Peptide/protein therapeutics have been significantly applied in the clinical treatment of various diseases such as cancer, diabetes, etc. owing to their high biocompatibility, specificity, and therapeutic efficacy. However, due to their immunogenicity, instability stemming from its complex tertiary and quaternary structure, vulnerability to enzyme degradation, and rapid renal clearance, the clinical application of protein/peptide therapeutics is significantly confined. Though nanotechnology has been demonstrated to prevent enzyme degradation of the protein therapeutics and thus enhance the half-life, issues such as initial burst release and uncontrollable release kinetics are still unsolved. Moreover, the traditional administration method results in poor patient compliance, limiting the clinical application of protein/peptide therapeutics. Exploiting the sustained-release formulations for more controllable delivery of protein/peptide therapeutics to decrease the frequency of injection and enhance patient compliance is thus greatly meaningful. In this review, we comprehensively summarize the substantial advancements of protein/peptide sustainedrelease systems in the past decades. In addition, the advantages and disadvantages of all these sustained-release systems in clinical application together with their future challenges are also discussed in this review.
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...
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