High Renal Clearance Research Articles

Biodegradable lipid bilayer-assisted indocyanine green J- aggregates for photothermal therapy: Formulation, in vitro toxicity and in vivo clearance

Indocyanine green (ICG) J-aggregates (IJA) are a unique form of aggregation that exhibits superior properties to monomeric ICG. Despite their higher photoacoustic (PA) signals for imaging and heating stability during photothermal therapy (PTT), they exhibit low stability under a biological milieu. Our group previously proposed a simple procedure for in-situ preparation of IJA into liposomes, accelerating their formation and optical properties. To comprehend their potential applications, we systematically investigated the effect of the lipid bilayer composition on ICG J-aggregation and stability. Moreover, their in vitro compatibility and photothermal toxicity in monolayers and cancer spheroids, besides their in vivo biodistribution and clearance were evaluated. Our findings revealed the importance of high cholesterol and PEG-lipid content and low charged lipids (∼ 5 mol %) in liposomes to promote a high IJA/ICG ratio and, thus, high heating stability. More importantly, IJA-liposomes revealed high biocompatibility in monolayer and cancer spheroids with efficient photothermal toxicity. Finally, IJA-liposomes were cleared from the body without toxicity. Interestingly, IJA-liposomes mainly showed lower affinity to the liver than monomeric ICG, resulting in higher renal clearance. Overall, our biodegradable IJA-liposomes could be an excellent alternative to gold-based agents suitable for PA imaging and cancer PTT.

Synthesis and preclinical evaluation of a novel PET/fluorescence dual-modality probe targeting fibroblast activation protein

Early diagnosis and precise surgical intervention are crucial for cancer patients. We aimed to develop a novel positron emission tomography (PET)/fluorescence dual-modality probe for preoperative diagnosis, intraoperative guidance, and postoperative monitoring of fibroblast activation protein (FAP)-positive tumors. FAPI-FAM was synthesized and labeled with gallium-68. [68Ga]Ga-FAPI-FAM showed favorable in vivo and in vitro characteristics, specific binding affinity, and excellent tumor accumulation in FAP-positive cells and mice xenografts. Excellent tumor-to-background contrast was found owing to high tumor uptake, prolonged retention, and rapid renal clearance of [68Ga]Ga-FAPI-FAM. Moreover, a specific fluorescence signal was detected in FAP-positive tumors during ex vivo fluorescence imaging, demonstrating the feasibility of whole-body tumor detection and intraoperative tumor delineation.

Somatostatin Receptor Subtype-2 Targeting System for Specific Delivery of Temozolomide.

Temozolomide (TMZ) is a DNA alkylating agent that produces objective responses in patients with neuroendocrine tumors (NETs) when the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is inactivated. At high doses, TMZ therapy exhausts MGMT activity but also produces dose-limiting toxicities. To reduce off-target effects, we converted the clinically approved radiotracer 68Ga-DOTA-TOC into a peptide-drug conjugate (PDC) for targeted delivery of TMZ to somatostatin receptor subtype-2 (SSTR2)-positive tumor cells. We used an integrated radiolabeling strategy for direct quantitative assessment of receptor binding, pharmacokinetics, and tissue biodistribution. In vitro studies revealed selective binding to SSTR2-positive cells with high affinity (5.98 ± 0.96 nmol/L), internalization, receptor-dependent DNA damage, cytotoxicity, and MGMT depletion. Imaging and biodistribution analysis showed preferential accumulation of the PDC in receptor-positive tumors and high renal clearance. This study identified a trackable SSTR2-targeting system for TMZ delivery and utilizes a modular design that could be broadly applied in PDC development.

A SPECT/NIR Fluorescence Dual-Modality Imaging Agent Composed of Drugs and Hospital Available Isotope for Preoperative Sentinel Lymph Node Mapping and Intraoperative Biopsy.

Sentinel lymph node (SLN) mapping-guided biopsy is crucial for cancer staging and treatment. Optical/nuclide dual-modality imaging agents for mapping SLN are ideal for preoperative planning and intraoperative biopsy, which are enabled by penetration-depth unlimited nuclide imaging and dynamic real-time optical imaging, respectively. However, commonly reported dual-modality imaging agents are composed of novel but safety-unproven materials, making their quick clinical translation challenging. Herein, we report a novel nanoparticle composed of facile hospital-available drugs and isotope for single-photon emission computed tomography (SPECT)/near-infrared (NIR) fluorescence imaging to detect SLNs. Indocyanine green-human serum albumin (ICG-HSA) nanoparticles (NPs) were synthesized by ICG-induced HSA self-assembly and further 99mTc-labeling via a one-step, facile hospital-available method. After injecting 99mTc-ICG-HSA into the rats' forepaw pads, the rats' draining axillary lymph nodes were visualized by preoperative mapping with SPECT/CT and intraoperative biopsy with NIR fluorescence. The axillary lymph nodes of rats were identified by pathology and fluorescent staining after execution. Additionally, its toxicity testing and comparison with 99mTc-sulfur colloid imaging were also explored. The study reported a self-assembled 99mTc-ICG-HSA with a high radiochemical yield (85.6 ± 3.8%). Compared with conventional 99mTc-sulfur colloid, 99mTc-ICG-HSA NPs showed faster SLN identification, higher renal clearance, and lower hepatic retention. Furthermore, NIRF imaging allowed for the accurate visualization of the SLN and guided SLN biopsy intraoperatively. Notably, the 99mTc-ICG-HSA NPs were composed of hospital-available drugs and isotope, which are safe for acute toxicity evaluation by a certified institute. The proposed 99mTc-ICG-HSA NPs are safe and capable of noninvasive SLN identification and biopsy guidance with multi-modal imaging strategies and could be a promising tool for clinically assisted SLN biopsy.

GHB toxicokinetics and renal monocarboxylate transporter expression are influenced by the estrus cycle in rats

BackgroundThe illicit use and abuse of gamma-hydroxybutyric acid (GHB) occurs due to its sedative/hypnotic and euphoric effects. Currently, there are no clinically available therapies to treat GHB overdose, and care focuses on symptom treatment until the drug is eliminated from the body. Proton- and sodium-dependent monocarboxylate transporters (MCTs (SLC16A) and SMCTs (SLC5A)) transport and mediate the renal clearance and distribution of GHB. Previously, it has been shown that MCT expression is regulated by sex hormones in the liver, skeletal muscle and Sertoli cells. The focus of the current study is to evaluate GHB toxicokinetics and renal monocarboxylate transporter expression over the estrus cycle in females, and in the absence of male and female sex hormones.MethodsGHB toxicokinetics and renal transporter expression of MCT1, SMCT1 and CD147 were evaluated in females over the estrus cycle, and in ovariectomized (OVX) female, male and castrated (CST) male rats. GHB was administered iv bolus (600 and 1000 mg/kg) and plasma and urine samples were collected for six hours post-dose. GHB concentrations were quantified using a validated LC/MS/MS assay. Transporter mRNA and protein expression was quantified by qPCR and Western Blot.ResultsGHB renal clearance and AUC varied between sexes and over the estrus cycle in females with higher renal clearance and a lower AUC in proestrus females as compared to males (intact and CST), and OVX females. We demonstrated that renal MCT1 membrane expression varies over the estrus cycle, with the lowest expression observed in proestrus females, which is consistent with the observed changes in GHB renal clearance.ConclusionsOur results suggest that females may be less susceptible to GHB-induced toxicity due to decreased exposure resulting from increased renal clearance, as a result of decreased renal MCT1 expression.

Development of a Novel Sulfur Quantum Dots: Synthesis, 99mTc Radiolabeling, and Biodistribution.

Sulfur quantum dots (SQDs) as free heavy metal element quantum dots have promising applications in diagnosis and therapy; however, SQDs' in vivo biodistribution has not been studied. In the current study, SQDs were synthesized directly from cheap sublimated sulfur powder via a one-pot solvothermal method, and sucrose was used as a stabilizer to enhance stability and biocompatibility. The as-obtained SQDs with an average size of 4.6 nm exhibited great water dispersity, highly favorable quantum yield (21.5%), and uniformly spherical shape which were confirmed by UV-Vis, fluorescence spectrophotometer, TEM, and FESEM/EDX/PSA analyses. Moreover, the as-synthesized SQDs had very low cytotoxicity based on cancer (C26) and normal (L929) cell lines via MTT assay. And also, SQDs were radio-labeled directly by Technetium-99m (99mTc), which had good stability ranging from 86 to 99% in PBS and human serum. The SQDs' cell uptake on C26 and L929 cell lines demonstrated that cancer cells had more uptake than normal cells by increasing concentrations. Moreover, SQDs' in vivo biodistribution results displayed high kidney dose accumulation and rapid renal clearance, making them suitable for imaging and therapeutic applications.

Design, development, and in-vitro/in-vivo evaluation of docetaxel-loaded PEGylated solid lipid nanoparticles in prostate cancer therapy

Docetaxel (DOC) is a potent anticancer molecule widely used to treat various cancers. However, its therapeutic efficacy as a potential anticancer agent has been limited owing to poor aqueous solubility, short circulation time, rapid reticuloendothelial system uptake, and high renal clearance, which consecutively showed poor bioavailability. In the present investigation, we developed polyethylene glycol (PEG) decorated solid lipid nanoparticles (SLN) using the solvent diffusion method to increase the biopharmaceutical properties of DOC. PEG monostearate (SA-PEG2000) was initially synthesized and characterized using various analytical techniques. Afterwards, DOC-loaded SLN was synthesized with and without SA-PEG2000and systematically characterized for in-vitro and in-vivo properties. Spherical-shaped SA-PEG2000-DOC SLN showed hydrodynamic diameter and zeta potential of 177 nm and −13 mV, respectively. During the in-vitro release study DOC-loaded SLN showed a controlledrelease of approximately 54.35 % ± 5.46 within 12 h with Higuchi release kinetics in the tumor microenvironment (pH 5.5).In an in-vitro cytotoxicity study,SA-PEG2000-DOC SLN showedsignificantlylower IC50values(p < 0.001)compared to DOC-SLN and DOC aloneagainst prostate cancer cell lines (PC-3). Similarly, an in-vitro cellular uptake study showed a significant increase in intracellular DOC concentration for SA-PEG2000-DOC SLN. Additionally, inin-vivostudies,PEGylated SLN of DOC showed around 2- and 15-fold increase in the maximum concentration of drug (Cmax) and area under the curve (AUC), respectively, as compared to plain DOC solution due to the uniquehydrophilicity and hydrophobicity balance and electrical neutrality of specially designed PEG architect. The biological half-life (t1/2) and mean residence time (MRT) was found to increase from 8.55 and 11.43 to 34.96 and 47.68 h, respectively, with SA-PEG2000-DOC SLN. Moreover, the bio-distribution study indicates high DOC concentration in the plasma which signifies the more pronounced blood residence time of SA-PEG2000-DOC SLN. In a nutshell, SA-PEG2000-DOC SLNwasfound to bea promising and efficient drug delivery platform for the management of Metastatic Prostate cancer.

Fast detection of liver fibrosis with collagen-binding single-nanometer iron oxide nanoparticles via T1-weighted MRI

SNIO-CBP, a single-nanometer iron oxide (SNIO) nanoparticle functionalized with a type I collagen-binding peptide (CBP), was developed as a T1-weighted MRI contrast agent with only endogenous elements for fast and noninvasive detection of liver fibrosis. SNIO-CBP exhibits 6.7-fold higher relaxivity compared to a molecular gadolinium-based collagen-binding contrast agent CM-101 on a per CBP basis at 4.7T. Unlike most iron oxide nanoparticles, SNIO-CBP exhibits fast elimination from the bloodstream with a 5.7min half-life, high renal clearance, and low, transient liver enhancement in healthy mice. We show that a dose of SNIO-CBP that is 2.5-fold lower than that for CM-101 has comparable imaging efficacy in rapid (within 15min following intravenous injection) detection of hepatotoxin-induced liver fibrosis using T1-weighted MRI in a carbon tetrachloride-induced mouse liver injury model. We further demonstrate the applicability of SNIO-CBP in detecting liver fibrosis in choline-deficient L-amino acid-defined high-fat diet mouse model of nonalcoholic steatohepatitis. These results provide a platform with potential for the development of high relaxivity, gadolinium-free molecular MRI probes for characterizing chronic liver disease.

In silico Characterization of Toxicophores Found in Lemongrass (Cymbopogon citratus) and its Molecular Interaction with Kidney and Liver Enzymes

BACKGROUND OF THE STUDY: Cymbopogon citratus (lemongrass) is known for its various therapeutic claims. However, the abuse and misuse of herbal medicine is not uncommon. This study investigates the potential toxicophores present in lemongrass plant extract and their binding interaction with kidney and liver enzymes in silico. MATERIALS AND METHODS: Phytochemicals were identified from 74 articles from various databases. The toxic substructures, oral bioavailability, and clearance of these phytochemicals were characterized virtually. The binding affinity of these phytochemicals to different liver and kidney enzymes, namely gamma-glutamyl transferase, glutathione S-transferase, glutathione synthase, renin, human alkaline phosphatase, and 1-alpha-hydroxylase, was predicted and visualized. RESULTS: There were twenty distinct phytochemicals present in lemongrass leaf extract identified from various research articles. Of these twenty phytochemicals, only five were determined to be both hepatotoxic and nephrotoxic despite the majority being found to have high oral bioavailability and low liver and renal clearance. Moreover, isoorientin, which has high liver and renal clearance, was the only phytochemical with a high binding affinity to the liver enzyme gamma-glutamyl transferase and kidney enzyme renin. Meanwhile, the rest of the phytochemicals did not demonstrate high binding affinity to the other liver and kidney enzymes, despite having low clearance. CONCLUSION: Overall, these findings suggest that 13 of the phytochemicals identified may not affect the selected enzymes but may influence other liver and kidney enzymes due to their low liver and renal clearance.

LB2306. Population Pharmacokinetic (PPK), Pharmacokinetic/Pharmacodynamic attainment (PTA), and Clinical Pharmacokinetic/Pharmacodynamic (PK/PD) Analyses for Sulbactam-Durlobactam (SUL-DUR) to Support Dose Selection for the Treatment of Acinetobacter baumannii-calcoaceticus Complex (ABC) Infections

LB2306. Population Pharmacokinetic (PPK), Pharmacokinetic/Pharmacodynamic attainment (PTA), and Clinical Pharmacokinetic/Pharmacodynamic (PK/PD) Analyses for Sulbactam-Durlobactam (SUL-DUR) to Support Dose Selection for the Treatment of <i>Acinetobacter baumannii-calcoaceticus</i> Complex (ABC) Infections

A Water-Soluble AIEgen for Noninvasive Diagnosis of Kidney Fibrosis via SWIR Fluorescence and Photoacoustic Imaging.

Early diagnosis of renal fibrosis is crucially significant on account of its worldwide prevalent tendency. Optical imaging in the near-infrared window has been recognized as an appealing technique for the timely detection of renal dysfunction. However, formulating a contrast agent that allows early monitoring of renal fibrosis and concurrently renally clearable in a normal group is still challenging. Herein, a nanosized fluorophore with aggregation-induced emission (AIE) features, namely AIE-4PEG550 NPs, is well-tailored and amenable to longitudinal visualization of the fibrosis progression specifically in the early-stage via short-wave infrared (SWIR, 900-1700nm) fluorescence and photoacoustic bimodal imaging. The small size (≈26nm), renally filtrable molecular weight (3.3kDa), high renal clearance efficiency (93.1 ± 1.7% excretion through the kidneys within 24h), outstanding imaging performance, and good biocompatibility, together make AIE-4PEG550 NPs remarkably impressive and far superior to clinical diagnostic assays. The finding in this study would provide a blueprint for the next generation of diagnostic agents for the extent of renal fibrosis.

Polyacrylic acid complexes to mineralize ultrasmall europium-doped calcium phosphate nanodots for fluorescent bioimaging

Nano calcium phosphate (nCaP), a bone mineral in mammals, shows a promising prospect in biomedicine. Herein, we report a biomimetic mineralization strategy, based on stoichiometric polyacrylic acid (PAA) complexation-precipitation process, to facilitate the development of nCaP as bioimaging agents. As a result, the monodisperse and sub-10 nm europium-doped calcium phosphate nanodots (PAA-Eu:CaP NDs) is controllably obtained with enhanced fluorescence properties, tumor passive targeting and bioimaging ability. Compared with europium-doped calcium phosphate nanoparticles (Eu:CaP NPs), the fluorescence emission, quantum yield and lifetime of PAA-Eu:CaP NDs are significantly improved up to 3.84, 4.48 and 5.59 times, respectively. Deriving from the synergy of surface effect and organic/inorganic hybrid crystal field effect, such CaP matrix brings to local asymmetry environment and distinguished anti-quenching for Eu3+ ion. The strongest radiance signal is improved to 117 % for in vivo imaging; moreover, the tumor accumulation is obviously increased to 5.15 times, and 7.09 times for tumor permeability. The accumulation is decreased 80.2 %, 79.4 % and 70.2 % in liver, spleen and lung suggesting lower clearance by mononuclear phagocyte system, while it’s increased up to 15.4 times in kidney indicating higher renal clearance. Eventually, it’s convinced that this study can provide help for promoting CaP application in nanomedicine.

Synthesis, Renal Clearance, and Photothermal Therapy Based on the Self-Assembly of a Nanomedicine Consisting of Quaterrylene Bisimide and Glycocluster Conjugates.

Renal-clearable nanomedicines are considered the next generation of nanomedicines, and show potential application for future clinical translations. However, it is important to determine whether self-assembly can form large aggregates that accrue in tumors and then tailor the size of these assemblies to be excreted renally. In this paper, a renal-clearable nanomedicine based on quanterrylene bisimide-mannose conjugates (QDI-Man) was developed. QDI-Man showed a high renal clearance efficiency of 80.31 ± 2.85% in mice. We confirmed that the self-assembly of QDI-Man exhibited a dynamic adjustment process through the renal filtration thresholds, that is, "aggregation → self-regulating the aggregate size through the renal filtration thresholds → reaggregating into aggregates". Benefiting from the modification of mannose-based glycoclusters, QDI-Man showed selective photothermal therapy because of the mannose receptors overexpressed in breast cancer cells, and showed good photothermal therapy in mice. This paper developed a dynamic adjustment theory for effective renal clearance based on organic self-assembly.

A Bright, Renal‐Clearable NIR‐II Brush Macromolecular Probe with Long Blood Circulation Time for Kidney Disease Bioimaging

AbstractEarly detection of kidney disease is of vital importance due to its current prevalence worldwide. Fluorescence imaging, especially in the second near‐infrared window (NIR‐II) has been regarded as a promising technique for the early diagnosis of kidney disease due to the superior resolution and sensitivity. However, the reported NIR‐II organic renal‐clearable probes are hampered by their low brightness (ϵmaxΦf&gt;1000 nm&lt;10 M−1 cm−1) and limited blood circulation time (t1/2&lt;2 h), which impede the targeted imaging performance. Herein, we develop the aza‐boron‐dipyrromethene (aza‐BODIPY) brush macromolecular probes (Fudan BDIPY Probes (FBP 912)) with high brightness (ϵmaxΦf&gt;1000 nm≈60 M−1 cm−1), which is about 10‐fold higher than that of previously reported NIR‐II renal‐clearable organic probes. FBP 912 exhibits an average diameter of ≈4 nm and high renal clearance efficiency (≈65 % excretion through the kidney within 12 h), showing superior performance for non‐invasively diagnosis of renal ischemia‐reperfusion injury (RIR) earlier than clinical serum‐based protocols. Additionally, the high molecular weight polymer brush enables FBP 912 with prolonged circulation time (t1/2≈6.1 h) and higher brightness than traditional PEGylated renal‐clearable control fluorophores (t1/2&lt;2 h), facilitating for 4T1 tumor passive targeted imaging and renal cell carcinoma active targeted imaging with higher signal‐to‐noise ratio and extended retention time.

A Bright, Renal-Clearable NIR-II Brush Macromolecular Probe with Long Blood Circulation Time for Kidney Disease Bioimaging.

Early detection of kidney disease is of vital importance due to its current prevalence worldwide. Fluorescence imaging, especially in the second near-infrared window (NIR-II) has been regarded as a promising technique for the early diagnosis of kidney disease due to the superior resolution and sensitivity. However, the reported NIR-II organic renal-clearable probes are hampered by their low brightness (ϵmax Φf>1000 nm <10 M-1 cm-1 ) and limited blood circulation time (t1/2 <2 h), which impede the targeted imaging performance. Herein, we develop the aza-boron-dipyrromethene (aza-BODIPY) brush macromolecular probes (Fudan BDIPY Probes (FBP 912)) with high brightness (ϵmax Φf>1000 nm ≈60 M-1 cm-1 ), which is about 10-fold higher than that of previously reported NIR-II renal-clearable organic probes. FBP 912 exhibits an average diameter of ≈4 nm and high renal clearance efficiency (≈65 % excretion through the kidney within 12 h), showing superior performance for non-invasively diagnosis of renal ischemia-reperfusion injury (RIR) earlier than clinical serum-based protocols. Additionally, the high molecular weight polymer brush enables FBP 912 with prolonged circulation time (t1/2 ≈6.1 h) and higher brightness than traditional PEGylated renal-clearable control fluorophores (t1/2 <2 h), facilitating for 4T1 tumor passive targeted imaging and renal cell carcinoma active targeted imaging with higher signal-to-noise ratio and extended retention time.

Edoxaban Exposure in Patients With Atrial Fibrillation and Estimated Creatinine Clearance Exceeding 100mL/min.

Edoxaban 60 mg is approved for stroke prevention in patients with atrial fibrillation (AF) not fulfilling any dose‐reduction criteria. As edoxaban is partially renally cleared (≈50%), this study compared pharmacokinetics (PK) and pharmacodynamics of edoxaban 60 mg once daily with edoxaban 75 mg once daily in patients with AF with high renal clearance (creatinine clearance > 100 mL/min) over 12 months. Primary PK and pharmacodynamics end points were plasma edoxaban exposure and anti–factor Xa (FXa) concentration. A population PK model estimated edoxaban exposure at steady state. Efficacy and safety outcomes included composites of stroke, transient ischemic attack, systemic embolism, and major and clinically relevant nonmajor bleeding. Of 607 patients, 303 and 304 were randomized to edoxaban 60 and 75 mg, respectively. Edoxaban 75 mg provided ≈25% higher exposure than 60 mg. This increase was accurately depicted in the population PK model; anti–factor Xa concentration correlated with edoxaban exposure. Rates of composite and individual outcomes were similarly low between doses. In conclusion, the 25% increase in edoxaban dose (60‐75 mg) resulted in ≈25% exposure increase in the 75‐mg group. Higher exposure was not associated with reduced stroke risk in patients with AF with high renal clearance.

1096. Evaluation of Vancomycin Pharmacokinetics in Intravenous Drug Users

BackgroundPeople who inject illicit drugs (PWID) are 16 times more likely to develop methicillin-resistant Staphylococcus aureus (MRSA) infections including severe infections like bacteremia and endocarditis. Vancomycin is recommended as the drug of choice for empiric and targeted coverage in both severe and non-severe MRSA infections. Pharmacokinetic literature has suggested up to 31% higher renal clearance in intravenous drug users (IVDU) compared to non-IVDUs. This increased clearance may theoretically lead to more frequent sub-therapeutic troughs in otherwise standard dosing schemes. There is a paucity of data examining vancomycin pharmacokinetics following typical dosing schemes in IVDU population.MethodsThis was a single-center, retrospective chart review that examined therapeutic drug monitoring in patients treated with vancomycin between January 1st, 2015 through July 31st, 2020. Patients were identified as either IVDU or non-IVUD groups based on ICD-9/10 codes. The primary outcome was the difference between mean first vancomycin steady state troughs. Secondary outcomes were differences in time to first therapeutic trough, mean number of days on vancomycin based on infection, rate of acute kidney injury (AKI) after vancomycin, and rate of vancomycin failure.ResultsA total of 158 patients were included in the analysis (77 IVDU vs. 81 non-IVDU). Mean first vancomycin steady state trough were significantly less in IVDU group compared to non-IVDU group (11.85 vs. 13.98 mcg/mL P = 0.007). Mean time to first therapeutic trough and mean number of days treated were significantly higher in IVDU versus non-IVDR samples (65.9 vs. 50.2 hours P = 0.044 and 5.4 vs. 12.3 days P = 0.017, respectively). There was no detectable difference in rates of AKI and vancomycin failure.Primary outcome graph for patients with IV drug use Primary outcome graph for patients without IV drug use ConclusionVancomycin use in patients with IVDU resulted in significantly lower steady state troughs compared to patients who were non-IVDU. These patients also had a longer time to first therapeutic trough. Patient populations who are IVDU may require additional consideration as a special population for future development of vancomycin pharmacokinetic models.Disclosures All Authors: No reported disclosures

Two experts and a newbie: [18F]PARPi vs [18F]FTT vs [18F]FPyPARP\u2014a comparison of PARP imaging agents

PurposeImaging of PARP expression has emerged as valuable strategy for prediction of tumor malignancy. While [18F]PARPi and [18F]FTT are already in clinical translation, both suffer from mainly hepatobiliary clearance hampering their use for detection of abdominal lesions, e.g., liver metastases. Our novel radiotracer [18F]FPyPARP aims to bridge this gap with a higher renal clearance and an easily translatable synthesis route for potential clinical application.MethodsWe developed a less lipophilic variant of [18F]PARPi by exchange of the fluorobenzoyl residue with a fluoronicotinoyl group and automated the radiosyntheses of the three radiotracers. We then conducted a comparative side-by-side study of [18F]PARPi, [18F]FPyPARP, and [18F]FTT in NOD.CB17-Prkdcscid/J mice bearing HCC1937 xenografts to assess xenograft uptake and pharmacokinetics focusing on excretion pathways.ResultsTogether with decent uptake of all three radiotracers in the xenografts (tumor-to-blood ratios 3.41 ± 0.83, 3.99 ± 0.99, and 2.46 ± 0.35, respectively, for [18F]PARPi, [18F]FPyPARP, and [18F]FTT), a partial shift from hepatobiliary to renal clearance of [18F]FPyPARP was observed, whereas [18F]PARPi and [18F]FTT show almost exclusive hepatobiliary clearance.ConclusionThese findings imply that [18F]FPyPARP is an alternative to [18F]PARPi and [18F]FTT for PET imaging of PARP enzymes.

Rapid Tumor Targeting of Renal-Clearable ZW800-1 Conjugate for Efficient Photothermal Cancer Therapy.

The combination of near-infrared (NIR) fluorophores and photothermal therapy (PTT) provides a new opportunity for safe and effective cancer treatment. However, the precise molecular design of functional NIR fluorophores with desired properties, such as high tumor targetability and low nonspecific uptake, remains challenging. In this study, a renal-clearable NIR fluorophore conjugate with high tumor targetability was developed for efficient photothermal cancer therapy. The isoniazid (INH)–ZW800-1 conjugate (INH–ZW) was synthesized by conjugating an antibiotic drug, INH, with a well-known zwitterionic NIR fluorophore, ZW800-1, to improve in vivo performance and fluorescence-guided cancer phototherapy. INH–ZW not only showed rapid tumor accumulation without nonspecific tissue/organ uptake within 1 h after the injection but also generated thermal energy to induce cancer cell death under NIR laser irradiation. Compared with previously reported ZW800-1 conjugates, INH–ZW preserved the ideal biodistribution of ZW800-1 and facilitated improved tumor targeting and PTT. Together, these results demonstrate that the INH–ZW conjugate has great potential to serve as an effective PTT agent capable of rapid tumor targeting and high renal clearance, with excellent photothermal efficacy.

Tebipenem pivoxil hydrobromide-No PICC, no problem!

Tebipenem pivoxil hydrobromide is a novel orally bioavailable prodrug of tebipenem, a carbapenem antimicrobial, that binds to penicillin-binding proteins, inhibiting the synthesis of the bacterial cell wall. This results in weakening of peptidoglycan, leading to lysis of bacterial cells. Tebipenem displays a broad spectrum of activity against anaerobic, gram-positive, and gram-negative pathogens, including extended-spectrum β-lactamase producing Enterobacterales. In a large phase 3clinical trial (ADAPT-PO), oral tebipenem pivoxil hydrobromide 600mg every 8h was shown to be non-inferior to intravenous ertapenem 1g every 24h. Overall response at test of cure was 58.8% [264/449] in the tebipenem pivoxil hydrobromide group compared to 61.6% [258/419] in the ertapenem group for the treatment of complicated urinary tract infections, including acute pyelonephritis. At the test of cure, clinical cure rates were 93.1% and 93.6% and microbiological eradication was 59.5% and 63.5% with tebipenem pivoxil hydrobromide and ertapenem, respectively. The most common adverse reactions associated with tebipenem pivoxil hydrobromide are diarrhea, headache, and nausea. As with other carbapenems, tebipenem pivoxil hydrobromide is expected to have the potential to decrease the seizure threshold and will likely require renal dosage adjustment for patients with altered renal function due to high renal clearance. If approved in the United States, tebipenem pivoxil hydrobromide can serve as a potential oral antimicrobial option to decrease hospital length of stay and prevent hospital admissions due to resistant pathogens.