Intravenous Injection Research Articles

IRIDA- An Indian perspective

Iron deficiency anemia (IDA) is the most common type of anemia globally (IDA), the treatment being iron supplementation. However, in a few individuals, there is absent to suboptimal response to iron supplementation due to iron not being taken up by the body of the individual. This condition is known as iron-refractory IDA (IRIDA). Iron refractory iron deficiency anemia is a rare genetic condition that follows an autosomal recessive inheritance due to a defect in the TMPRSS6 gene encoding Matriptase-2. This protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation, and normal/high serum hepcidin values. The anemia appears in the post-natal period, although in some cases it is only diagnosed in adulthood. The disease is refractory to oral iron treatment but shows a slow response to intravenous iron injections and partial correction of the anemia. This condition is likely being missed or under-diagnosed in our iron deficient endemic setting due to a lack of general awareness amongst physicians in establishing the diagnosis or due to the lack of availability of proper genetic testing.

Combined use of dexmedetomidine and nalbuphine in laparoscopic radical gastrectomy for gastric cancer.

Radical laparoscopic gastrectomy is an important treatment modality for gastric cancer. Surgery requires general anesthesia, and patients are susceptible to the effects of anesthetic drugs and carbon dioxide insufflation during the procedure, leading to inflammation or severe pain, which can affect patient outcome. To explore the efficacy of combining dexmedetomidine (DEX) with nalbuphine in patients underwent laparoscopic radical gastrectomy for gastric cancer. Patients scheduled to undergo laparoscopic radical gastrectomy were selected and randomly assigned to A or B group. In A group, patients received an intravenous injection of nalbuphine 0.2 mg/kg + DEX 0.4 μg/kg 10 min before the end of surgery; in B group, patients received only an intravenous injection of nalbuphine. The trends in hemodynamic parameter fluctuations, awakening quality during the recovery period, serum inflammatory markers, agitation scores, cough severity, incidence, and duration of postoperative delirium (POD) were compared. The mean arterial pressure and heart rate in the A group were more stable (P < 0.05). The A group had a lower average awakening time, extubation time, and agitation scores during recovery than the B group. Agitation control in the A group was more effective at different time points (P < 0.05). Patients in the A group had lower serum interleukin (IL)-6, tumour necrosis factor alpha, and IL-10 levels at 1 h after surgery than the B group. The incidence of coughing and duration of POD were lower and shorter in the A group than in the B group. Adverse reactions caused by the two anesthesia methods were less frequent in the A group than in the B group (P < 0.05). The use of DEX and nalbuphine in patients undergoing laparoscopic radical gastrectomy for gastric cancer help reducing the inflammatory response, cough severity, and agitation and helps maintain hemodynamic stability.

Evaluation of cerebral microcirculation in a mouse model of systemic inflammation.

Perturbations in the microcirculatory system have been observed in neurological conditions, such as Alzheimer's disease or systemic inflammation. However, changes occurring at the level of the capillary are difficult to translate to biomarkers that could be measured macroscopically. We aim to evaluate whether transit time changes reflect capillary stalling and to what degree. We employ a combined spectral optical coherence tomography (OCT) and fluorescence optical imaging (FOI) system to investigate the relation between capillary stalling and transit time in a mouse model of systemic inflammation induced by intraperitoneal injection of lipopolysaccharide. Angiograms are obtained using OCT, and fluorescence signal images are acquired by the FOI system upon intravenous injection of fluorescein isothiocyanate via a catheter inserted into the tail vein. Our findings reveal that lipopolysaccharide (LPS) administration significantly increases both the percentage and duration of capillary stalling compared to mice receiving a 0.9% saline injection. Moreover, LPS-induced mice exhibit significantly prolonged arteriovenous transit time compared to control mice. These observations suggest that capillary stalling, induced by inflammation, modulates cerebral mean transit time, a measure that has translational potential.

In vivo turnover and biodistribution of soluble AXL: implications for biomarker development

Soluble biomarkers are paramount to personalized medicine. However, the in vivo turnover and biodistribution of soluble proteins is seldom characterized. The cleaved extracellular domain of the AXL receptor (sAXL) is a prognostic biomarker in several diseases and a predictive marker of AXL targeting agents. Plasma sAXL reflects a balance between production in tissues with lymphatic transport into the circulation and removal from blood by degradation or excretion. It is unclear how this transport cycle affects plasma sAXL levels that are the metric for biomarker development. Radiolabeled mouse sAxl was monitored after intravenous injection to measure degradation and urinary excretion of sAxl, and after intradermal injection to mimic tissue or tumor production. sAxl was rapidly taken-up and degraded by the liver and kidney cortex. Surprisingly, intact sAxl was detectable in urine, indicating passage through the glomerular filter and a unique sampling opportunity. The structure of sAxl showed an elongated, flexible molecule with a length of 18 nm and a thickness of only 3 nm, allowing passage through the glomerulus and excretion into the urine. Intradermally injected sAxl passed through local and distant lymph nodes, followed by uptake in liver and kidney cortex. Low levels of sAxl were seen in the plasma, consistent with an extended transit time from local tissue to circulation. The rapid plasma clearance of sAxl suggests that steady-state levels in blood will sensitively and dynamically reflect the rate of production of sAxl in the tissues but will be influenced by perturbations of liver and kidney function.

Triphenylphosphonium-modified catiomers enhance in vivo mRNA delivery through stabilized polyion complexation.

Nanocarriers based on cationic materials play a central role in the success of mRNA-based therapies. Traditionally, amine-bearing lipids and polymers have been successfully employed for creating mRNA-loaded nanocarriers, though they still present challenges, such as physical and biological instability, limiting both delivery efficiency and therapeutic potential. Non-amine cations could be a promising avenue in addressing these limitations. However, such alternatives remain notably underexplored. Herein, we introduced triphenylphosphonium (TPP) as an alternative cationic moiety for mRNA delivery, leveraging its advantageous properties for nucleic acid complexation. Through the modification of amine-bearing catiomers, we replaced traditional amine-based counterparts with TPP to create innovative polymeric micelles as mRNA nanocarriers. A comprehensive analysis, encompassing physicochemical, thermodynamic, and computational approaches, revealed that the TPP substitution significantly influenced polymer self-assembly, mRNA binding, and the overall stability of mRNA-loaded polymeric micelles. Upon intravenous injection, TPP-bearing micelles demonstrated a remarkable increase in mRNA bioavailability, facilitating efficient protein production in solid tumors. These findings provide a compelling rationale for substituting amines with TPP, emphasizing their potential for advancing mRNA therapeutics.

In vivo synthetic anticancer approach by resourcing mouse blood albumin as a biocompatible artificial metalloenzyme.

Methods for producing drugs directly at the cancer site, particularly using bioorthogonal metal catalysts, are being explored to mitigate the side effects of therapy. Albumin-based artificial metalloenzymes (ArMs) catalyze reactions in living mice while protecting the catalyst in the hydrophobic pocket. Here, we describe the in situ preparation and application of biocompatible tumor-targeting ArMs using circulating albumin, which is abundant in the bloodstream. The ArM was formed using blood albumin through the intravenous injection of ruthenium conjugated with an albumin-binding ligand; the tumor-targeting unit was conjugated to the ArM using its catalytic activity, and the ArM was transported to the cancer site. The delivered ArM catalyzed a second tagging reaction of the proapoptotic peptide on the cancer surface, successfully suppressing cancer proliferation. This approach, which efficiently leveraged the persisting reactivity twice in vivo, holds promise for future in vivo metal-catalyzed drug synthesis utilizing endogenous albumin.

Evaluating the impact of delayed-phase imaging in Contrast-Enhanced Mammography on breast cancer staging: A comparative study of abbreviated versus complete protocol.

Contrast-enhanced mammography (CEM) is an innovative imaging tool for breast cancer detection, involving intravenous injection of a contrast medium and the assessment of lesion enhancement in two phases: early and delayed. The aim of the study was to analyze the topographic concordance of lesions detected in the early- versus delayed phase acquisitions. Approved by the Ethics Committee (No. 118/20), this prospective study included 100 women with histopathological confirmed breast neoplasia (B6) at the Radiodiagnostics Department of the Maggiore della Carità Hospital of Novara, Italy from May 1, 2021, to October 17, 2022. Participants underwent CEM examinations using a complete protocol, encompassing both early- and delayed image acquisitions. Three experienced radiologists blindly analyzed the CEM images for contrast enhancement to determine the topographic concordance of the identified lesions. Two readers assessed the complete study (protocol A), while one reader assessed the protocol without the delayed phase (protocol B). The average glandular dose (AGD) of the entire procedure was also evaluated. The analysis demonstrated high concordance among the three readers in the topographical identification of lesions within individual quadrants of both breasts, with a Cohen's κ > 0.75, except for the lower inner quadrant of the right breast and the retro-areolar region of the left breast. The mean whole AGD was 29.2mGy. The mean AGD due to CEM amounted to 73% of the whole AGD (21.2mGy). The AGD attributable to the delayed phase of CEM contributed to 36% of the whole AGD (10.5mGy). As we found no significant discrepancy between the readings of the two protocols, we conclude that delayed-phase image acquisition in CEM does not provide essential diagnostic benefits for effective disease management. Instead, it contributes to unnecessary radiation exposure.

Evaluation of Postoperative Pain in Posterior Segment Surgery of the Eye at the CHU-IOTA

Postoperative pain is predictable and therefore preventable; its management should be a priority. Posterior segment surgery is an underestimated source of pain. The objective of this work is to highlight the intensity of postoperative pain in this type of surgery. This was a 6-month prospective descriptive longitudinal study. Involving 67 patients operated for a pathology of the posterior segment. The simple verbal scale was used to assess pain in the postoperative period at HO, H8, H16 and H24. During the period, posterior segment surgery accounted for 1.88% of the institute's surgical activities. Male predominates with 88%; The mean age was 45.7 years with extremes of 7 and 75 years, vitrectomy accounted for 71.6% and scleral cryoindentation 28.4%. Peribulbar anaesthesia combining bupivacaine and xylocaine was the most commonly used with 80.6%. Intravenous injection of morphine intraoperatively was associated with peribulbar anesthesia in 19.4% of cases of scleral cryoindentation. In the immediate postoperative period (H0), pain was intense in 37%, moderate in 52% and low in 11% of patients after cryoindentation while it was absent in 52% and low in 48% of patients after vitrectomy. At H8 and H16, severe pain was reported in 47% of cryoindentations; It was reported as weak to moderate after vitrectomy in 91.66%. At H24, after treatment, patients had moderate pain in 69%, and low pain in 31% after cryoindentation; It was low in 85.71% after vitrectomy. This work allowed us to highlight the feelings of patients operated on in the posterior segment and to propose a postoperative management protocol. Keywords: Pain, Posterior segment, Locoregional anesthesia, Verbal scale.

The Current Role of Contrast-Enhanced Ultrasound (CEUS) in the Diagnosis and Staging of Bladder Cancer: A Review of the Available Literature.

Contrast-enhanced ultrasound (CEUS) is an advanced imaging technique that integrates conventional US with the intravenous injection of specific US contrast agents (UCAs), combining the non-invasiveness of US with the higher accuracy of contrast-enhanced imaging. In contrast with magnetic resonance imaging (MRI), computed tomography (CT) and cystoscopy, CEUS has few contraindications, and UCAs are non-nephrotoxic agents that can be safely used in patients with kidney failure. CEUS is a well-established method for the detection of liver lesions and for echocardiography, and its indications are expanding. The updated 2018 WFUMB-EFSUMB guidelines have added the urinary bladder under non-hepatic applications of CEUS. The technique is able to distinguish between benign tissue, such as clots or hematoma, and malignant lesions by perfusing the mass with contrast agent. Thanks to the different perfusion rates of the various layers of the bladder wall, CEUS is also able to predict tumor invasion depth and stage. Despite that, current urological guidelines do not include CEUS as a plausible imaging technique for bladder urothelial carcinoma. The main reason for this omission might be the presence of scarce randomized evidence and the absence of large validated series. In this review, we describe the rationale behind the use of CEUS in bladder cancer and the added value of this imaging technique in the detection and staging of bladder lesions. In addition, we researched the available literature on the topic and then described the results of randomized clinical trials and a meta-analysis investigating the accuracy of CEUS in bladder cancer diagnosis and staging. The reported studies show that CEUS is a highly accurate diagnostic and staging tool for BC, reaching levels of specificity and sensitivity in differentiating between Ta-T1, or low-grade BC, and T2, or high-grade BC, that are comparable to those shown by the reference standard methods. Nonetheless, several limitations were found and are highlighted in this review. The aim of this study is to further validate and promote the use of CEUS as a quick, economic and effective diagnostic tool for this high-impact disease.

Aqueous Grown Quantum Dots with Robust Near-Infrared Fluorescence for Integrated Traumatic Brain Injury Diagnosis and Surgical Monitoring.

Surgical intervention is the most common first-line treatment for severe traumatic brain injuries (TBIs) associated with high intracranial pressure, while the complexity of these surgical procedures often results in complications. Surgeons often struggle to comprehensively evaluate the TBI status, making it difficult to select the optimal intervention strategy. Here, we introduce a fluorescence imaging-based technology that uses high-quality silver indium selenide-based quantum dots (QDs) for integrated TBI diagnosis and surgical guidance. These engineered, poly(ethylene glycol)-capped QDs emit in the near-infrared region, are resistant to phagocytosis, and importantly, are ultrastable after the epitaxial growth of an aluminum-doped zinc sulfide shell in the aqueous phase that renders the QDs resistant to long-term light irradiation and complex physiological environments. We found that intravenous injection of QDs enabled both the precise diagnosis of TBI in a mouse model and, more importantly, the comprehensive evaluation of the TBI status before, during, and after an operation to distinguish intracranial from superficial hemorrhages, provide real-time monitoring of the secondary hemorrhage, and guide the decision making on the evacuation of intracranial hematomas. This QD-based diagnostic and monitoring system could ultimately complement existing clinical tools for treating TBI, which may help surgeons improve patient outcomes and avoid unnecessary procedures.

Novel technetium-99m-labeled bivalent PSMA-targeting probe based on hydroxamamide chelate for diagnosis of prostate cancer.

Prostate-specific membrane antigen (PSMA) is a well-known biomarker of prostate cancer. Previously, our group reported that the succinimidyl-cystatin-urea-glutamate (SCUE) moiety has a high affinity for PSMA. In this study, we developed the novel technetium-99m-labeled PSMA-targeting probe "[99mTc]Tc-(Ham-SCUE)2" based on a hydroxamamide chelate with a bivalent SCUE and evaluated its potential as a SPECT imaging probe for the diagnosis of PSMA-expressing prostate cancer. Ham-SCUE was synthesized by a one-step reaction with Ham-Mal and cysteine-urea-glutamine. Then, Ham-SCUE was reacted with [99mTc]NaTcO4 for 10min at room temperature to obtain [99mTc]Tc-(Ham-SCUE)2. [99mTc]Tc-(Ham-SCUE)2 was added to LNCaP (high PSMA expression) cells or PC3 (low PSMA expression) cells, and their radioactivity was measured 60min after administration. The blocking study was performed by co-incubation of LNCaP cells with various concentrations of 2-PMPA (a PSMA inhibitor) for 15min before adding [99mTc]Tc-(Ham-SCUE)2. The biodistribution of [99mTc]Tc-(Ham-SCUE)2 in LNCaP/PC3 dual xenografted C.B.-17/Icr scid/scid Jcl mice was evaluated for 120min after intravenous injection. The blocking study was performed by pretreatment of mice with 2-PMPA (10mg/kg weight). [99mTc]Tc-(Ham-SCUE)2 was acquired at radiochemical yields of 56% with a radiochemical purity of over 95%. The cellular uptake level of [99mTc]Tc-(Ham-SCUE)2 by LNCaP cells was significantly higher than that by PC3 cells (LNCaP: 11.12 ± 0.71 vs. PC3: 1.40 ± 0.13%uptake/mg protein, p < 0.01), and the uptake was significantly suppressed by pretreatment with 2-PMPA (2.56 ± 0.37%uptake/mg protein, p < 0.05). IC50 of 2-PMPA was 245 ± 47nM. In the in vivo study, the radioactivity of LNCaP tumor tissue was significantly higher than that of PC3 tumor tissue at 120min after the administration of [99mTc]Tc-(Ham-SCUE)2 (LNCaP: 9.97 ± 2.79, PC3: 1.16 ± 0.23%ID/g, p < 0.01), and was suppressed by pretreatment with 2-PMPA (2.50 ± 0.45%ID/g, p < 0.01). [99mTc]Tc-(Ham-SCUE)2 has the potential to be a SPECT imaging agent for diagnosing high PSMA-expressing prostate cancer.

Current Advances in Nanomaterials Affecting Functions and Morphology of Platelets.

Nanomaterials have been extensively used in the biomedical field due to their unique physical and chemical properties. They promise wide applications in the diagnosis, prevention, and treatment of diseases. Nanodrugs are generally transported to target tissues or organs by coupling targeting molecules or enhanced permeability and retention effect (EPR) passively. As intravenous injection is the most common means of administration of nanomedicine, the transport process inevitably involves the interactions between nanoparticles (NPs) and blood cells. Platelets are known to not only play a critical role in normal coagulation by performing adhesion, aggregation, release, and contraction functions, but also be associated with pathological thrombosis, tumor metastasis, inflammation, and immune reactions, making it necessary to investigate the effects of NPs on platelet function during transport, particularly the way in which their physical and chemical properties determine their interaction with platelets and the underlying mechanisms by which they activate and induce platelet aggregation. However, such data are lacking. This review is intended to summarize the effects of NPs on platelet activation, aggregation, release, and apoptosis, as well as their effects on membrane proteins and morphology in order to shed light on such key issues as how to reduce their adverse reactions in the blood system, which should be taken into consideration in NP engineering.

Cyanotic heart disease due to a hypoplastic right ventricle with pulmonary valve atresia, an intact ventricular septum, with atrial level shunting in a day‐old Arabian foal

AbstractAn 8‐h‐old Arabian foal was presented for evaluation of progressive weakness since birth. The foal presented laterally recumbent with pale and muddy mucous membranes, a grade III/VI left basilar murmur, and an irregularly, irregular rhythm. Transthoracic echocardiogram along with an electrocardiogram (EKG) was performed. Atrial fibrillation was recorded throughout the examination. The left and right atria were both significantly enlarged. A right to left shunt across the atrial septum was confirmed via an intravenous injection of agitated saline. The tricuspid valve was rudimentary without apparent atrioventricular flow and no ventricular septal defect was appreciated. The animal was euthanased, and necropsy found dysplasia of the tricuspid valve, a hypoplastic right ventricle with pulmonary valve atresia, and an intact ventricular septum. This condition is similar, both haemodynamically and in terms of prognosis, to tricuspid atresia, which has been described previously in Arabian foals, with the exception that there is the complete absence of connection between the atrium and ventricle in the case of tricuspid atresia. Of 14 previously reported cases of tricuspid atresia in neonatal foals, nine were Arabian foals. Further investigation into the possibility of hypoplastic right ventricle as a familial condition in the Arabian breed should be considered.

Cyanotic heart disease due to a hypoplastic right ventricle with pulmonary valve atresia, an intact ventricular septum, with atrial level shunting in a day‐old Arabian foal

AbstractAn 8‐h‐old Arabian foal was presented for evaluation of progressive weakness since birth. The foal presented laterally recumbent with pale and muddy mucous membranes, a grade III/VI left basilar murmur, and an irregularly, irregular rhythm. Transthoracic echocardiogram along with an electrocardiogram (EKG) was performed. Atrial fibrillation was recorded throughout the examination. The left and right atria were both significantly enlarged. A right to left shunt across the atrial septum was confirmed via an intravenous injection of agitated saline. The tricuspid valve was rudimentary without apparent atrioventricular flow and no ventricular septal defect was appreciated. The animal was euthanased, and necropsy found dysplasia of the tricuspid valve, a hypoplastic right ventricle with pulmonary valve atresia, and an intact ventricular septum. This condition is similar, both haemodynamically and in terms of prognosis, to tricuspid atresia, which has been described previously in Arabian foals, with the exception that there is the complete absence of connection between the atrium and ventricle in the case of tricuspid atresia. Of 14 previously reported cases of tricuspid atresia in neonatal foals, nine were Arabian foals. Further investigation into the possibility of hypoplastic right ventricle as a familial condition in the Arabian breed should be considered.

Automatic dressing change and monitoring infusion speed control system

Intravenous drip is a common form of treatment, but the wrong rate of injection or dose of medication can have serious consequences for patients. Monitoring devices can detect the speed of drug infusion and drug response in real time, helping medical care personnels adjust treatment regimens in a timely manner and reduce the risk of human error. At present, some rooms in the Intensive Care Unit (ICU) require a sterile environment. In view of the above situation, this paper proposes a new device, which adds the function of automatic dressing change to the intravenous injection monitoring device, and synchronizes the obtained data to the user interface in real time by using the Internet of Things (IoT), so as to reduce the frequency of medical staff entering and leaving the ICU, realize remote monitoring of the intravenous injection process and data related to automatic dressing change, and improve the treatment effect of patients and the work efficiency of medical staff.

Early bifurcation of the common hepatic artery: A pitfall that should be known and recognized

Early bifurcation of the common hepatic artery (EBCHA) is a rare anatomical variation (1%), that is often overlooked but can lead to accidental ligation of the right branch of the hepatic artery with consequent arterial ischemia of the right liver and potentially very serious complications during pancreaticoduodenectomy, partial hepatectomy, or liver harvesting for transplantation. It may be difficult to diagnose EBCHA using transverse imaging sections. However, on standard CT sections with intravenous contrast injection, three warning signs should allow the image reader to suspect it: presence of two hepatic arteries to the right of the celiac trunk, presence of a retro-portal hepatic artery, and absence of a right hepatic artery arising from the superior mesenteric artery. Analysis of the CT with reconstruction then allows for definitive diagnosis and limits the risk of accidental arterial injury or ligation.

Evidence-Based Severity Assessment of Animal Models for Pancreatic Cancer.

Animal models are crucial to preclinical oncological research and drug development. Animal experiments must be performed in accordance with the 3R principles of replacement and reduction, if possible, and refinement where these procedures remain crucial. In addition, European Union legislations demand a continuous refinement approach, as well as pro- and retrospective severity assessment. In this study, an objective databased severity assessment was performed in murine models for pancreatic cancer induced by orthotopic, subcutaneous, or intravenous injection of Panc02 cells. Parameters such as body weight change, distress score, perianal temperature, mouse grimace scale, burrowing, nesting behavior, and the concentration of corticosterone in plasma and its metabolites in feces were monitored during tumor progression. The most important parameters were combined into a score and mapped against a reference data set by the Relative Severity Assessment procedure (RELSA) to obtain the maximum achieved severity for each animal (RELSAmax). This scoring revealed a significantly higher RELSAmax for the orthotopic model than for the subcutaneous and intravenous models. However, compared to animal models such as pancreatitis and bile duct ligation, the pancreatic cancer models are shown to be less severe. Data-based animal welfare assessment proved to be a valuable tool for comparing the severity of differently induced cancer models.

Comparison of strain specific pathogenicity of Herpes Simplex Virus Type 1 by high-throughput sequencing

Herpes Simplex Virus Type 1 (HSV-1) is a widespread human pathogen known for causing a spectrum of clinical manifestations, ranging from mild cold sores to severe complications like encephalitis. Understanding the strain-specific variations of HSV-1 is crucial for elucidating its pathogenesis and developing targeted therapeutic interventions. In this multifaceted study, we investigated the strain-specific characteristics of HSV-1 using an in vivo rat model. Firstly, a pilot study was conducted to assess the capacity of three HSV-1 strains (Fisher (F), KOS (K), and MacIntyre (M)) to induce cold sores in rats. Remarkably, the F strain exhibited pronounced pathogenicity, inducing erythema, swelling, and disrupted epidermis with ulceration, distinguishing it from the K and M strains. Subsequently, the treatment capability of intravenous acyclovir injection in HSV-1 F strain-infected rats was evaluated. Acyclovir treatment resulted in a significant reduction in HSV-1 viral copy numbers in serum and dissected neuronal tissues, particularly in the spinal cord, brain, and lower lip. Lastly, whole genome sequencing data revealed that high-impact mutations occurred in the K and M strains within the UL49, US2, and US3 genes. These mutations may play a pivotal role in influencing viral replication, dissemination, pathogenesis, and infectivity. In contrast, the moderate missense variant mutations detected in the US12, US8, UL3, UL30, UL31, and UL36 genes appeared to have no effect on viral pathogenesis and infectivity, based on RT-PCR data for spinal cord, trigeminal nerve, brain, and the lower lip. These strain-specific mutations underscore the dynamic nature of HSV-1 evolution. Collectively, our findings contribute to a deeper understanding of HSV-1 strain diversity and pave the way for the development of targeted therapeutic strategies against this medically significant virus.

PEGylation renders carnosine resistant to hydrolysis by serum carnosinase and increases renal carnosine levels

Carnosine’s protective effect in rodent models of glycoxidative stress have provided a rational for translation of these findings in therapeutic concepts in patient with diabetic kidney disease. In contrast to rodents however, carnosine is rapidly degraded by the carnosinase-1 enzyme. To overcome this hurdle, we sought to protect hydrolysis of carnosine by conjugation to Methoxypolyethylene glycol amine (mPEG-NH2). PEGylated carnosine (PEG-car) was used to study the hydrolysis of carnosine by human serum as well as to compare the pharmacokinetics of PEG-car and L-carnosine in mice after intravenous (IV) injection. While L-carnosine was rapidly hydrolyzed in human serum, PEG-car was highly resistant to hydrolysis. Addition of unconjugated PEG to carnosine or PEG-car did not influence hydrolysis of carnosine in serum. In mice PEG-car and L-carnosine exhibited similar pharmacokinetics in serum but differed in half-life time (t1/2) in kidney, with PEG-car showing a significantly higher t1/2 compared to L-carnosine. Hence, PEGylation of carnosine is an effective approach to prevent carnosine degradations and to achieve higher renal carnosine levels. However, further studies are warranted to test if the protective properties of carnosine are preserved after PEGylation.

Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and the third leading cause for cancer-related death worldwide. The tumor is difficult-to-treat due to its inherent resistance to chemotherapy. Antistromal therapy is a novel therapeutic approach, targeting cancer-associated fibroblasts (CAF) in the tumor microenvironment. CAF-derived microfibrillar-associated protein 5 (MFAP-5) is identified as a novel target for antistromal therapy of HCC with high translational relevance. Biocompatible polypept(o)ide-based polyion complex micelles (PICMs) constructed with a triblock copolymer composed of a cationic poly(l-lysine) complexing anti-MFAP-5 siRNA (siMFAP-5) via electrostatic interaction, a poly(γ-benzyl-l-glutamate) block loading cationic amphiphilic drug desloratatine (DES) via π-πinteraction as endosomal escape enhancer and polysarcosine poly(N-methylglycine) for introducing stealth properties, are generated for siRNA delivery. Intravenous injection of siMFAP-5/DES PICMs significantly reduces the hepatic tumor burden in a syngeneic implantation model of HCC, with a superior MFAP-5 knockdown effect over siMFAP-5 PICMs or lipid nanoparticles. Transcriptome and histological analysis reveal that MFAP-5 knockdown inhibited CAF-related tumor vascularization, suggesting the anti-angiogenic effect of RNA interference therapy. In conclusion, multicompartment PICMs combining siMFAP-5 and DES in a single polypept(o)ide micelle induce a specific knockdown of MFAP-5 and demonstrate a potent antitumor efficacy (80% reduced tumor burden vs untreated control) in a clinically relevant HCC model.