Rapidly Blocking the Calcium Overload/ROS Production Feedback Loop to Alleviate Acute Kidney Injury via Microenvironment‐Responsive BAPTA‐AM/BAC Co‐Delivery Nanosystem

Abstract

AKI is a common clinical syndrome with manifestations of progressive decrease in glomerular filtration rate to less than 75%, an abnormal increase in creatinine (CRE) and blood urea nitrogen (BUN), and a urine output of less than 0.5 mL kg −1 h −1 . [2] Continued deterioration of renal function to the point of toxin accumulation, dehydration/electrolyte disturbance, and acid-base imbalance can result in acute renal failure with a hospital mortality rate of 50% or more if not treated promptly and thoroughly. [3] Currently, there are no effective therapeutic drugs for the clinical management of AKI, which is primarily treated by hemodialysis or kidney transplantation. However, these supportive means still have a series of disadvantages, including high cost, low patient compliance, and a high incidence of complications. [4] Even though organ transplantation can significantly reduce the mortality rate of AKI, immunological rejection after transplantation requires patients to take immunosuppressive drugs for an extended period of time, resulting in decreased resistance and increased disease risk (hypertension, anemia, arthritis, cancer, etc.). [5] Therefore, there is an urgent need to develop effective drugs for AKI that can rapidly reverse AKI within a short period of time (few hours) and promote renal function recovery in order to prevent complications and improve the survival rate of AKI.The specific pathophysiological process underlying I/Rinduced AKI is as described below: (1) During renal ischemia, the drop in oxygen partial pressure accelerates the degradation of ATP into hypoxanthine. Rapid depletion of ATP causes depolarization of the cell membrane and activation of the Na + -Ca 2+ exchange mechanism, resulting in a substantial influx of extracellular Ca 2+ . [6] (2) After reperfusion, hypoxic cells are reoxygenated, and hypoxanthine accumulated during hypoxia reacts with oxygen molecules to produce large amounts of ROS, which can damage the cell membrane and endoplasmic reticulum (ER), resulting in an influx of extracellular and ER Ca 2+ into the cytoplasm. [7] Ca 2+ deficiency in the lumen of the ER can worsen ER stress (ERS) by disrupting Ca 2+ -dependent chaperone activity and accumulating unfolded proteins, leading to renal cell death Calcium overload and ROS overproduction, two major triggers of acute kidney injury (AKI), are self-amplifying and mutually reinforcing, forming a complicated cascading feedback loop that induces kidney cell "suicide" and ultimately renal failure. There are currently no clinically effective drugs for the treatment of AKI, excluding adjuvant therapy. In this study, a porous siliconbased nanocarrier rich in disulfide bond skeleton (<50 nm) is developed that enables efficient co-loading of the hydrophilic drug borane amino complex and the hydrophobic drug BAPTA-AM, with its outer layer sealed by the renal tubule-targeting peptide PEG-LTH. Once targeted to the kidney injured site, the nanocarrier structure collapses in the high glutathione environment of the early stage of A...

Nephroprotective Effects of Cardamonin on Renal Ischemia Reperfusion Injury/UUO-Induced Renal Fibrosis

“…Endothelial dysfunction induced by this endothelial damage in turn aggravates the reduction of organ blood flow during I/R through inflammatory response and changing vascular tone . Previous reports suggested that ameliorating calcium overload and microvascular endothelial dysfunction will lessen I/R-generated renal damage. , The regulatory relationships of CAD on calcium overload and endothelial dysfunction are rarely reported, which also motivates us to figure out their relationship in future studies. The established studies validated CAD’s biomedical properties in diversified disorders including ovarian cancer, cardiotoxicity, colon tumorigenesis, breast cancer, etc. , We originally figured out that CAD application could prevent the progression and end point of UUO or renal I/R surgery through anti-inflammatory and antioxidative authorities.…”

“…54 Previous reports suggested that ameliorating calcium overload and microvascular endothelial dysfunction will lessen I/Rgenerated renal damage. 53,54 The regulatory relationships of CAD on calcium overload and endothelial dysfunction are rarely reported, which also motivates us to figure out their relationship in future studies. The established studies validated CAD's biomedical properties in diversified disorders including ovarian cancer, cardiotoxicity, colon tumorigenesis, breast cancer, etc.…”

“…Rapid adenosine triphosphate (ATP) depletion induced by the ischemia stage inevitably leads to excessive aggregation of extracellular Ca 2+ via activating Na + –Ca 2+ exchange channels and speeding cell membrane depolarization. Continuously increasing Ca 2+ concentrations in the cytoplasm during the reperfusion stage severely disrupts the structure and function of crucial cell organelles including mitochondria, endoplasmic reticulum, etc., which in turn leads to cell death and induces AKI through various cascade reactions. , Abnormal biological processes during the I/R stage would also impair parenchymal cells including renal endothelium and deteriorate vascular function. Endothelial dysfunction induced by this endothelial damage in turn aggravates the reduction of organ blood flow during I/R through inflammatory response and changing vascular tone .…”

Targeting the Kidneys at the Nanoscale: Nanotechnology in Nephrology

“…Several passive targeting approaches were used, including: (1) small NPs (,10 nm) which pass through the glomerular filtration barrier and are reabsorbed in the nephron, (2) somewhat larger NPs which pass through the glomerular endothelial fenestrations and arrest in the glomerular mesangium (typically up to 80 nm), (3) somewhat larger (approximately 100 nm) NPs which pass through only disrupted glomerular filtration barriers and are reabsorbed in the nephron, and (4) NPs which do not interact with the glomerulus and cross from the peritubular endothelium into the tubular epithelium. Active targeting of NPs to the kidneys has taken several different approaches, including serine modifications which purportedly bind kidney injury molecule-1, 64,71,83,93 charge-based binding to the megalin receptor, 55,59,60,75 or other cell surface receptor or basement membrane binding. 51,68,70,85 Regarding therapeutic cargoes, we found that many of the active pharmaceutical ingredients (APIs) involved short interfering RNA (siRNA) delivery-about 10 of those we found.…”

UV Irradiation-Induced Cyclic-to-Linear Topological Changes of a Light/pH Dual-Sensitive Cyclic Copolymer for Enhanced Drug Delivery

“…Meanwhile, a stabilized nanocarrier must undergo a structural change for efficient intracellular destabilization induced by one or more external/internal triggers to exert the desired therapeutic efficiency. , In this regard, the leading strategies adopted to induce the destabilization of a cyclic polymer-based nanocarrier mainly focused on the modification and functionalization of the side chains of cyclic polymers. − Notable examples were cyclic polymers constructed with either stimuli-responsive monomers or intracellular triggers-cleavable links, which, however, inevitably led to inadequate intracellular drug release due to the lack of cyclic topology disruption . A stimuli-responsive cyclic backbone is thus highly desirable for promoted intracellular drug release but remains relatively unexplored likely due to the synthetic challenge.…”