Immunoinformatic approach to design an efficient multi-epitope peptide vaccine against melanoma.

Melanoma is known to be the most hazardous and life-threatening type of skin cancer. Although numerous treatments have been authorized in recent years, they often result in severe side effects and may not fully cure the disease. To combat this issue, immunotherapy has emerged as a promising approach for the prevention and treatment of melanoma. Specifically, the use of epitope melanoma vaccine, a subset of immunotherapy, has recently gained attention. The aim of this study was to create a multi-epitope melanoma vaccine using immunoinformatic methods. Two well-known antigens, NYESO-1 and MAGE-C2, were selected due to their strong immunogenicity and high expression in melanoma. To enhance the immunogenicity of the peptide vaccine, Brucella cell-surface protein 31 (BCSP31), the G5 domain of resuscitation-promoting factor B (RpfB) adjuvants, and the helper epitope of pan HLADR-binding epitope (PADRE) were incorporated to vaccine construct. These different segments were connected with suitable linkers and the resulting vaccine structure was evaluated for its physicochemical, structural, and immunological properties using computational tools. The designed vaccine was found to have satisfactory allergenicity, antigenicity, and physicochemical parameters. Additionally, a high-quality tertiary structure of the vaccine was achieved through modeling, refinement, and validation. Docking and molecular dynamics studies showed that the vaccine had a stable and appropriate interaction with the cognate TLR2 and TLR4 receptors during the simulation period. Finally, in silico immune simulation analysis revealed a significant increase in the levels of helper and cytotoxic T cells, as well as the cytokines interferon-gamma and interleukin-2, after repeated exposure to the melanoma vaccine. These results suggest that the designed vaccine has the potential to be an effective therapeutic option for melanoma. However, additional in vitro and in vivo validations are crucial to assess real-world efficacy and safety.

Gold nanostructures in melanoma: Advances in treatment, diagnosis, and theranostic applications.

Melanoma, a lethal form of skin cancer, poses a significant challenge in oncology due to its aggressive nature and high mortality rates. Gold nanostructures, including gold nanoparticles (GNPs), offer myriad opportunities in melanoma therapy and imaging due to their facile synthesis and functionalization, robust stability, tunable physicochemical and optical properties, and biocompatibility. This review explores the emerging role of gold nanostructures and their composites in revolutionizing melanoma treatment paradigms, bridging the gap between nanotechnology and clinical oncology, and offering insights for researchers, clinicians, and stakeholders. It begins by elucidating the potential of nanotechnology-driven approaches in cancer therapy, highlighting the unique physicochemical properties and versatility of GNPs in biomedical applications. Various therapeutic modalities, including photothermal therapy, photodynamic therapy, targeted drug delivery, gene delivery, and nanovaccines, are discussed in detail, along with insights from ongoing clinical trials. In addition, the utility of GNPs in melanoma imaging and theranostics is explored, showcasing their potential in diagnosis, treatment monitoring, and personalized medicine. Furthermore, safety considerations and potential toxicities associated with GNPs are addressed, underscoring the importance of comprehensive risk assessment in clinical translation. Finally, the review concludes by discussing current challenges and future directions, emphasizing the need for innovative strategies to maximize the clinical impact of GNPs in melanoma therapy.

Hypoxia-preconditioned WJ-MSC spheroid-derived exosomes delivering miR-210 for renal cell restoration in hypoxia-reoxygenation injury.

BACKGROUND: Recent advancements in mesenchymal stem cell (MSC) technology have paved the way for innovative treatment options for various diseases. These stem cells play a crucial role in tissue regeneration and repair, releasing local anti-inflammatory and healing signals. However, challenges such as homing issues and tumorigenicity have led to exploring MSC-exosomes as a promising alternative. MSC-exosomes have shown therapeutic potential in conditions like renal ischemia-reperfusion injury, but low production yields hinder their clinical use. METHODS: To address this limitation, we examined hypoxic preconditioning of Wharton jelly-derived MSCs (WJ-MSCs) 3D-cultured in spheroids on isolated exosome yields and miR-21 expression. We then evaluated their capacity to load miR-210 into HEK-293 cells and mitigate ROS production, consequently enhancing their survival and migration under hypoxia-reoxygenation conditions. RESULTS: MiR-210 overexpression was significantly induced by optimized culture and preconditioning conditions, which also improved the production yield of exosomes from grown MSCs. The exosomes enriched with miR-210 demonstrated a protective effect by improving survival, reducing apoptosis and ROS accumulation in damaged renal cells, and ultimately promoting cell migration. CONCLUSION: The present study underscores the possibility of employing advanced techniques to maximize the therapeutic attributes of exosomes produced from WJ-MSC spheroid for improved recovery outcomes in ischemia-reperfusion injuries.

Expanding horizons in cancer therapy by immunoconjugates targeting tumor microenvironments.

Immunoconjugates are promising molecules combining antibodies with different agents, such as toxins, drugs, radionuclides, or cytokines that primarily aim to target tumor cells. However, tumor microenvironment (TME), which comprises a complex network of various cells and molecular cues guiding tumor growth and progression, remains a major challenge for effective cancer therapy. Our review underscores the pivotal role of TME in cancer therapy with immunoconjugates, examining the intricate interactions with TME and recent advancements in TME-targeted immunoconjugates. We explore strategies for targeting TME components, utilizing diverse antibodies such as neutralizing, immunomodulatory, immune checkpoint inhibitors, immunostimulatory, and bispecific antibodies. Additionally, we discuss different immunoconjugates, elucidating their mechanisms of action, advantages, limitations, and applications in cancer immunotherapy. Furthermore, we highlight emerging technologies enhancing the safety and efficacy of immunoconjugates, such as antibody engineering, combination therapies, and nanotechnology. Finally, we summarize current advancements, perspectives, and future developments of TME-targeted immunoconjugates.

The effects of simvastatin-loaded nanoliposomes on human multilineage liver fibrosis microtissue.

In this in vitro study, for the first time, we evaluate the effects of simvastatin-loaded liposome nanoparticles (SIM-LipoNPs) treatment on fibrosis-induced liver microtissues, as simvastatin (SIM) has shown potential benefits in the non-alcoholic fatty liver disease process. We developed multicellular liver microtissues composed of hepatic stellate cells, hepatoblastoma cells and human umbilical vein endothelial cells. The microtissues were supplemented with a combination of palmitic acid and oleic acid to develop fibrosis models. Subsequently, various groups of microtissues were exposed to SIM and SIM-LipoNPs at doses of 5 and 10 mg/mL. The effectiveness of the treatments was evaluated by analysing cell viability, production of reactive oxygen species (ROS) and nitric oxide (NO), the expression of Kruppel-like factor (KLF) 2, and pro-inflammatory cytokines (interleukin(IL)-1 α, IL-1 ß, IL-6 and tumour necrosis factor-α), and the expression of collagen I. Our results indicated that SIM-LipoNPs application showed promising results. SIM-LipoNPs effectively amplified the SIM-klf2-NO pathway at a lower dosage compatible with a high dosage of free SIM, which also led to reduced oxidative stress by decreasing ROS levels. SIM-LipoNPs administration also resulted in a significant reduction in pro-inflammatory cytokines and Collagen I mRNA levels, as a marker of fibrosis. In conclusion, our study highlights the considerable therapeutic potential of using SIM-LipoNPs to prevent liver fibrosis progress, underscoring the remarkable properties of SIM-LipoNPs in activating the KLF2-NO pathway and anti-oxidative and anti-inflammatory response.

Erythrocyte membrane-camouflaged mesoporous silica composite nanoparticles for loading and controlled release of the hepatoprotective agent silibinin: A-synthesis and physicochemical characterization.

OBJECTIVES: Milk thistle has long been used in the treatment of liver and biliary disorders. In the present study, to make a long-acting delivery system for silibinin (SBN, a major active constituent of milk thistle seeds with antioxidant and hepatoprotective function), mesoporous silica composite nanoparticles (NC) were synthesized and coated with RBC membrane. METHODS: A modified Stöber method was used for NC synthesis, which was then characterized using FE-SEM, DLS, TEM, FTIR, and EDAX techniques. A suitable lysis buffer was used to prepare RBC-ghost, and sonication was used to coat SBN-loaded NC (SBN-NC). The RBC-ghost coated SBN-NC (SBN-NC-RBCG) was evaluated by SDS-PAGE, Bradford, TEM, EDAX, and DLS methods. SBN release was then compared for the SBN-NC and SBN-NC-RBCG samples. KEY FINDINGS: the RBC membrane proteins were recovered from the coating of SBN-NC-RBCG, and SBN release was sustained over 24 h when compared with the SBN-NC. CONCLUSIONS: Overall, through prolonging circulation in the bloodstream and evading the immune system, the developed system can improve SBN bioavailability in liver inflammation and fibrosis conditions that need further research.

Harnessing the Potential of Self-Assembled Peptide Hydrogels for Neural Regeneration and Tissue Engineering.

Spinal cord injury, traumatic brain injury, and neurosurgery procedures usually lead to neural tissue damage. Self-assembled peptide (SAP) hydrogels, a type of innovative hierarchical nanofiber-forming peptide sequences serving as hydrogelators, have emerged as a promising solution for repairing tissue defects and promoting neural tissue regeneration. SAPs possess numerous features, such as adaptable morphologies, biocompatibility, injectability, tunable mechanical stability, and mimicking of the native extracellular matrix. This review explores the capacity of neural cell regeneration and examines the critical aspects of SAPs in neuroregeneration, including their biochemical composition, topology, mechanical behavior, conductivity, and degradability. Additionally, it delves into the latest strategies involving SAPs for central or peripheral neural tissue engineering. Finally, the prospects of SAP hydrogel design and development in the realm of neuroregeneration are discussed.

Simvastatin-Releasing Nanofibrous Peptide Hydrogels for Accelerated Healing of Diabetic Wounds.

Wound healing is one of the major global health concerns in diabetic patients. Simvastatin (SMV) is a poorly soluble oral cholesterol-lowering drug that may aid diabetic wound healing. In the current study, a thixotropic peptide hydrogel of Fmoc-diphenylalanine (FmocFF) containing SMV was designed to accelerate skin wound healing effectively and safely in diabetic mice. FmocFF hydrogels were prepared at various concentrations by using the solvent-triggering technique and characterized by spectroscopic methods such as attenuated total reflection Fourier transform infrared (FT-IR) spectroscopy and fluorimetry. Mechanical behaviors were explored by oscillatory rheology. In model mice, the regenerative potential of the FmocFF-SMV hydrogel was evaluated in terms of wound contraction and closure, tissue regeneration, acute and chronic inflammation, granulation, and re-epithelization. The results showed that FmocFF-SMV hydrogels had an entangled nanofibrous microstructure and shear-thinning characteristics. FmocFF-SMV demonstrated a sustained drug release over 7 days. Compared to the unloaded FmocFF hydrogel, treatment with FmocFF-SMV led to superior diabetic wound recovery and reduced inflammation. Therefore, the utilization of the sustained-release FmocFF-SMV hydrogel formulation could become an attractive choice for topical wound therapy in diabetes patients.

Biocompatibility of graphene oxide nanosheets functionalized with various amino acids towards mesenchymal stem cells.

Graphene and its derivatives have gained popularity due to their numerous applications in various fields, such as biomedicine. Recent reports have revealed the severe toxic effects of these nanomaterials on cells and organs. In general, the chemical composition and surface chemistry of nanomaterials affect their biocompatibility. Therefore, the purpose of the present study was to evaluate the cytotoxicity and genotoxicity of graphene oxide (GO) synthesized by Hummer's method and functionalized by different amino acids such as lysine, methionine, aspartate, and tyrosine. The obtained nanosheets were identified by FT-IR, EDX, RAMAN, FE-SEM, and DLS techniques. In addition, trypan blue and Alamar blue methods were used to assess the cytotoxicity of mesenchymal stem cells extracted from human embryonic umbilical cord Wharton jelly (WJ-MSCs). The annexin V staining procedure was used to determine apoptotic and necrotic death. In addition, COMET and karyotyping techniques were used to assess the extent of DNA and chromosome damage. The results of the cytotoxicity assay showed that amino acid modifications significantly reduced the concentration-dependent cytotoxicity of GO to varying degrees. The GO modified with aspartic acid had the lowest cytotoxicity. There was no evidence of chromosomal damage in the karyotyping method, but in the comet assay, the samples modified with tyrosine and lysine showed the greatest DNA damage and rate of apoptosis. Overall, the aspartic acid-modified GO caused the least cellular and genetic damage to WJ-MSCs, implying its superior biomedical applications such as cell therapy and tissue engineering over GO.

Dendritic hybrid materials comprising polyhedral oligomeric silsesquioxane (POSS) and hyperbranched polyglycerol for effective antifungal drug delivery and therapy in systemic candidiasis.

Systemic Candida infections are routinely treated with amphotericin B (AMB), a highly effective antimycotic drug. However, due to severe toxicities linked to the parenteral administration of conventional micellar formulations (Fungizone®), its clinical utility is limited. Hyperbranched polyglycerols (HPGs) are multi-branched three-dimensional hydrophilic macromolecules that can be used to lessen the toxicity of AMB while also increasing its aqueous solubility. In the current research, to improve the safety and therapeutic efficacy of AMB, we developed new polyhedral oligomeric silsesquioxane - hyperbranched polyglycerol dendrimers with cholesterol termini (POSS-HPG@Chol) using azide-alkyne click reaction. Compared with Fungizone®, the as-synthesized POSS-HPG@Chol/AMB had lower minimum inhibitory and fungicidal concentrations against almost all studied Candida spp., as well as much less hemolysis and cytotoxicity. POSS-HPG@Chol/AMB revealed total protection of Balb/C mice from severe Candida infections in an experimental model of systemic candidiasis and can effectively reduce or eliminate AMB liver and kidney tissue injuries. Thanks to their safety, biocompatibility, and unique therapeutic properties, the developed POSS-polyglycerol dendrimers could be viable nanostructures for the delivery of poorly soluble drugs like AMB.

L-asparaginase immobilization in supramolecular nanogels of PEG-grafted poly HPMA and bis(α-cyclodextrin) to enhance pharmacokinetics and lower enzyme antigenicity.

L-asparaginase (ASNase) enzyme has limited therapeutic use due to its poor pharmacokinetics and immunogenicity. To overcome these obstacles, we immobilized ASNase in biocompatible poly hydroxypropyl methacrylamide (P(HPMA))-based nanogels simply formed through the host-guest inclusion complex of ASNase-conjugated random copolymer of HPMA and polyethylene glycol (PEG) acrylate (P(HPMA-MPEGA)) and α-cyclodextrin dimer (bisCD) using cystamine as a linker. The effects of bisCD and polymer concentrations on particle size, gelation time, and recovery of enzyme activity were investigated. The ASNase-conjugated bisCD nanogels were discrete, homogeneous, and spherical with a mean projected diameter of 148 ± 41 nm. ASNase immobilized in the bisCD nanogels caused cytotoxicity on HL-60 cell line with IC50 of 3 IU/ml. In-vivo rat study revealed that the immobilized ASNase reduced the enzyme antigenicity and resulted in 8.1 folds longer circulation half-life than the native enzyme. Conclusively, immobilization of ASNase in P(HPMA-MPEGA) and bisCD supramolecular nanogels could enhance the therapeutic value of ASNase in cancer chemotherapy.

Indirect co-culture of islet cells in 3D biocompatible collagen/laminin scaffold with angiomiRs transfected mesenchymal stem cells.

Diabetes is an autoimmune disease in which the pancreatic islets produce insufficient insulin. One of the treatment strategies is islet isolation, which may damage these cells as they lack vasculature. Biocompatible scaffolds are one of the efficient techniques for dealing with this issue. The current study is aimed to determine the effect of transfected BM-MSCS with angiomiR-126 and -210 on the survival and functionality of islets loaded into a 3D scaffold via laminin (LMN). AngiomiRs/Poly Ethylenimine polyplexes were transfected into bone marrow-mesenchymal stem cells (BM-MSCs), followed by 3-day indirect co-culturing with islets laden in collagen (Col)-based hydrogel scaffolds containing LMN. Islet proliferation and viability were significantly increased in LMN-containing scaffolds, particularly in the miRNA-126 treated group. Insulin gene expression was superior in Col scaffolds, especially, in the BM-MSCs/miRNA-126 treated group. VEGF was upregulated in the LMN-containing scaffolds in both miRNA-treated groups, specifically in the miRNA-210, leading to VEGF secretion. MiRNAs' target genes showed no downregulation in LMN-free scaffolds; while a drastic downregulation was seen in the LMN-containing scaffolds. The highest insulin secretion was recorded in the Oxidized dextran (Odex)/ColLMN+ group with miRNA-126. LMN-containing biocompatible scaffolds, once combined with angiomiRs and their downstream effectors, promote islets survival and restore function, leading to enhanced angiogenesis and glycemic status.

Nanotechnology-based cell-mediated delivery systems for cancer therapy and diagnosis.

The global prevalence of cancer is increasing, necessitating new additions to traditional treatments and diagnoses to address shortcomings such as ineffectiveness, complications, and high cost. In this context, nano and microparticulate carriers stand out due to their unique properties such as controlled release, higher bioavailability, and lower toxicity. Despite their popularity, they face several challenges including rapid liver uptake, low chemical stability in blood circulation, immunogenicity concerns, and acute adverse effects. Cell-mediated delivery systems are important topics to research because of their biocompatibility, biodegradability, prolonged delivery, high loading capacity, and targeted drug delivery capabilities. To date, a variety of cells including blood, immune, cancer, and stem cells, sperm, and bacteria have been combined with nanoparticles to develop efficient targeted cancer delivery or diagnosis systems. The review paper aimed to provide an overview of the potential applications of cell-based delivery systems in cancer therapy and diagnosis.

PEGylated nanohydrogels delivering anti-MicroRNA-21 suppress ovarian tumor-associated angiogenesis in matrigel and chicken chorioallantoic membrane models.

Introduction: Recently, MicroRNAs have gained increasing popularity as a novel nucleic acid-mediated medicine to regulate cancer-related protein expression. MicroRNA-21 (miR-21) is known as an oncogenic microRNA which is overexpressed in almost all cancers, including ovarian carcinoma that causes cisplatin (cis-Pt) resistance and vascular endothelial growth factor (VEGF) upregulation. So, miRNA-based therapy can be regarded as knocking down miR-21 expression, inducing tumor cell apoptosis, and suppressing tumor-associated angiogenesis. Methods: PEG5k-carboxymethylated polyethyleneimine nanohydrogels (PEG5k-CMPEI) were loaded with AntagomiR-21 (As-21) at different ratios of nitrogen to phosphorus (N/P). Particle size and ζ potential were determined for the As-21 loaded nanohydrogels. In the cellular experiments, miR-21 expression, cytotoxicity, and cis-Pt sensitivity were studied on A2780 ovarian cancer cell lines. Finally, tumor cell apoptosis and tumor cell-associated angiogenesis were explored in vitro and in vivo. Results: The nanohydrogels, featuring homogeneous size distribution and redox-responsiveness, were steadily loaded by As-21 at the optimum N/P ratio of 5 without any aggregation as determined by transmission electron microscopy (TEM). As-21-loaded nanohydrogels caused sequence-specific suppression of miR-21 expression and provoked apoptosis through ROS generation and caspase 3 activation. Cisplatin cytotoxicity was remarkably enhanced in A2780R as compared to A2780S following co-incubation with As-21-loaded nanohydrogels. Interestingly, the condition of the medium derived from As-21 nanohydrogel-treated A2780R cells inhibited VEGF suppression in human umbilical vein endothelial cells (HUVECs) and the formation of tubes in Matrigel. Moreover, the condition medium caused angiogenesis inhibition in the chicken chorioallantoic membrane (CAM) model. Conclusion: These results suggest that nanohydrogel-based delivery of As-21 can be a promising neoadjuvant therapy for treating resistant tumors via apoptosis induction and angiogenesis suppression.

A computational study of metal-organic frameworks (MOFs) as potential nanostructures to combat SARS-CoV-2.

The COVID-19 causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a critical surface protein called spike protein (S protein), which is the target of many vaccines and drugs developments. Among non-structural proteins of SARS-CoV-2, main protease (Mpro) has drawn much attention to itself for designing antiviral drugs since it is very crucial for the virus replication in host cells. In the first part of the present study, the application of metal-organic frameworks (MOFs), one of the developing nanomaterials in the deformation and consequently inhibition of S protein binding to the receptor, angiotensin-converting enzyme 2 (ACE 2), is investigated. In this line, various S protein inhibitors were designed virtually, including ZIF, UIO, and IRMOF that their interactions with S protein and were investigated using molecular dynamics (MD) simulation. The results revealed that ZIF is the best candidate among the investigated MOFs with the least amount of energy interference with S protein. In the second part, the interaction of three-dimensional (3D) MOFs (such as ZIF, IRMOF, and HKUST) with SARS-CoV-2 Mpro was investigated. HKUST had the most potent interaction with Mpro and showed more promise in deforming this protein's secondary structure among all materials tested. Furthermore, we investigated the interaction of HKUST-OH with Mpro to determine the effect of functionalization. The findings of this study could be used in future studies to introduce bioconjugates of MOFs and biological molecules (e.g., antibody or nanobody) or to use MOFs as carriers for antiviral drug delivery.

PLGA-graphene quantum dot nanocomposites targeted against αvß3 integrin receptor for sorafenib delivery in angiogenesis.

Angiogenesis is a vital step in many severe diseases such as cancer, diabetic retinopathy, and rheumatoid arthritis. Sorafenib (SFB), a multi-tyrosine kinase inhibitor, has recently been shown to inhibit tumor progression and suppress angiogenesis. Its narrow therapeutic window, however, has limited its clinical application and therapeutic efficacy. Accordingly, in this study, a nanocomposite formulation comprising of graphene quantum dots (GQDs) and poly (D, l-lactide-co-glycolide) (PLGA) nanoparticles was functionalized with an integrin-targeting ligand (RGD peptide) to improve SFB delivery for the treatment of angiogenesis. Physicochemical and biological properties of the targeted nanocomposite were evaluated in terms of chemical structure, morphology, particle size, zeta potential, photoluminescence, and cell toxicity. The loading capacity of the nanocomposite was optimized at different drug-to-PLGA ratios. Drug release behavior was also investigated at 37 °C in pH = 7.4. The SFB-to-PLGA ratio of 1:3 was selected as the optimum condition which resulted in the encapsulation efficiency and encapsulation capacity of 68.93 ± 1.39 and 18.77 ± 0.46, respectively. Photoluminescence properties of GQD in nanocomposite were used to track the delivery system. The results indicated that conjugating targeting ligand could enhance cellular uptake of nanocomposite in cells overexpressing integrin receptors. In vivo anti-angiogenesis activity of targeted nanocomposite was investigated in chick chorioallantoic membrane (CAM). The findings showed that SFB loaded in the targeted nanocomposite reduced VEGF secretion in vitro and its anti-angiogenic effect surpass free SFB. Thanks to its unique therapeutic and bioimaging properties, the developed nanocomposite could be an effective drug delivery system for poorly water-soluble therapeutic agents.

Integrin receptor-binding nanofibrous peptide hydrogel for combined mesenchymal stem cell therapy and nitric oxide delivery in renal ischemia/reperfusion injury.

BACKGROUND: Mesenchymal-based therapy has been utilized as a practical approach in the treatment of renal ischemia/reperfusion (I/R) injury. However, low cell retention and survival in the ischemic site have remained challenging issues. To bridge this gap, the integrin receptor-binding RGD peptide-functionalized, s-nitroso-n-acetyl penicillamine (SNAP)-loaded hydrogel was used to transplant Wharton's jelly-mesenchymal stem cells (WJ-MSCs). METHODS: Apart from physicochemical and rheological characterizations that confirmed entangled interlocking ß-sheets with nanofibrous morphology, real-time RT-PCR, ROS production, serum biomarker concentrations, and histopathological alterations were explored in a mouse model to assess the therapeutic efficacy of formulations in the treatment of renal I/R injury. RESULTS: The RGD-functionalized Fmoc-diphenylalanine (Fmoc-FF + Fmoc-RGD) hydrogel supported the spread and proliferation of WJ-MSCs in vivo. Notably, intralesional injection of nitric oxide donor combined with the embedded WJ-MSCs caused superior recovery of renal I/R injury compared to free WJ-MSCs alone in terms of histopathological scores and renal function indices. Compared to the I/R control group, oxidative stress and inducible nitric oxide synthase (iNOS) expression biomarkers showed a significant decline, whereas endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) expression exhibited a significant increment, indicating regeneration of the injured endothelial tissue. CONCLUSION: The findings confirmed that the hydrogels containing WJ-MSCs and nitric oxide donors can promote the regeneration of renal I/R injuries by increasing angiogenic factors and cell engraftment.

Amphiphilic hyperbranched polyglycerol nanoarchitectures for Amphotericin B delivery in Candida infections.

Although Amphotericin B (AMB) is considered the most effective anti-mycotic agent for treating Candida infections, its clinical use is limited due to its high toxicity. To address this issue, we developed cholesterol-based dendritic micelles of hyperbranched polyglycerol (HPG), including cholesterol-cored HPG (Chol-HPG) and cholesterol end-capped HPG (HPG@Chol), for AMB delivery. The findings suggested that the presence of cholesterol moieties could control AMB loading and release properties. Dendritic micelles inhibited AMB hemolysis and cytotoxicity in HEK 293 and RAW 264.7 cell lines while increasing antifungal activity against C. albicans biofilm formation. Furthermore, significantly lower levels of renal and liver toxicity biomarkers compared to Fungizone® ensured AMB-incorporated dendritic micelle biosafety, which was confirmed by histopathological evaluations. Overall, the Chol-HPG and HPG@Chol dendritic micelles may be a viable alternative to commercially available AMB formulations as well as an effective delivery system for other poorly soluble antifungal agents.

Bioengineering exosomes for treatment of organ ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) injury is a leading cause of death worldwide. It arises from blood reflowing after tissue hypoxia induced by ischemia that causes severe damages due to the accumulation of reactive oxygen species and the activation of inflammatory responses. Exosomes are the smallest members of the extracellular vesicles' family, which originate from nearly all eukaryotic cells. Exosomes have a great potential in the treatment of I/R injury either in native or modified forms. Native exosomes are secreted by different cell types, such as stem cells, and contain components such as specific miRNA molecules with tissue protective properties. On the other hand, exosome bioengineering has recently received increased attention in context of current advances in the purification, manipulation, biological characterization, and pharmacological applications. There are various pre-isolation and post-isolation manipulation approaches that can be utilized to increase the circulation half-life of exosomes or the availability of their bioactive cargos in the target site. In this review, the various therapeutic actions of native exosomes in different I/R injury will be discussed first. Exosome bioengineering approaches will then be explained, including pre- and post-isolation manipulation methods, applicability for delivery of bioactive agents to injured tissue, clinical translation issues, and future perspectives.

Nanoscale aggregation of doxorubicin-short peptide conjugates for enzyme-responsive delivery with various MOF carriers: In-silico steps towards smart cancer chemotherapy.

Drug conjugation with enzyme-sensitive peptides is one of the innovative smart delivery systems for cancer therapy. This delivery method has some advantages, such as lowering side effects and increasing treatment selectivity. Herein, two conjugates of doxorubicin and small peptide are designed that are sensitive to Cathepsin B, a tumor homing enzyme. The formation of nanoparticles at three different numbers of drug peptide prodrugs (including 30, 50, and 70 prodrugs) was studied. In addition, three metal-organic frameworks (MOF) nanocarriers, including Zeolitic Imidazolate Frameworks (ZIF), Universitetet I Oslo MOF (UIO-66), and MOF of Hong Kong University of Science and Technology (HKUST-1), were used to increase the resistance of the prodrugs to decomposition during blood flow circulation. Then, the interactions between doxorubicin's prodrug and different MOFs were investigated. Furthermore, the impact of microfluidics on nanoparticle interactions was studied. Molecular dynamic simulation was used to investigate thermodynamic and conformational parameters. The results showed that the concentration of doxorubicin prodrugs affected cluster formation. Moreover, based on Gibb's free energy analysis, the interaction of these prodrugs with various types of MOFs revealed more spontaneous interactions in microfluidic modeling conditions. ZIF had the best and most stable interactions with the prodrugs in bulk and microfluidic modeling. As a result, the best and most stable state was associated with a lower concentration of these prodrugs with ZIF in the microfluidic condition.