scholarly journals Liposomal PHD2 Inhibitors and the Enhanced Efficacy in Stabilizing HIF-1α

Nanomaterials ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 163
Author(s):  
Cheng-Bang Jian ◽  
Xu-En Yu ◽  
Hua-De Gao ◽  
Huai-An Chen ◽  
Ren-Hua Jheng ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Hypoxia Inducible Factor ◽  
Drug Efficacy ◽  
Microscopy Imaging ◽  
Liposome Formulation ◽  
Remote Loading ◽  
Localized Disease ◽  
Efficient Loading ◽  
Important Therapeutic Target

Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome’s interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors—vadadustat and roxadustat—to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions.

scholarly journals Hypoxia Preconditioning of Human MSCs: a Direct Evidence of HIF-1α and Collagen Type XV Correlation

2018 ◽  
Vol 51 (5) ◽  
pp. 2237-2249 ◽  
Author(s):  
Elisabetta Lambertini ◽  
Letizia Penolazzi ◽  
Marco Angelozzi ◽  
Leticia Scussel Bergamin ◽  
Cristina Manferdini ◽  
...  
Keyword(s):  
Collagen Type ◽  
Therapeutic Potential ◽  
Hypoxia Inducible Factor ◽  
Culture Conditions ◽  
Luciferase Reporter ◽  
Osteogenic Potential ◽  
Human Mscs ◽  
Short Period ◽  
Hypoxia Preconditioning

Background/Aims: Mesenchymal stromal cells (MSCs) hold considerable promise in bone tissue engineering, but their poor survival and potency when in vivo implanted limits their therapeutic potential. For this reason, the study on culture conditions and cellular signals that can influence the potential therapeutic outcomes of MSCs have received considerable attention in recent years. Cell maintenance under hypoxic conditions, in particular for a short period, is beneficial for MSCs, as low O2 tension is similar to that present in the physiologic niche, however the precise mechanism through which hypoxia preconditioning affects these cells remains unclear. Methods: In order to explore what happens during the first 48 h of hypoxia preconditioning in human MSCs (hMSCs) from bone marrow, the cells were exposed to 1.5% O2 tension in the X3 Hypoxia Hood and Culture Combo – Xvivo System device. The expression modulation of critical genes which could be good markers of increased osteopotency has been investigated by Western blot, immunufluorescence and ELISA. Luciferase reporter assay and Chromatin immunoprecipitation was used to investigate the regulation of the expression of Collagen type XV (ColXV) gene. Results: We identified ColXV as a new low O2 tension sensitive gene, and provided a novel mechanistic evidence that directly HIF-1α (hypoxia-inducible factor-1 alpha) mediates ColXV expression in response to hypoxia, since it was found specifically in vivo recruited at ColXV promoter, in hypoxia-preconditioned hMSCs. This finding, together the evidence that also Runx2, VEGF and FGF-2 expression increased in hypoxia preconditioned hMSCs, is consistent with the possibility that increased ColXV expression in response to hypoxia is mediated by an early network that supports the osteogenic potential of the cells. Conclusion: These results add useful information to understand the role of a still little investigated collagen such as ColXV, and identify ColXV as a marker of successful hypoxia preconditioning. As a whole, our data give further evidence that hypoxia preconditioned hMSCs have greater osteopotency than normal hMSCs, and that the effects of hypoxic regulation of hMSCs activities should be considered before they are clinically applied.

Anti-HER2 VHH Targeted Fluorescent Liposome as Bimodal Nanoparticle for Drug Delivery and Optical Imaging

2021 ◽  
Vol 16 ◽  
Author(s):  
Sepideh Khaleghi ◽  
Fatemeh Rahbarizadeh ◽  
Shahryar Khoshtinat Nikkhoi
Keyword(s):  
Drug Delivery ◽  
Real Time ◽  
Targeted Delivery ◽  
Cell Tracking ◽  
Physicochemical Characterization ◽  
Target Cells ◽  
Wide Field ◽  
Cell Trafficking ◽  
Microscopy Imaging ◽  
Intracellular Drug Delivery

Objective: The aim of this study was to formulate fluorescent-labeled targeted immunoliposome to visualize the delivery and distribution of drugs in real-time. Methods: In this study, fluorescent-labeled liposomes were decorated with anti-HER2 VHH or Herceptin to improve the monitoring of intracellular drug delivery and tumor cell tracking with minimal side effects. The conjugation efficiency of antibodies was analyzed by SDS-PAGE silver staining. In addition, the physicochemical characterization of liposomes was performed using DLS and TEM. Finally, confocal microscopy visualized nanoparticles in the target cells. Results: Quantitative and qualitative methods characterized the intracellular uptake of 110±10 nm particles with near 70% conjugation efficiency. In addition, live-cell trafficking during hours of incubation was monitored by wide-field microscopy imaging. The results show that the fluorescent-labeled nanoparticles can specifically bind to HER2-positive breast cancer with minimal off-target delivery. Conclusion: This kind of nanoparticles can have several applications in personalized medicine, especially drug delivery and real-time visualization of cancer therapy. Moreover, this method also can be applied in the targeted delivery of contrast agents in imaging and thermotherapy.

scholarly journals Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1110
Author(s):  
Blerina Shkodra ◽  
Adrian T. Press ◽  
Antje Vollrath ◽  
Ivo Nischang ◽  
Stephanie Schubert ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Targeted Delivery ◽  
Near Infrared ◽  
Water Solubility ◽  
Analytical Ultracentrifugation ◽  
Therapeutic Potential ◽  
Kinase C ◽  
Protein Kinase C Inhibitor

Bisindolylmaleimide I (BIM-I) is a competitive pan protein kinase C inhibitor with anti-inflammatory and anti-metastatic properties, suggested to treat inflammatory diseases and various cancer entities. However, despite its therapeutic potential, BIM-I has two major drawbacks, i.e., it has a poor water solubility, and it binds the human ether-à-go-go-related gene (hERG) ion channels, potentially causing deadly arrhythmias. In this case, a targeted delivery of BIM-I is imperative to minimize peripheral side effects. To circumvent these drawbacks BIM-I was encapsulated into nanoparticles prepared from poly(lactic-co-glycolic acid) (PLGA) functionalized by the near-infrared dye DY-635. DY-635 served as an active targeting moiety since it selectively binds the OATP1B1 and OATP1B3 transporters that are highly expressed in liver and cancer cells. PLGA-DY-635 (BIM-I) nanoparticles were produced by nanoprecipitation and characterized using dynamic light scattering, analytical ultracentrifugation, and cryogenic transmission electron microscopy. Particle sizes were found to be in the range of 20 to 70 nm, while a difference in sizes between the drug-loaded and unloaded particles was observed by all analytical techniques. In vitro studies demonstrated that PLGA-DY-635 (BIM-I) NPs prevent the PKC activation efficiently, proving the efficacy of the inhibitor after its encapsulation, and suggesting that BIM-I is released from the PLGA-NPs. Ultimately, our results present a feasible formulation strategy that improved the cytotoxicity profile of BIM-I and showed a high cellular uptake in the liver as demonstrated in vivo by intravital microscopy investigations.

scholarly journals Targeted Delivery of Mesenchymal Stem Cell-Derived Nanovesicles for Spinal Cord Injury Treatment

2020 ◽  
Vol 21 (11) ◽  
pp. 4185
Author(s):  
Ju-Ro Lee ◽  
Jae Won Kyung ◽  
Hemant Kumar ◽  
Sung Pil Kwon ◽  
Seuk Young Song ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Clinical Application ◽  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Systemic Injection ◽  
Cord Injury ◽  
Macrophage Membrane

Due to the safety issues and poor engraftment of mesenchymal stem cell (MSC) implantation, MSC-derived exosomes have been spotlighted as an alternative therapy for spinal cord injury (SCI). However, insufficient productivity of exosomes limits their therapeutic potential for clinical application. Moreover, low targeting ability of unmodified exosomes is a critical obstacle for their further applications as a therapeutic agent. In the present study, we fabricated macrophage membrane-fused exosome-mimetic nanovesicles (MF-NVs) from macrophage membrane-fused umbilical cord blood-derived MSCs (MF-MSCs) and confirmed their therapeutic potential in a clinically relevant mouse SCI model (controlled mechanical compression injury model). MF-NVs contained larger quantity of ischemic region-targeting molecules compared to normal MSC-derived nanovesicles (N-NVs). The targeting molecules in MF-NVs, which were derived from macrophage membranes, increased the accumulation of MF-NVs in the injured spinal cord after the in vivo systemic injection. Increased accumulation of MF-NVs attenuated apoptosis and inflammation, prevented axonal loss, enhanced blood vessel formation, decreased fibrosis, and consequently, improved spinal cord function. Synthetically, we developed targeting efficiency-potentiated exosome-mimetic nanovesicles and present their possibility of clinical application for SCI.

scholarly journals Active Cellular and Subcellular Targeting of Nanoparticles for Drug Delivery

Pharmaceutics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 543 ◽  
Author(s):  
Okhil K. Nag ◽  
James B. Delehanty
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Drug Targeting ◽  
Drug Efficacy ◽  
Subcellular Targeting ◽  
Target Drug ◽  
Therapeutic Outcomes ◽  
Traditional Drug ◽  
Near Future ◽  
Current Clinical Trial

Nanoparticle (NP)-mediated drug delivery (NMDD) for active targeting of diseases is a primary goal of nanomedicine. NPs have much to offer in overcoming the limitations of traditional drug delivery approaches, including off-target drug toxicity and the need for the administration of repetitive doses. In the last decade, one of the main foci in NMDD has been the realization of NP-mediated drug formulations for active targeted delivery to diseased tissues, with an emphasis on cellular and subcellular targeting. Advances on this front have included the intricate design of targeted NP-drug constructs to navigate through biological barriers, overcome multidrug resistance (MDR), decrease side effects, and improve overall drug efficacy. In this review, we survey advancements in NP-mediated drug targeting over the last five years, highlighting how various NP-drug constructs have been designed to achieve active targeted delivery and improved therapeutic outcomes for critical diseases including cancer, rheumatoid arthritis, and Alzheimer’s disease. We conclude with a survey of the current clinical trial landscape for active targeted NP-drug delivery and how we envision this field will progress in the near future.

scholarly journals Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1α

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 113 ◽  
Author(s):  
Alaa A. A. Aljabali ◽  
Hamid A. Bakshi ◽  
Faruck L. Hakkim ◽  
Yusuf A. Haggag ◽  
Khalid M. Al-Batanyeh ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Therapeutic Potential ◽  
Hypoxia Inducible Factor ◽  
In Vitro Cytotoxicity ◽  
Colon Cancer Cells ◽  
Chemical Colitis ◽  
Clinical Trails

Piceatannol (PIC) is known to have anticancer activity, which has been attributed to its ability to block the proliferation of cancer cells via suppression of the NF-kB signaling pathway. However, its effect on hypoxia-inducible factor (HIF) is not well known in cancer. In this study, PIC was loaded into bovine serum albumin (BSA) by desolvation method as PIC–BSA nanoparticles (NPs). These PIC–BSA nanoparticles were assessed for in vitro cytotoxicity, migration, invasion, and colony formation studies and levels of p65 and HIF-1α. Our results indicate that PIC–BSA NPs were more effective in downregulating the expression of nuclear p65 and HIF-1α in colon cancer cells as compared to free PIC. We also observed a significant reduction in inflammation induced by chemical colitis in mice by PIC–BSA NPs. Furthermore, a significant reduction in tumor size and number of colon tumors was also observed in the murine model of colitis-associated colorectal cancer, when treated with PIC–BSA NPs as compared to free PIC. The overall results indicate that PIC, when formulated as PIC–BSA NPs, enhances its therapeutic potential. Our work could prompt further research in using natural anticancer agents as nanoparticels with possible human clinical trails. This could lead to the development of a new line of safe and effective therapeutics for cancer patients.

Hypoxia-Inducible Factor 1 in Lower Limb Ischemia

Vascular ◽  
2006 ◽  
Vol 14 (6) ◽  
pp. 321-327 ◽  
Author(s):  
Teik K. Ho ◽  
David J. Abraham ◽  
Carol M. Black ◽  
Daryll M. Baker
Keyword(s):  
Skeletal Muscle ◽  
Lower Limb ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Hypoxia Inducible Factor ◽  
Limb Ischemia ◽  
Limb Amputation ◽  
Western World ◽  
High Morbidity ◽  
Activity Increase

In the Western world, peripheral vascular disease (PVD) has a high prevalence and is associated with high morbidity and mortality. More patients are presenting with critical limb ischemia (CLI), the end stage of PVD, because of an increased life expectancy owing to improved medical care. In a large percentage of these patients, lower limb amputation is still required, despite current advances in surgery and interventional radiology. Studies of ischemic skeletal muscles disclosed evidence of endogenous angiogenesis and adaptive skeletal muscle metabolic changes in response to hypoxia. Many of the genes responsible for these responses are regulated by hypoxia-inducible factor (HIF)-1. HIF-1, consisting of HIF-1α and HIF-1β subunits, is a major transcription factor that functions as a master regulator of oxygen homeostasis that plays essential roles in cellular and systemic pathophysiology. HIF-1α expression and HIF-1 transcriptional activity increase exponentially as cellular oxygen concentration is decreased. More than 60 target genes that are transactivated by HIF-1 have been identified. Many of the target genes, such as vascular endothelial growth factor, have been studied extensively, especially in tumors. However, only recently that interest in HIF-1 is growing in relation to ischemic diseases. Most of the studies concentrated mainly on the angiogenic property of HIF-1. In contrast, there is a lack of information on the role of HIF-1 in skeletal muscle metabolic adaptive changes as the end-organ in PVD. This review aims to summarize our current understanding of HIF-1 roles and the therapeutic potential in PVD.

scholarly journals Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle

2020 ◽  
Author(s):  
Mariana Conceição ◽  
Laura Forcina ◽  
Oscar P. B. Wiklander ◽  
Dhanu Gupta ◽  
Joel Z. Nordin ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Extracellular Vesicle ◽  
Signalling Pathway ◽  
Peptide Sequence ◽  
Target Cells ◽  
Dimerization Domain ◽  
Decoy Receptor ◽  
Stat3 Phosphorylation

AbstractThe cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two different mechanisms, the classical and transsignalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 transsignalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstrating in vivo activity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.

Sign in / Sign up

Export Citation Format

Share Document