Role of Nanotechnology and Their Perspectives in the Treatment of Kidney Diseases

Nanoparticles (NPs) are differing in particle size, charge, shape, and compatibility of targeting ligands, which are linked to improved pharmacologic characteristics, targetability, and bioavailability. Researchers are now tasked with developing a solution for enhanced renal treatment that is free of side effects and delivers the medicine to the active spot. A growing number of nano-based medication delivery devices are being used to treat renal disorders. Kidney disease management and treatment are currently causing a substantial global burden. Renal problems are multistep processes involving the accumulation of a wide range of molecular and genetic alterations that have been related to a variety of kidney diseases. Renal filtration is a key channel for drug elimination in the kidney, as well as a burgeoning topic of nanomedicine. Although the use of nanotechnology in the treatment of renal illnesses is still in its early phases, it offers a lot of potentials. In this review, we summarized the properties of the kidney and characteristics of drug delivery systems, which affect a drug’s ability should focus on the kidney and highlight the possibilities, problems, and opportunities.

Smart Nanocarriers as an Emerging Platform for Cancer Therapy: A Review

Cancer is a group of disorders characterized by uncontrolled cell growth that affects around 11 million people each year globally. Nanocarrier-based systems are extensively used in cancer imaging, diagnostics as well as therapeutics; owing to their promising features and potential to augment therapeutic efficacy. The focal point of research remains to develop new-fangled smart nanocarriers that can selectively respond to cancer-specific conditions and deliver medications to target cells efficiently. Nanocarriers deliver loaded therapeutic cargos to the tumour site either in a passive or active mode, with the least drug elimination from the drug delivery systems. This review chiefly focuses on current advances allied to smart nanocarriers such as dendrimers, liposomes, mesoporous silica nanoparticles, quantum dots, micelles, superparamagnetic iron-oxide nanoparticles, gold nanoparticles and carbon nanotubes, to list a few. Exhaustive discussion on crucial topics like drug targeting, surface decorated smart-nanocarriers and stimuli-responsive cancer nanotherapeutics responding to temperature, enzyme, pH and redox stimuli have been covered.

The role of angiotensin signalling in anthracycline-induced cardiotoxicity

Anthracyclines (e.g. epirubicin, doxorubicin, daunorubicin) are widely used for the treatment of adult and paediatric cancers. Despite their therapeutic efficacy, anthracyclines are associated with both acute and late-onset cardiac toxicities. Meta-analyses report an overt cardiotoxicity incidence of 6.3%, whilst sub-clinical cardiotoxicity incidence is 17.9% (1). Angiotensin converting enzyme (ACE) inhibitors are used to treat anthracycline-induced cardiotoxicity (AIC) (2) and despite their efficacy being well studied for the treatment of heart failure, hypertension and post-acute coronary syndromes, their mechanism(s) for treating and preventing AIC remain unknown. Using in vitro cardiomyocytes, we evaluated the angiotensin signalling mechanisms stimulated by doxorubicin chemotherapy, applying quantitative PCR, immunofluorescence and real-time cell analysis technologies. In vitro adult human ventricular cardiomyocytes (AC10 cell line) treated with clinically relevant sub-toxic concentrations of doxorubicin, demonstrate a dose and time-dependent increase in angiotensin II type-1 receptor (AT1R) gene expression. Maximal AT1R expression was observed after 24 hours' exposure at 250 nanomolar (nM), with qPCR recording up to 13-fold increases in expression relative to control (figure 1). Consistent with gene expression studies, doxorubicin also induced expression of AT1R at the protein level, with immunofluorescence imaging displaying up-regulation of AT1R in association with doxorubicin concentrations up to 500nM (figure 2). Western blot results also support the induction of AT1R, however no relationship was observed between either doxorubicin concentration or drug exposure time. Cellular growth and morphological changes of cardiomyocytes in response to clinically relevant doses of doxorubicin treatment were evaluated with real-time cell analysis using impedance-based xCELLigence technology. During the early phases of doxorubicin exposure, an increase in cell size was observed, whilst experiments modelling the pharmacokinetics and serial half-lives of doxorubicin demonstrated reversibility of doxorubicin-induced cardiomyocyte injury following drug elimination. These data support the mechanistic hypothesis that a relationship exists between AIC and modulation of the angiotensin signalling pathway in cardiomyocytes. We demonstrate that cardiomyocyte exposure to doxorubicin induces AT1R gene and protein expression, whilst doxorubicin-induced cardiomyocyte injury displays reversibility following drug elimination. Genetic polymorphisms within the ACE gene have been associated with cardiomyopathy and left ventricular hypertrophy. Our research now provides the platform to ascertain whether the ACE genotype contributes to heart failure from AIC, and whether an elevation in pro-hypertrophic angiotensin II levels could exacerbate anthracycline-induced hypertrophy and promote the development of late-onset anthracycline-induced heart failure. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Cancer Research UK PhD research grant

The effect of hemoadsorption on rivaroxaban blood plasma concentration in emergency cardiac surgery

Hemoadsorption was used in a 59-year-old patient with an acute type A aortic dissection, who was on rivaroxaban and dual antiplatelet therapy with clopidogrel and acetylsalicylic acid. Our aim was to expeditiously remove rivaroxaban preoperatively. After 8 h of hemoadsorption, the rivaroxaban blood plasma concentration (RBPC) did not decrease below 42.1 μg/l. Intraoperatively, hemoadsorption was repeated during extracorporeal circulation. Sixteen hours after surgery and a total of 13 h of hemoadsorption, the RBPC was 40.1 μg/l. Thereafter, the RBPC spontaneously decreased to 24.7 μg/l within 14 h. In our patient, hemoadsorption may have enhanced rivaroxaban removal at higher RBPC (cutoff value 40–50 μg/l). At lower RBPC, the removal of rivaroxaban may depend solely on the natural drug elimination process. The evolution of the RBPC under hemoadsorption in vivo warrants a thorough investigation. Further clinical studies are required to assess the effectiveness and limitations of hemoadsorption to preclude a fatal bleeding event in patients with rivaroxaban in need of major emergency surgery.

Prediction of Kidney Drug Clearance: A Comparison of Tubular Secretory Clearance and Glomerular Filtration Rate

BackgroundAlthough proximal tubular secretion is the primary mechanism of kidney drug elimination, current kidney drug dosing strategies are on the basis of eGFR.MethodsIn a dedicated pharmacokinetic study to compare GFR with tubular secretory clearance for predicting kidney drug elimination, we evaluated stable outpatients with eGFRs ranging from 21 to 140 ml/min per 1.73 m2. After administering single doses of furosemide and famciclovir (metabolized to penciclovir), we calculated their kidney clearances on the basis of sequential plasma and timed urine measurements. Concomitantly, we quantified eight endogenous secretory solutes in plasma and urine using liquid chromatography-tandem mass spectrometry and measured GFR by iohexol clearance (iGFR). We computed a summary secretion score as the scaled average of the secretory solute clearances.ResultsMedian iGFR of the 54 participants was 73 ml/min per 1.73 m2. The kidney furosemide clearance correlated with iGFR (r=0.84) and the summary secretion score (r=0.86). The mean proportionate error (MPE) between iGFR-predicted and measured furosemide clearance was 30.0%. The lowest MPE was observed for the summary secretion score (24.1%); MPEs for individual secretory solutes ranged from 27.3% to 48.0%. These predictive errors were statistically indistinguishable. Penciclovir kidney clearance was correlated with iGFR (r=0.83) and with the summary secretion score (r=0.91), with similar predictive accuracy of iGFR and secretory clearances. Combining iGFR with the summary secretion score yielded only modest improvements in the prediction of the kidney clearance of furosemide and penciclovir.ConclusionsSecretory solute clearance measurements can predict kidney drug clearances. However, tight linkage between GFR and proximal tubular secretory clearance in stable outpatients provides some reassurance that GFR, even when estimated, is a useful surrogate for predicting secretory drug clearances in such patients.