Search

Background: The reactive oxygen species (ROS) and inflammation, a critical contributor to tissue damage, is well-known to be associated with various disease. The kidney is susceptible to hypoxia and vulnerable to ROS. Thus, the vicious cycle between oxidative stress and renal hypoxia critically contributes to the progression of chronic kidney disease and finally, end-stage renal disease. Thus, delivering therapeutic agents to the ROS-rich inflammation site and releasing the therapeutic agents is a feasible solution. Results: We developed a longer-circulating, inflammation-sensing, ROS-scavenging versatile nanoplatform by stably loading catalase-mimicking 1-dodecanethiol stabilized Mn3O4 (dMn3O4) nanoparticles inside ROS-sensitive nanomicelles (PTC), resulting in an ROS-sensitive nanozyme (PTC-M). Hydrophobic dMn3O4 nanoparticles were loaded inside PTC micelles to prevent premature release during circulation and act as a therapeutic agent by ROS-responsive release of loaded dMn3O4 once it reached the inflammation site. Conclusions: The findings of our study demonstrated the successful attenuation of inflammation and apoptosis in the IRI mice kidneys, suggesting that PTC-M nanozyme could possess promising potential in AKI therapy. This study paves the way for high-performance ROS depletion in treating various inflammation-related diseases. [ABSTRACT FROM AUTHOR]

Background: Recently, we developed hydrophobically modified glycol chitosan (HGC) nanomicelles loaded with tacrolimus (TAC) (HGC-TAC) for the targeted renal delivery of TAC. Herein, we determined whether the administration of the HGC-TAC nanomicelles decreases kidney injury in a model of lupus nephritis. Lupus-prone female MRL/lpr mice were randomly assigned into three groups that received intravenous administration of either vehicle control, an equivalent dose of TAC, or HGC-TAC (0.5 mg/kg TAC) weekly for 8 weeks. Age-matched MRL/MpJ mice without Faslpr mutation were also treated with HGC vehicle and used as healthy controls. Results: Weekly intravenous treatment with HGC-TAC significantly reduced genetically attributable lupus activity in lupus nephritis-positive mice. In addition, HGC-TAC treatment mitigated renal dysfunction, proteinuria, and histological injury, including glomerular proliferative lesions and tubulointerstitial infiltration. Furthermore, HGC-TAC treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and glomerular fibrosis. Moreover, HGC-TAC administration regulated renal injury via the TGF-β1/MAPK/NF-κB signaling pathway. These renoprotective effects of HGC-TAC treatment were more potent in lupus mice compared to those of TAC treatment alone. Conclusion: Our study indicates that weekly treatment with the HGC-TAC nanomicelles reduces kidney injury resulting from lupus nephritis by preventing inflammation, fibrosis, and apoptosis. This advantage of a new therapeutic modality using kidney-targeted HGC-TAC nanocarriers may improve drug adherence and provide treatment efficacy in lupus nephritis mice. [ABSTRACT FROM AUTHOR]

To date, numerous delivery systems based on either organic or inorganic material have been developed to achieve efficient and sustained delivery of therapeutics. Hydrogels, which are three dimensional networks of crosslinked hydrophilic polymers, have a significant role in solving the clinical and pharmacological limitations of present systems because of their biocompatibility, ease of preparation and unique physical properties such as a tunable porous nature and affinity for biological fluids. Development of an in situ forming injectable hydrogel system has allowed excellent spatial and temporal control, unlike systemically administered therapeutics. Injectable hydrogel systems can offset difficulties with conventional hydrogel-based drug delivery systems in the clinic by forming a drug/gene delivery or cell-growing depot in the body with a single injection, thereby enabling patient compliance and comfort. Carbohydrate polymers are widely used for the synthesis of injectable in situ -forming hydrogels because of ready availability, presence of modifiable functional groups, biocompatibility and other physiochemical properties. In this review, we discuss different aspects of injectable hydrogels, such as bulk hydrogels/macrogels, microgels, and nanogels derived from natural polymers, and their importance in the delivery of therapeutics such as genes, drugs, cells or other biomolecules and how these revolutionary systems can complement existing therapeutic delivery systems. [ABSTRACT FROM AUTHOR]

In this study, we propose using IR 780-loaded, CD44-targeted hyaluronic acid-based micelles (HA-IR 780) for enhanced photothermal therapy (PTT) effects in tumors. Two kinds of HA-C18 micelles were synthesized from different C18 feed ratios with degree of substitution of 3% and 13% respectively. Three different IR 780 weight percentages were used for micelle formation with loading content of 4.6%, 7.9%, and 10.3% respectively. The IC 50 value of HA-IR 780 in TC1 cells was 21.89 μg mL −1 (32.81 μM). Upon irradiation of the tumor site with an 808-nm laser (2Wcm −2 ) for 2 min, the temperature in the tumor in the HA-IR 780-treated groups reached 49.9 °C which exceeds the temperature threshold to induce irreversible tissue damage. Toxicity studies showed that HA-IR 780 does not cause any adverse effects in organs, including heart, liver, lungs, kidney and spleen, although it selectively caused cell damage in the tumor region upon laser irradiation. Therefore, the present study suggests that HA-IR 780 can cause selective cell death in tumor regions due to its enhanced tumor-targeting and photothermal capabilities. [ABSTRACT FROM AUTHOR]

The physiological condition of the human body is a composite of different environments, each with its own parameters that may differ under normal, as well as diseased conditions. These environmental conditions include factors, such as pH, temperature and enzymes that are specific to a type of cell, tissue or organ or a pathological state, such as inflammation, cancer or infection. These conditions can act as specific triggers or stimuli for the efficient release of therapeutics at their destination by overcoming many physiological and biological barriers. The efficacy of conventional treatment modalities can be enhanced, side effects decreased and patient compliance improved by using stimuli-responsive material that respond to these triggers at the target site. These stimuli or triggers can be physical, chemical or biological and can be internal or external in nature. Many smart/intelligent stimuli-responsive therapeutic gene carriers have been developed that can respond to either internal stimuli, which may be normally present, overexpressed or present in decreased levels, owing to a disease, or to stimuli that are applied externally, such as magnetic fields. This review focuses on the effects of various internal stimuli, such as temperature, pH, redox potential, enzymes, osmotic activity and other biomolecules that are present in the body, on modulating gene expression by using stimuli-regulated smart polymeric carriers. [ABSTRACT FROM AUTHOR]

[Display omitted] ACE inhibitors or angiotensin II receptor blockers (ACEi/ARBs) have been a cornerstone of the management in kidney disease, but their use is often limited by undesired systemic effects, such as symptomatic hypotension. To minimize the extra-renal effects of ACEi/ARBs, we formulated hydrophobically modified glycol chitosan (HGC) nanomicelles releasing olmesartan (HGC-Olm) that specifically accumulated in the kidney, and investigated whether kidney-specific delivery of olmesartan by HGC nanomicelles could ameliorate organ damage in Col4a3 −/− mouse, a murine model of progressive chronic kidney disease mimicking human Alport syndrome. Ex vivo tracing demonstrated that intravenously injected HGC-Olm nanomicelles were specifically delivered to the kidney, with sustained release of olmesartan for more than 48 h. Contrary to the conventional delivery of olmesartan via oral route, injection of HGC-Olm nanomicelles did not alter blood pressure in Col4a3 −/− mice. Immunohistochemistry revealed that HGC nanomicelles were diffusely distributed from the cortex and glomeruli to the outer medulla, sparing the inner medulla. Phenotypic analysis showed that the attenuation of kidney fibrosis in the kidney of Col4a3 −/− mice by HGC-Olm nanomicelles was comparable to that noted with conventionally delivered olmesartan. Therefore, our results suggest that HGC-Olm nanomicelles could be a safe and effective alternative drug delivery system for kidney diseases. [ABSTRACT FROM AUTHOR]

• Hydrophobically modified glycol chitosan polymeric nanomicelles (HGC) loaded with hydrophobic drug tacrolimus (TAC). • Selective deposition of TAC into the kidney because of the in-built property of glycol chitosan to target the kidney. • Megalin receptor-mediated endocytosis is involved in the uptake and retention of HGC-TAC nanomicelles in the kidney. • Demonstrates the potential of HGC nanomicelles as a novel strategy to deliver drugs specifically to kidneys without any systemic toxicity. In this study, we propose the use of glycol chitosan for the targeted delivery of hydrophobic drugs such as tacrolimus (TAC) towards the kidney. We synthesized a hydrophobically modified glycol chitosan (HGC) polymeric nanomicelle followed by loading TAC resulting in TAC loaded HGC nanomicelles (HGC-TAC). The HGC-TAC nanomicelles displayed spherical morphology with superior drug loading content and encapsulation efficiency. in vitro and in vivo evaluations demonstrated that HGC-TAC nanomicelles are non toxic and delivered TAC preferentially to kidney while lowering the plasma concentrations. The therapeutic effects of HGC-TAC and unencapsulated ("bare") TAC on the kidneys showed that a single intravenous administration of HGC-TAC achieved a therapeutic efficacy comparable to that obtained from daily intraperitoneal injections of TAC for 14 days without any systemic side effects. Thus, HGC-TAC nanomicelles could be effectively used for delivery of TAC towards the kidney, highlighting its potential as a safe modality for renal-targeted delivery of therapeutics. [ABSTRACT FROM AUTHOR]

Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effect in malignant cancers, the currently available nanocarriers offer the limited capabilities for selective toxicity, drug release and tumor penetration. Herein, we developed photoactivatable nanomicelles, which are constructed by self-assembling of poly (ethylene glycol) (PEG)-stearamine (C18) conjugate (PTS) with a ROS-sensitive thioketal linker (TL) and co-loaded with doxorubicin (DOX) and photosensitizer pheophorbide A (PhA), for enhanced locoregional chemo-photodynamic therapy. Upon accumulation in tumor region, the resulting PTS nanomicelles loaded with Dox and PhA (PTS-DP) demonstrated reactive oxygen species (ROS) cascade responsive release of the DOX and PhA loaded inside. Initial intracellular release of DOX and PhA from the PTS-DP was triggered by the intrinsic presence of endogenous ROS within cancer cells. Furthermore, upon laser irradiation on the tumor region, enhanced singlet oxygen (1O 2) was generated by PhA released initially in cancer cells, which in turns accelerated the cytoplasmic release of DOX through rapid dissociation of nanomicelles. The gradual elevation of local ROS level generated by light-activated PhA subsequent ROS-triggered release of DOX synergistically inhibited tumor growth and enhances the anti-tumor immunity. Findings of our study suggested that ROS-sensitive PTS nanomicelles could be a promising and innovative nanocarrier for locoregional chemo-photodynamic therapy. [ABSTRACT FROM AUTHOR]