ß 3 integrin and (3) total α v ß 3 integrin expression, as well as (4) the vascular area fraction. Sensitivity and specificity to differentiate benign from malignant lesions were calculated for each marker by receiver operating characteristics (ROC) analyses. Whereas vessel density, as commonly used, did not significantly differ between benign and malignant lesions (AUROC: 0.54), VEGFR-2 and α v ß 3 integrin levels were gradually up-regulated in carcinoma versus fibroadenoma versus healthy tissue. The highest diagnostic accuracy for differentiating carcinoma from fibroadenoma was found for total α v ß 3 integrin expression (AUROC: 0.76), followed by VEGFR-2 (AUROC: 0.71) and endothelial α v ß 3 integrin expression (AUROC: 0.68). In conclusion, total α v ß 3 integrin expression is the best discriminator between breast cancer, fibroadenoma and normal breast tissue. With respect to vascular targeting and molecular imaging of angiogenesis, endothelial VEGFR-2 appeared to be slightly superior to endothelial α v ß 3 for differentiating benign from cancerous lesions.

Imalytics Preclinical: Interactive Analysis of Biomedical Volume Data.

A software tool is presented for interactive segmentation of volumetric medical data sets. To allow interactive processing of large data sets, segmentation operations, and rendering are GPU-accelerated. Special adjustments are provided to overcome GPU-imposed constraints such as limited memory and host-device bandwidth. A general and efficient undo/redo mechanism is implemented using GPU-accelerated compression of the multiclass segmentation state. A broadly applicable set of interactive segmentation operations is provided which can be combined to solve the quantification task of many types of imaging studies. A fully GPU-accelerated ray casting method for multiclass segmentation rendering is implemented which is well-balanced with respect to delay, frame rate, worst-case memory consumption, scalability, and image quality. Performance of segmentation operations and rendering are measured using high-resolution example data sets showing that GPU-acceleration greatly improves the performance. Compared to a reference marching cubes implementation, the rendering was found to be superior with respect to rendering delay and worst-case memory consumption while providing sufficiently high frame rates for interactive visualization and comparable image quality. The fast interactive segmentation operations and the accurate rendering make our tool particularly suitable for efficient analysis of multimodal image data sets which arise in large amounts in preclinical imaging studies.

Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases.

Progressive kidney diseases and renal fibrosis are associated with endothelial injury and capillary rarefaction. However, our understanding of these processes has been hampered by the lack of tools enabling the quantitative and noninvasive monitoring of vessel functionality. Here, we used micro-computed tomography (µCT) for anatomical and functional imaging of vascular alterations in three murine models with distinct mechanisms of progressive kidney injury: ischemia-reperfusion (I/R, days 1-56), unilateral ureteral obstruction (UUO, days 1-10), and Alport mice (6-8 weeks old). Contrast-enhanced in vivo µCT enabled robust, noninvasive, and longitudinal monitoring of vessel functionality and revealed a progressive decline of the renal relative blood volume in all models. This reduction ranged from -20% in early disease stages to -61% in late disease stages and preceded fibrosis. Upon Microfil perfusion, high-resolution ex vivo µCT allowed quantitative analyses of three-dimensional vascular networks in all three models. These analyses revealed significant and previously unrecognized alterations of preglomerular arteries: a reduction in vessel diameter, a prominent reduction in vessel branching, and increased vessel tortuosity. In summary, using µCT methodology, we revealed insights into macro-to-microvascular alterations in progressive renal disease and provide a platform that may serve as the basis to evaluate vascular therapeutics in renal disease.

Histidine-rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease.

UNLABELLED: Pathogen- and injury-related danger signals as well as cytokines released by immune cells influence the functional differentiation of macrophages in chronic inflammation. Recently, the liver-derived plasma protein, histidine-rich glycoprotein (HRG), was demonstrated, in mouse tumor models, to mediate the transition of alternatively activated (M2) to proinflammatory (M1) macrophages, which limit tumor growth and metastasis. We hypothesized that liver-derived HRG is a critical endogenous modulator of hepatic macrophage functionality and investigated its implications for liver inflammation and fibrosis by comparing C57BL/6N wild-type (WT) and Hrg(-/-) mice. In homeostatic conditions, hepatic macrophages were overall reduced and preferentially polarized toward the anti-inflammatory M2 subtype in Hrg(-/-) mice. Upon chronic liver damage induced by CCl4 or methionine-choline-deficient (MCD) diet, liver injury and fibrosis were attenuated in Hrg(-/-) , compared to WT, mice. Macrophage populations were reduced and skewed toward M2 polarization in injured livers of Hrg(-/-) mice. Moreover, HRG-deficient mice showed significantly enhanced hepatic vascularization by micro-computed tomography and histology, corroborating proangiogenic activities of M2-polarized liver macrophages. Purified HRG protein induced, but HRG-deficient serum prevented, M1 macrophage differentiation in vitro. Accordingly, Hrg(-/-) mice transplanted with Hrg(+/+) bone marrow, but not Hrg(-/-) -transplanted Hrg(+/+) mice, remained protected from experimental steatohepatitis. Consistent with these findings, patients with chronic hepatitis C and nonalcoholic steatohepatitis significantly up-regulated hepatocytic HRG expression, which was associated with M1 polarization of adjacent macrophages. CONCLUSIONS: Liver-derived HRG, similar to alarmins, appears to be an endogenous molecular factor promoting polarization of hepatic macrophages toward the M1 phenotype, thereby promoting chronic liver injury and fibrosis progression, but limiting angiogenesis. Therefore, controlling tissue levels of HRG or PGF might be a promising strategy in chronic inflammatory liver diseases.

Role of chemokine pathways in hepatobiliary cancer.

Persistent hepatic inflammation resulting from hepatitis B or C virus infections (HBV or HCV, respectively), obesity-associated non-alcoholic steatohepatitis (NASH) or alcohol abuse is a hallmark feature of chronic liver diseases and appears to be an essential prerequisite of hepatocarcinogenesis. The inflammatory processes in the liver are regulated by various chemokines, which orchestrate the interaction between parenchymal liver cells, Kupffer cells (resident macrophages), hepatic stellate cells (HSC), endothelial cells, and infiltrating immune cells. In consequence, these cellular interactions result in the re-modeling of the hepatic microenvironment toward a pro-inflammatory, pro-fibrotic, pro-angiogenic and thus pre-neoplastic milieu. Once developed, liver neoplasms provoke pro- and anti-tumor immune responses that are also critically regulated through differential activation of chemokine pathways. With respect to hepatobiliary cancers, including hepatocellular carcinoma (HCC), gallbladder cancer and cholangiocellular carcinoma (cholangiocarcinoma), together belonging to the highest causes of cancer-related deaths worldwide, this review article will give an overview of chemokine pathways involved in both the establishment of a pro-tumorigenic microenvironment as well as the development and progression of hepatobiliary cancer. Pharmaceutical targeting of chemokine pathways is a promising approach to treat or even prevent hepatobiliary cancer.

Role of platelet-derived growth factor-CC in capillary rarefaction in renal fibrosis.

We have identified platelet-derived growth factor (PDGF)-CC as a potent profibrotic mediator in kidney fibrosis and pro-angiogenic mediator in glomeruli. Because renal fibrosis is associated with progressive capillary rarefaction, we asked whether PDGF-CC neutralization in fibrosis might have detrimental anti-angiogenic effects leading to aggravated peritubular capillary loss. We analyzed capillary rarefaction in mice with and without PDGF-CC neutralization (using genetically deficient mice and neutralizing antibodies), in three different models of renal interstitial fibrosis, unilateral ureteral obstruction, unilateral ischemia-reperfusion, Col4a3-deficient (Alport) mice, and healthy animals. Independent of the effect of PDGF-CC neutralization on renal fibrosis, we found no difference in capillary rarefaction between PDGF-CC-neutralized mice and mice with intact PDGF-CC. We also found no differences in microvascular leakage (determined by extravasation of Evans Blue Dye) and in renal relative blood volume quantified using in vivo microcomputed tomography. PDGF-CC neutralization had no effects on renal microvasculature in healthy animals. Capillary endothelium did not express PDGF receptor-α, suggesting that potential PDGF-CC effects would have to be indirect. PDGF-CC neutralization or deficiency was not associated with preservation or accelerated loss of peritubular capillaries, suggesting no significant pro-angiogenic effects of PDGF-CC during renal fibrosis. From a clinical perspective, the profibrotic effects of PDGF-CC outweigh the pro-angiogenic effects and, thus, do not limit a potential therapeutic use of PDGF-CC inhibition in renal fibrosis.

Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Π-Π Stacking Stabilized Polymeric Micelles.

Treatment of cancer patients with taxane-based chemotherapeutics, such as paclitaxel (PTX), is complicated by their narrow therapeutic index. Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of PTX, as they can be tailored to encapsulate large amounts of hydrophobic drugs and achiv prolonged circulation kinetics. As a result, PTX deposition in tumors is increased, while drug exposure to healthy tissues is reduced. However, many PTX-loaded micelle formulations suffer from low stability and fast drug release in the circulation, limiting their suitability for systemic drug targeting. To overcome these limitations, we have developed PTX-loaded micelles which are stable without chemical cross-linking and covalent drug attachment. These micelles are characterized by excellent loading capacity and strong drug retention, attributed to π-π stacking interaction between PTX and the aromatic groups of the polymer chains in the micellar core. The micelles are based on methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl)methacrylamide) (mPEG-b-p(HPMAm-Bz)) block copolymers, which improved the pharmacokinetics and the biodistribution of PTX, and substantially increased PTX tumor accumulation (by more than 2000%; as compared to Taxol or control micellar formulations). Improved biodistribution and tumor accumulation were confirmed by hybrid µCT-FMT imaging using near-infrared labeled micelles and payload. The PTX-loaded micelles were well tolerated at different doses, while they induced complete tumor regression in two different xenograft models (i.e., A431 and MDA-MB-468). Our findings consequently indicate that π-π stacking-stabilized polymeric micelles are promising carriers to improve the delivery of highly hydrophobic drugs to tumors and to increase their therapeutic index.

Theranostic USPIO-Loaded Microbubbles for Mediating and Monitoring Blood-Brain Barrier Permeation.

Efficient and safe drug delivery across the blood-brain barrier (BBB) remains to be one of the major challenges of biomedical and (nano-) pharmaceutical research. Here, we show that poly(butyl cyanoacrylate)-based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles within their shell, can be used to mediate and monitor BBB permeation. Upon exposure to transcranial ultrasound pulses, USPIO-MB are destroyed, resulting in acoustic forces inducing vessel permeability. At the same time, USPIO are released from the MB shell, they extravasate across the permeabilized BBB and they accumulate in extravascular brain tissue, thereby providing non-invasive R2*-based magnetic resonance imaging information on the extent of BBB opening. Quantitative changes in R2* relaxometry were in good agreement with 2D and 3D microscopy results on the extravascular deposition of the macromolecular model drug FITC-dextran into the brain. Such theranostic materials and methods are considered to be useful for mediating and monitoring drug delivery across the BBB, and for enabling safe and efficient treatment of CNS disorders.