High Renal Clearance Research Articles

Polymer based Drug Delivery Systems- benchtop to Bedside Transition

Research in the field of polymers and polymeric materials has garnered immense attention in the past few decades due to the versatile functional and structural capabilities of polymers which often can be manipulated for applications in the field of therapy and diagnosis for a host of diseases and disorders. Polymer therapeutics comprises polymer-drug and polymer-protein conjugates as well as supramolecular systems used as drug delivery systems. Although the pharmacological industry invests immensely in the design and discovery of novel drug molecules, small molecular drugs are often inefficient in targeting many diseases like deep seated low vasculature tumours, metastasized cancers and various autoimmune diseases. Coupled with a rapid clearance rate, low solubility, drug resistance and high off target toxicity these small molecular drugs often present modest benefits for a host of common diseases. In order to improve the therapeutic index of pre-existing drugs and shortening the translation from preclinical validation to clinical approval, a vast area of drug delivery research focuses on the improvement of drug carriers by various alterations. The major challenges currently faced by drug delivery systems include a low payload, transition through the desmoplastic barrier for solid tumours and high hepatic and renal clearance. In order to address these issues numerous polymer–protein and polymer-drug conjugates have been engineered and have reported to enhance the stability and pharmacokinetic properties of the active drugs. Highly toxic anticancer drugs like doxorubicin, cis-platin and gemcitabine have successfully been coupled with high molecular weight polymers to formulate targeted drug delivery agents, some of which have undergone successful clinical trials. Apart from PEGylated polymers, dendritic polymers and polyplexes with DNA or RNA moieties have also been considered as candidates for improving the therapeutic index of various drugs. Ongoing efforts in the development of polymer-based therapeutics are promising and open new horizons for personalized medicine for effective cure of various life-threatening diseases.

Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones

BackgroundThe ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described.MethodsThe compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs.ResultsAlthough both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60–100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10–30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg.ConclusionSJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators.

Fluoro-photoacoustic polymeric renal reporter for real-time dual imaging of acute kidney injury.

In this chapter, we introduced a diagnostic approach for acute kidney injury (AKI) via photoacoustic imaging. We provided detailed synthetic procedures of a biomarker-activatable photoacoustic agent (FPRR) with high renal clearance efficiency. We also provided protocols for in vitro characterization, live-cell imaging, and in vivo imaging in a drug-induced AKI mice model. Compared to near-infrared fluorescence imaging, photoacoustic imaging is more sensitive with higher signal-to-background ratio. As such, our approach serves as a general guideline in the development of photoacoustic agents for diagnosis of urological diseases. With this tool in hand, researchers in the field of optical imaging may be inspired to develop other photoacoustic agents for early stage disease diagnosis.

A New Class of NIR‐II Gold Nanocluster‐Based Protein Biolabels for In Vivo Tumor‐Targeted Imaging

AbstractThe design of bright NIR‐II luminescent nanomaterials that enable efficient labelling of proteins without disturbing their physiological properties in vivo is challenging. We developed an efficient strategy to synthesize bright NIR‐II gold nanoclusters (Au NCs) protected by biocompatible cyclodextrin (CD). Leveraging the ultrasmall size of Au NCs (<2 nm) and strong macrocycle‐based host–guest chemistry, the as‐synthesized CD‐Au NCs can readily label proteins/antibodies. Moreover, the labelled proteins/antibodies enable highly efficient in vivo tracking during blood circulation, without disturbing their biodistribution and tumor targeting ability, thus leading to a sensitive tumor‐targeted imaging. CD‐Au NCs are stable in the harsh biological environment and show good biocompatibility and high renal clearance efficiency. Therefore, the NIR‐II biolabels developed in this study provide a promising platform to monitor the physiological behavior of biomolecules in living organisms.

A New Class of NIR-II Gold Nanocluster-Based Protein Biolabels for In Vivo Tumor-Targeted Imaging.

The design of bright NIR-II luminescent nanomaterials that enable efficient labelling of proteins without disturbing their physiological properties in vivo is challenging. We developed an efficient strategy to synthesize bright NIR-II gold nanoclusters (Au NCs) protected by biocompatible cyclodextrin (CD). Leveraging the ultrasmall size of Au NCs (<2 nm) and strong macrocycle-based host-guest chemistry, the as-synthesized CD-Au NCs can readily label proteins/antibodies. Moreover, the labelled proteins/antibodies enable highly efficient in vivo tracking during blood circulation, without disturbing their biodistribution and tumor targeting ability, thus leading to a sensitive tumor-targeted imaging. CD-Au NCs are stable in the harsh biological environment and show good biocompatibility and high renal clearance efficiency. Therefore, the NIR-II biolabels developed in this study provide a promising platform to monitor the physiological behavior of biomolecules in living organisms.

Ultrasmall platinum nanozymes as broad-spectrum antioxidants for theranostic application in acute kidney injury

Acute kidney injury (AKI) is a common kidney disease with high mortality rate, while surprisingly, the supportive treatment and renal replacement are the only available clinical treatment options to date. The onset of AKI is often triggered by excessive toxic reactive oxygen/nitrogen species (RONS), and hence, the development of antioxidants with high renal accumulation and effective renal clearance is highly demanded to consume RONS in the kidneys. In this study, we developed ultrasmall polyvinylpyrrolidone-coated platinum nanoparticles (Pt NPs-PVP, ~3 nm) as multienzyme mimetics (catalase, peroxidase, and superoxide dismutase). Thanks to their excellent RONS scavenging ability, Pt NPs-PVP effectively reduced the hydrogen peroxide induced cellular damage. Analytical (inductively coupled plasma mass spectrometry) as well as imaging (photoacoustic and computed tomography) techniques revealed the preferential renal uptake and high enrichment of ultrasmall Pt NPs-PVP after intravenous administration, offering remarkable relief of the clinical symptoms of glycerol-induced AKI mice without any apparent systemic toxicity in vivo. Importantly, because of their ultrasmall size, Pt NPs-PVP exhibited rapid excretion from healthy mice, presenting relatively low toxicity and side effects. In conclusion, our work demonstrated ultrasmall Pt nanozyme as a state of the art antioxidant for dual-modal imaging guided treatment of AKI with improved treatment efficacy.

Abstract 464: Allicin, a potent new ornithine decarboxylase inhibitor in neuroblastoma

Abstract The purpose of this study was to test if allicin inhibits ornithine decarboxylase (ODC) in pediatric neuroblastoma (NB). The natural product allicin is a reactive sulfur species (RSS) from garlic (Allium sativum L.). NB is an early childhood cancer arising from the developing peripheral nervous system. In up to 25% of cases MYCN gene amplification is correlated to high tumor stage and poor patient prognosis. High stage NB relapses frequently despite multimodal therapy and relapsed tumors are virtually untreatable. Therefore, there is a clear need for specific, novel therapeutics. MYCN transactivates the E-box gene ODC1, and the gene product ODC is a rate-limiting enzyme in polyamine biosynthesis. The increase of polyamines (putrescine, spermidine, spermine) triggers cell hyperproliferation in NB and other MYC-driven cancers through the activation of Rb-regulated cell cycle progression. ODC is a validated drug target and α-difluoromethylornithine (DFMO) is an ODC inhibitor under investigation in phase II NB trials. Although a safe drug with clinical promise, DFMO has various challenges including the need for exceptionally high treatment doses and rapid renal clearance in the urine. In an effort to identify pharmacologically superior ODC inhibitors, we identified allicin as a potent ODC inhibitor using a specific radioactive in vitro activity assay with purified ODC. Allicin also inhibited ODC activity in actively growing NB cells, reduced polyamine levels, and induced apoptosis in cell cultures. ODC is a homodimer with 12 cysteines per monomer and allicin S-thioallylates cysteines. Allicin reacts with, and is titrated-out by, low molecular weight thiols like dithiothreitol (DTT). Removal of DTT from the ODC activity assay reaction resulted in significantly higher allicin potency (IC50 at 11 nM). Although allicin has multiple cellular targets, our data reveal that one mode of action is ODC inhibition, which suppresses polyamine accumulation and induces apoptosis. The natural product allicin could be used in conjunction with other anticancer treatments, the latter at a lower than usual dosage, to achieve drug synergism with good prognosis and less side-effects. Citation Format: Chad R. Schultz, Martin C. Gruhlke, Alan J. Slusarenko, Andre S. Bachmann. Allicin, a potent new ornithine decarboxylase inhibitor in neuroblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 464.

Near‐Infrared Chemiluminescent Reporters for In Vivo Imaging of Reactive Oxygen and Nitrogen Species in Kidneys

AbstractDespite the superior sensitivity of chemiluminescence over fluorescence, most chemiluminescence reporters only emit visible light, and have low water solubility, making them poorly equipped for in vivo imaging applications. Herein two near‐infrared (NIR) chemiluminescent reporters (NCRs) with high renal clearance for real‐time imaging of reactive oxygen and nitrogen species in the kidneys are synthesized. NCRs comprise a β‐cyclodextrin unit and a modified dicyanomethylene‐4H‐pyran containing Schaap's dioxetane as the renal‐clearance enabler and the chemiluminescent moiety, respectively. NCR1 and NCR2 specifically activate their NIR chemiluminescence towards superoxide anion (O2•−) and peroxynitrite (ONOO−), respectively. By virtue of their nanomolar sensitivity and high renal clearance, NCRs not only detect subtle upregulation of endogenous RONS in cells but also enable noninvasive monitoring of RONS in the kidneys under nephrotoxic exposure. The earlier activation of NCR1 relative to NCR2 implies the sequential upregulation of O2•− and ONOO− during drug‐induced acute kidney injury (AKI). Moreover, detection of the fluorescence of excreted NCRs permits urinalysis of AKI, detecting the upregulation of RONS at least 24 h earlier than histological analysis. Thus, this study not only introduces ultrasensitive NIR chemiluminescent probes but also provides guidelines to transform them into legitimate imaging agents for organ‐specific in vivo detection.

Higher Dosage of Ciprofloxacin Necessary in Critically Ill Patients: A New Dosing Algorithm Based on Renal Function and Pathogen Susceptibility.

The objective of the present study was to develop a dosing algorithm for ciprofloxacin based on both renal function and pathogen susceptibility in critically ill patients. In this observational prospective multicenter pharmacokinetic study, a total of 39 adult intensive care unit patients receiving ciprofloxacin were included. On two occasions a total of 531 samples of ciprofloxacin were collected. Renal function is a significant covariate on ciprofloxacin clearance. A dose of 400 mg every 12 hours was sufficient to reach the preestablished target of area under the curve (AUC) in relation to the minimum inhibitory concentration (MIC) (AUC/MIC) > 125 in patients with an estimated glomerular filtration rate (eGFR) < 130 mL/min and an infection caused by a pathogen with an MIC ≤ 0.125 mg/L. For patients with infections caused by pathogens with an MIC ≥ 0.5 mg/L and eGFR> 100 mL/min, doses up to 600 mg four times daily or more were estimated to be required. This study provides a new dosing algorithm for ciprofloxacin in critically ill patients. In order to achieve adequate target attainment, the dosing of ciprofloxacin should be based on renal function and the MIC of the causative pathogen. Higher doses than the standard licensed dose are necessary to obtain target attainment for less susceptible pathogens and patients with high renal clearance. In the setting of impaired renal function, a daily dose of 400 mg (which is currently recommended) will not result in adequate target attainment for less susceptible pathogens.

Fluoro-Photoacoustic Polymeric Renal Reporter for Real-Time Dual Imaging of Acute Kidney Injury.

Photoacoustic (PA) imaging agents detect disease tissues and biomarkers with increased penetration depth and enhanced spatial resolution relative to traditional optical imaging, and thus hold great promise for clinical applications. However, existing PA imaging agents often encounter the issues of slow body excretion and low-signal specificity, which compromise their capability for in vivo detection. Herein, a fluoro-photoacoustic polymeric renal reporter (FPRR) is synthesized for real-time imaging of drug-induced acute kidney injury (AKI). FPRR simultaneously turns on both near-infrared fluorescence (NIRF) and PA signals in response to an AKI biomarker (γ-glutamyl transferase) with high sensitivity and specificity. In association with its high renal clearance efficiency (78% at 24 h post-injection), FPRR can detect cisplatin-induced AKI at 24 h post-drug treatment through both real-time imaging and optical urinalysis, which is 48 h earlier than serum biomarker elevation and histological changes. More importantly, the deep-tissue penetration capability of PA imaging results in a signal-to-background ratio that is 2.3-fold higher than NIRF imaging. Thus, the study not only demonstrates the first activatable PA probe for real-time sensitive imaging of kidney function at molecular level, but also highlights the polymeric probe structure with high renal clearance.

A Renal‐Clearable Macromolecular Reporter for Near‐Infrared Fluorescence Imaging of Bladder Cancer

AbstractBladder cancer (BC) is a prevalent disease with high morbidity and mortality; however, in vivo optical imaging of BC remains challenging because of the lack of cancer‐specific optical agents with high renal clearance. Herein, a macromolecular reporter (CyP1) was synthesized for real‐time near‐infrared fluorescence (NIRF) imaging and urinalysis of BC in living mice. Because of the high renal clearance (ca. 94 % of the injection dosage at 24 h post‐injection) and its cancer biomarker (APN=aminopeptidase N) specificity, CyP1 can be efficiently transported to the bladder and specially turn on its NIRF signal to report the detection of BC in living mice. Moreover, CyP1 can be used for optical urinalysis, permitting the ex vivo tracking of tumor progression for therapeutic evaluation and easy translation of CyP2 as an in vitro diagnostic assay. This study not only provides new opportunities for non‐invasive diagnosis of BC, but also reveals useful guidelines for the development of molecular reporters for the detection of bladder diseases.

A Renal-Clearable Macromolecular Reporter for Near-Infrared Fluorescence Imaging of Bladder Cancer.

Bladder cancer (BC) is a prevalent disease with high morbidity and mortality; however, in vivo optical imaging of BC remains challenging because of the lack of cancer-specific optical agents with high renal clearance. Herein, a macromolecular reporter (CyP1) was synthesized for real-time near-infrared fluorescence (NIRF) imaging and urinalysis of BC in living mice. Because of the high renal clearance (ca. 94 % of the injection dosage at 24 h post-injection) and its cancer biomarker (APN=aminopeptidase N) specificity, CyP1 can be efficiently transported to the bladder and specially turn on its NIRF signal to report the detection of BC in living mice. Moreover, CyP1 can be used for optical urinalysis, permitting the ex vivo tracking of tumor progression for therapeutic evaluation and easy translation of CyP2 as an in vitro diagnostic assay. This study not only provides new opportunities for non-invasive diagnosis of BC, but also reveals useful guidelines for the development of molecular reporters for the detection of bladder diseases.

Continuous versus intermittent infusion of cefotaxime in critically ill patients: a randomized controlled trial comparing plasma concentrations.

In critical care patients, reaching optimal β-lactam concentrations poses challenges, as infections are caused more often by microorganisms associated with higher MICs, and critically ill patients typically have an unpredictable pharmacokinetic/pharmacodynamic profile. Conventional intermittent dosing frequently yields inadequate drug concentrations, while continuous dosing might result in better target attainment. Few studies address cefotaxime concentrations in this population. To assess total and unbound serum levels of cefotaxime and an active metabolite, desacetylcefotaxime, in critically ill patients treated with either continuously or intermittently dosed cefotaxime. Adult critical care patients with indication for treatment with cefotaxime were randomized to treatment with either intermittent dosing (1 g every 6 h) or continuous dosing (4 g/24 h, after a loading dose of 1 g). We defined a preset target of reaching and maintaining a total cefotaxime concentration of 4 mg/L from 1 h after start of treatment. CCMO trial registration number NL50809.042.14, Clinicaltrials.gov NCT02560207. Twenty-nine and 30 patients, respectively, were included in the continuous dosing group and the intermittent dosing group. A total of 642 samples were available for analysis. In the continuous dosing arm, 89.3% met our preset target, compared with 50% in the intermittent dosing arm. Patients not reaching this target had a significantly higher creatinine clearance on the day of admission. These results support the application of a continuous dosing strategy of β-lactams in critical care patients and the practice of therapeutic drug monitoring in a subset of patients with higher renal clearance and need for prolonged treatment for further optimization, where using total cefotaxime concentrations should suffice.

A Renal-Clearable Duplex Optical Reporter for Real-Time Imaging of Contrast-Induced Acute Kidney Injury.

Despite its high morbidity and mortality, contrast-induced acute kidney injury (CIAKI) remains a diagnostic dilemma because it relies on in vitro detection of insensitive late-stage blood and urinary biomarkers. We report the synthesis of an activatable duplex reporter (ADR) for real-time in vivo imaging of CIAKI. ADR is equipped with chemiluminescence and near-infrared fluorescence (NIRF) signaling channels that can be activated by oxidative stress (superoxide anion, O2.- ) and lysosomal damage (N-acetyl-β-d-glucosaminidase, NAG), respectively. By virtue of its high renal clearance efficiency (80 % injected doses after 24 h injection), ADR detects sequential upregulation of O2.- and NAG in the kidneys of living mice prior to a significant decrease in glomerular filtration rate (GFR) and tissue damage in the course of CIAKI. ADR outperforms the typical clinical assays and detects CIAKI at least 8 h (NIRF) and up to 16 h (chemiluminescence) earlier.

A Renal‐Clearable Duplex Optical Reporter for Real‐Time Imaging of Contrast‐Induced Acute Kidney Injury

AbstractDespite its high morbidity and mortality, contrast‐induced acute kidney injury (CIAKI) remains a diagnostic dilemma because it relies on in vitro detection of insensitive late‐stage blood and urinary biomarkers. We report the synthesis of an activatable duplex reporter (ADR) for real‐time in vivo imaging of CIAKI. ADR is equipped with chemiluminescence and near‐infrared fluorescence (NIRF) signaling channels that can be activated by oxidative stress (superoxide anion, O2.−) and lysosomal damage (N‐acetyl‐β‐d‐glucosaminidase, NAG), respectively. By virtue of its high renal clearance efficiency (80 % injected doses after 24 h injection), ADR detects sequential upregulation of O2.− and NAG in the kidneys of living mice prior to a significant decrease in glomerular filtration rate (GFR) and tissue damage in the course of CIAKI. ADR outperforms the typical clinical assays and detects CIAKI at least 8 h (NIRF) and up to 16 h (chemiluminescence) earlier.

Renal-clearable Molecular Semiconductor for Second Near-Infrared Fluorescence Imaging of Kidney Dysfunction.

Real-time imaging of kidney function is important to assess the nephrotoxicity of drugs and monitor the progression of renal diseases; however, it remains challenging because of the lack of optical agents with high renal clearance and high signal-to-background ratio (SBR). Herein, a second near-infrared (NIR-II) fluorescent molecular semiconductor (CDIR2) is synthesized for real-time imaging of kidney dysfunction in living mice. CDIR2 not only has a high renal clearance efficiency (≈90 % injection dosage at 24 h post-injection), but also solely undergoes glomerular filtration into urine without being reabsorbed and secreted in renal tubules. Such a unidirectional renal clearance pathway of CDIR2 permits real-time monitoring of kidney dysfunction in living mice upon nephrotoxic exposure. Thus, this study not only introduces a molecular renal probe but also provides useful molecular guidelines to increase the renal clearance efficiency of NIR-II fluorescent agents.

Antimicrobial Disposition During Pediatric Continuous Renal Replacement Therapy Using an Ex Vivo Model.

Little is known on the impact of continuous renal replacement therapy on antimicrobial dose requirements in children. In this study, we evaluated the pharmacokinetics of commonly administered antimicrobials in an ex vivo continuous renal replacement therapy model. An ex vivo continuous renal replacement therapy circuit was used to evaluate drug-circuit interactions and determine the disposition of five commonly used antimicrobials (meropenem, piperacillin, liposomal amphotericin B, caspofungin, and voriconazole). University research laboratory. None. Antimicrobials were administered into a reservoir containing whole human blood. The reservoir was connected to a pediatric continuous renal replacement therapy circuit programmed for a 10 kg child. Continuous renal replacement therapy was performed in the hemodiafiltration mode and in three phases correlating with three different continuous renal replacement therapy clearance rates: 1) no clearance (0 mL/kg/hr, to measure adsorption), 2) low clearance (20 mL/kg/hr), and 3) high clearance (40 mL/kg/hr). Blood samples were drawn directly from the reservoir at baseline and at 5, 20, 60, and 180 minutes during each phase. Five independent continuous renal replacement therapy runs were performed to assess inter-run variability. Antimicrobial concentrations were measured using validated liquid chromatography-mass spectrometry assays. A closed-loop, flow-through pharmacokinetic model was developed to analyze concentration-time profiles for each drug. Circuit adsorption of antimicrobials ranged between 13% and 27%. Meropenem, piperacillin, and voriconazole were cleared by the continuous renal replacement therapy circuit and clearance increased with increasing continuous renal replacement therapy clearance rates (7.66 mL/min, 4.97 mL/min, and 2.67 mL/min, respectively, for high continuous renal replacement therapy clearance). Amphotericin B and caspofungin had minimal circuit clearance and did not change with increasing continuous renal replacement therapy clearance rates. Careful consideration of drug-circuit interactions during continuous renal replacement therapy is essential for appropriate drug dosing in critically ill children. Antimicrobials have unique adsorption and clearance profiles during continuous renal replacement therapy, and this knowledge is important to optimize antimicrobial therapy.

Pharmacokinetics in Children - What is Important for Correct Drug Dosage?

Under- or overdosage of medication can lead to severe side effects in children. To avoid this, precise knowledge of age-specific liberation, absorption, distribution, metabolism and excretion - LADME for short - is necessary. Absorption can take place intravenously, orally, rectally, intranasally, transdermally or epidurally/caudally and is associated with numerous special features in children, depending on age and route of application. The distribution in children is faster due to more permeable organ barriers between individual organs and must be adapted for hydrophilic and lipophilic drugs to the patient's age as well as their fat and fat-free body parts. Drug biotransformation takes place through Phase I and Phase II reactions, predominantly in the liver and kidneys. The cytochrome P450 (CYP450) enzyme system is the most important system for this and requires dose adjustment for numerous drugs in the first phase of life. Due to immature kidney function, all drugs with high renal clearance have a prolonged duration of action in the first months of life. Biliary excretion is particularly important for substances with a molecular weight of > 500 g/mol and is of limited functionality during the first months of life. The amount of substrate that is eliminated by the liver and kidneys within a defined period of time is known as clearance and is strongly dependent on the substance and age of the child. Reciprocal to this is the elimination half-life, which has to be considered especially with repetitive administration. Only with sufficient experience with pharmacokinetic variations or comedications within the different age groups, a patient-adapted, individually correct dose application is possible. The knowledge of the age-specific pharmacokinetics together with the knowledge of patient-specific peculiarities and comedications allow an individual drug application characterized by heuristics.

Molecular optical imaging probes for early diagnosis of drug-induced acute kidney injury.

Drug-induced acute kidney injury (AKI) with a high morbidity and mortality is poorly diagnosed in hospitals and deficiently evaluated in drug discovery. Here, we report the development of molecular renal probes (MRPs) with high renal clearance efficiency for in vivo optical imaging of drug-induced AKI. MRPs specifically activate their near-infrared fluorescence or chemiluminescence signals towards the prodromal biomarkers of AKI including the superoxide anion, N-acetyl-β-D-glucosaminidase and caspase-3, enabling an example of longitudinal imaging of multiple molecular events in the kidneys of living mice. Importantly, they in situ report the sequential occurrence of oxidative stress, lysosomal damage and cellular apoptosis, which precedes clinical manifestation of AKI (decreased glomerular filtration). Such an active imaging mechanism allows MRPs to non-invasively detect the onset of cisplatin-induced AKI at least 36 h earlier than the existing imaging methods. MRPs can also act as exogenous tracers for optical urinalysis that outperforms typical clinical/preclinical assays, demonstrating their clinical promise for early diagnosis of AKI.

Manganese oxide-carbon quantum dots nano-composites for fluorescence/magnetic resonance (T1) dual mode bioimaging, long term cell tracking, and ROS scavenging

Multimodal long-term imaging probes with capability of extracting complementary information are highly important in biomedical engineering for disease diagnosis and monitoring of therapeutics distribution. However, most of the theranostics probes used are transient and have inherent problem of toxicity mostly related to generation of free radicals. In current study, a simple microwave assisted synthesis of multimodal imaging nanoprobe (T1 contrast in MR/fluorescence) is reported via doping carbon quantum dots into manganese oxide nanoparticles. The nanostructures were characterized by US-Vis spectroscopy, fluorescence spectroscopy, FTIR, Raman spectroscopy, TEM, XRD, AFM and XPS. The average particle size was observed to be around 20–40 nm with a height of 7–9 nm and approximate quantum yield of 0.23. The nanostructures were useful for bio imaging and cell tracking via fluorescence microscopy up to 12 generations with nominal cytotoxicity. The material was capable of scavenging free radicals from cellular microenvironment and downregulate gene expression of free radical scavenging enzymes. The material has significant relaxivity (r1) value of 3.98 mM−1.sec−1 at 1.5 T. It was also observed to create significant contrast with high circulation time (30 min) and renal clearance property. The histological analysis of kidney and liver sections were observed to have no significant toxicity from the nanostructure.