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Matrix metalloproteinases (MMPs) play critical roles in the invasiveness of cancerous cells and metastasis of solid tumors. MMP-9 is a member of this protease family, which is extremely overexpressed in metastatic cells. Here, we described a cyclic peptide which inhibits the MMP-9 activity with high potency. This inhibitor selectively binds to the MMP-9 fibronectin domain and interferes with the interaction of gelatinous substrates with MMP-9, thereby suppressing its gelatinolytic activity. Previously, we isolated and developed a linear peptide, named as RSH-12, from a phage display library which displayed promising results in the inhibition of MMP-9. Next, we decided to improve its biostability via cyclization chemistry and show that RSH-12 has a considerably enhanced stability in human serum. Moreover, the cyclic peptide is still associated with a high potency to inhibit the invasion activity of a human fibrosarcoma cell line. These results demonstrate that the designed cyclic peptide might be considered as a promising therapeutic moiety to target the MMP-9 for the treatment of cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] Blindness in the elderly is often caused by age-related macular degeneration (AMD). The advanced type of AMD known as neovascular AMD (nAMD) has been linked to being the predominant cause of visual impairment in these people. Multiple neovascular structures including choroidal neovascular (CNV) membranes, fluid exudation, hemorrhages, and subretinal fibrosis, are diagnostic of nAMD. These pathological alterations ultimately lead to anatomical and visual loss. It is known that vascular endothelial growth factor (VEGF), a type of proangiogenic factor, mediates the pathological process underlying nAMD. Therefore, various therapies have evolved to directly target the disease. In this review article, an attempt has been made to discuss general explanations about this disease, all common treatment methods based on anti-VEGF drugs, and the use of drug delivery systems in the treatment of AMD. Initially, the pathophysiology, angiogenesis, and different types of AMD were described. Then we described current treatments and future treatment prospects for AMD and outlined the advantages and disadvantages of each. In this context, we first examined the types of therapeutic biomolecules and anti-VEGF drugs that are used in the treatment of AMD. These biomolecules include aptamers, monoclonal antibodies, small interfering RNAs, microRNAs, peptides, fusion proteins, nanobodies, and other therapeutic biomolecules. Finally, we described drug delivery systems based on liposomes, nanomicelles, nanoemulsions, nanoparticles, cyclodextrin, dendrimers, and composite vehicles that are used in AMD therapy. [ABSTRACT FROM AUTHOR]

Cancer is a disease advanced via surplus angiogenesis. The development of new anti-angiogenic therapeutic agents with more efficacy and fewer side effects is still quite necessary. Conventional therapies saving the life of many cancer patients but due to drug resistance and lack of specificity utilizing these methods is faced with limits. Recently, new therapeutic agents have been developed and used to treat cancers such as scaffold proteins, monoclonal antibodies, tyrosine kinase inhibitors, and peptides. In antiangiogenic drug development, anti-angiogenic peptides design is a significant aim. Peptides have developed as substantial therapeutics that are being carefully investigated in angiogenesis-dependent diseases because of their high penetrating rate into the cancer cells, high specificity, and low toxicity. In this review, we focus on anti-angiogenic peptides in the field of cancer therapy that are designed, screened, or derived from nanobodies, mimotopes, phage displays, and natural resources. [ABSTRACT FROM AUTHOR]

To investigate the efficacy of RSH-12, a novel selective matrix metalloproteinase 9 (MMP-9) inhibitor peptide in rabbit models of dry eye syndrome (DES). In vitro toxicity of RSH-12 on cultured human corneal fibroblasts was investigated with MTT. Ocular toxicity of RSH-12 was investigated by clinical examinations, histology, and TUNEL assay. Experimental model of dry eye was induced by 1.0% atropine sulfate administration followed after 15 min by treatment with PBS, RSH-12, and Restasis in individual groups, three times a day for 7 days. In addition to performing Schirmer's test for evaluating basic tear secretion and tear break-up time test for investigating tear stability, the occurrence of superficial punctate keratopathy was also investigated in the study groups. MTT assay demonstrated that RSH-12 was not toxic to human corneal fibroblasts in different concentrations. During the administration of atropine, TBUT values and tear volume were decreased in vehicle group while these indices improved significantly in groups treated with RSH-12 in a promising manner. RSH-12 increased the mean value of tear volume from 4.85 to 10.75 mm (P =.0001) and mean of TBUT values from 20.3 s to 34.5 s (P =.0001) compared with the vehicle. In contrast to the presence of severe superficial punctate keratopathy in the controls, no significant dotted staining was observed in the RSH-12 and Restasis groups. These outcomes propose that RSH-12 has a therapeutic effect in the rabbit model of dry eye and might be a potential treatment for severe DES. [ABSTRACT FROM AUTHOR]

For induction of an appropriate immune response, especially in the case of an inactivated vaccine, the use of an adjuvant is crucial. In this study, adjuvanticity effect of G2 dendrimer in veterinary rabies vaccine has been investigated. A nonlinear globular G2 dendrimer comprising citric acid and polyethylene glycol 600 (PEG-600) was synthesized and the toxicity was studied in vitro on the J774A.1 cell line. The adjuvanticity effect of the dendrimer was then investigated on rabies virus in NMRI mice as a model. Different concentrations of dendrimer were used to determine the best formulation for the survival of the mice after virus challenge. The rise of neutralizing antibody was also checked by rapid fluorescent focus inhibition test (RFFIT). The relative potency of the prepared formulation was finally calculated using standard NIH test and the results were compared (and discussed) with the commercially available rabies vaccine. The accuracy of dendrimer synthesis was confirmed using Fourier transform infrared (FT-IR), size, and zeta potential analysis. The in vitro toxicity assay revealed that no significant toxic effect is observed in cells when data are compared with the control group. The in vivo assay showed that a higher survival rate in the mice received a special formulation due to adjuvanticity effect of dendrimer, which is also confirmed by RFFIT. However, the relative potency of that formulation does not give expected results when compared with the alum-containing rabies vaccine. In the current investigation, the adjuvanticity effect of G2 dendrimer was demonstrated for the first time in rising of neutralizing antibodies against rabies virus. Our data confirm that nanoparticles can enhance immune responses in an appropriate manner. Moreover, engineered nanoparticles will enable us to develop novel potent multivalent adjuvants in vaccine technology. [ABSTRACT FROM AUTHOR]

• Angiogenesis factors upregulation motivates tumor growth and metastasis. • Nanobodies exhibited promising results in cancer research, diagnostics and therapy. • Nanobodies can target the angiogenesis factors for cancer imaging and therapy. Solid cancers are affiliate on angiogenesis for preservation. The FDA-approved monoclonal antibodies like Bevacizumab are currently being administered effectively as inhibitors of angiogenesis against various types of tumors. Despite the clinical achievements in this regard, monoclonal antibodies suffer from considerable disadvantages, including the potential to develop therapeutic resistance, a high production cost, and the restricted tumor penetration, which consequently limit their therapeutic applications. In the past decades, some significant methods such as miniaturization of the antibodies, containing those inhibiting tumor angiogenesis, have been proposed to enhance cancer therapeutics efficiency. Since their discovery, small single-domain antigen binding antibody fragments, known as nanobodies, have been broadly utilized in the fields of cancer research, diagnosis, and treatment. Due to their desired functional attributes and a unique structure, nanobodies are becoming promising therapeutic and diagnostic biomolecules in oncology field. Moreover, they displayed a substantial translational potential in preclinical and clinical studies. This review was performed with the aim of highlighting the potential of nanobodies in blocking the angiogenic process by targeting of angiogenic biomolecules for cancer therapy and the application of labeled nanobodies in non-invasive in vivo tumor imaging. [ABSTRACT FROM AUTHOR]

Background: Fibroblast growth factor receptor 3 is known as a favorable aim in vast range of cancers, particularly in bladder cancer treatment. Pharmacophore and QSAR modeling approaches are broadly utilized for developing novel compounds for the determination of inhibitory activity versus the biological target. In this study, these methods employed to identify FGFR3 potential inhibitors. Methods: To find the potential compounds for bladder cancer targeting, ZINC and NCI databases were screened. Pharmacophore and QSAR modeling of FGFR3 inhibitors were utilized for dataset screening. Then, with regard to several factors such as Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties and Lipinski's Rule of Five, the recognized compounds were filtered. In further step, utilizing the flexible docking technique, the obtained compounds interactions with FGFR3 were analyzed. Results: The best five compounds, namely ZINC09045651, ZINC08433190, ZINC00702764, ZINC00710252 and ZINC00668789 were selected for Molecular Dynamics (MD) studies. Off-targeting of screened compounds was also investigated through CDD search and molecular docking. MD outcomes confirmed docking investigations and revealed that five selected compounds could make steady interactions with the FGFR3 and might have effective inhibitory potencies on FGFR3. Conclusion: These compounds can be considered as candidates for bladder cancer therapy with improved therapeutic properties and less adverse effects. [ABSTRACT FROM AUTHOR]

Cell-penetrating peptides (CPPs), also known as protein transduction domains, are a class of diverse amino acid sequences with the ability to cross cellular membranes. CPPs can deliver several bioactive cargos, including proteins, peptides, nucleic acids and chemotherapeutics, into cells. Ever since their discovery, synthetic and natural CPPs have been utilized in therapeutics delivery, gene editing and cell imaging in fundamental research and clinical experiments. Over the years, CPPs have gained significant attention due to their low cytotoxicity and high transduction efficacy. In the last decade, multiple investigations demonstrated the potential of CPPs as carriers for the delivery of therapeutics to treat various types of cancer. Besides their remarkable efficacy owing to fast and efficient delivery, a crucial benefit of CPP-based cancer treatments is delivering anticancer agents selectively, rather than mediating toxicities toward normal tissues. To obtain a higher therapeutic index and to improve cell and tissue selectivity, CPP-cargo constructions can also be complexed with other agents such as nanocarriers and liposomes to obtain encouraging outcomes. This review summarizes various types of CPPs conjugated to anticancer cargos. Furthermore, we present a brief history of CPP utilization as delivery systems for anticancer agents in the last decade and evaluate several reports on the applications of CPPs in basic research and preclinical studies. [ABSTRACT FROM AUTHOR]

Dry eye syndrome (DES) and tear dysfunction are multifactorial conditions affecting meibomian glands, lacrimal glands, and ocular surface. This ocular disorder can cause eye irritation, irregular cornea, corneal barrier disruption, and blurred vision. Uncontrolled increase in matrix metalloproteinase-9 (MMP-9) level and activity has been detected in the tears and ocular surface in the patients with DES, which has been proved to be related to disruption of tight junctions in apical corneal epithelium associated with severe signs of DES. These uncontrolled activities of MMP-9 lead to desquamation of ocular surface epithelia. Therefore, this review study was conducted to summarize the evidence regarding MMP-9 contribution in DES, and inhibition of MMP-9, as a therapeutic target for treatment of DES. For this purpose, herein, the related studies designed novel pharmaceutical compounds for direct and indirect inhibition of MMP-9 as treatment approaches for DES were reviewed. These compounds were designed to improve corneal barrier function, reduce inflammation on ocular surface, and restore tear production. • Recently inhibition of Matrix Metalloproteinase-9 (MMP-9) is considered as valuable strategy for Dry Eye Syndrome (DES) treatment. • Pathogenic role of MMP-9 in corneal disease introduced MMP-9 as an effective disease-relevant therapeutic target in DES. • In this review, we focus on the multiple compounds with ability of inhibition of the MMP-9 as possible therapeutic agents. [ABSTRACT FROM AUTHOR]

Cytokines are the first modern immunotherapeutic agents used for activation immunotherapy. Interleukin-18 (IL-18) has emerged as a potent anticancer immunostimulatory cytokine over the past three decades. IL-18, structurally is a stable protein with very low toxicity at biological doses. IL-18 promotes the process of antigen presentation and also enhances innate and acquired immune responses. It can induce the production of proinflammatory cytokines and increase tumor infiltration of effector immune cells to revert the immunosuppressive milieu of tumors. Furthermore, IL-18 can reduce tumorigenesis, suppress tumor angiogenesis, and induce tumor cell apoptosis. These characteristics present IL-18 as a promising option for cancer immunotherapy. Although several preclinical studies have reported the immunotherapeutic potential of IL-18, clinical trials using it as a monotherapy agent have reported disappointing results. These results may be due to some biological characteristics of IL-18. Several bioengineering approaches have been successfully used to correct its defects as a bioadjuvant. Currently, the challenge with this anticancer immunotherapeutic agent is mainly how to use its capabilities in a rational combinatorial therapy for clinical applications. The present study discussed the strengths and weaknesses of IL-18 as an immunotherapeutic agent, followed by comprehensive review of various promising bioengineering approaches that have been used to overcome its disadvantages. Finally, this study highlights the promising application of IL-18 in modern combinatorial therapies, such as chemotherapy, immune checkpoint blockade therapy, cell-based immunotherapy and cancer vaccines to guide future studies, circumventing the barriers to administration of IL-18 for clinical applications, and bring it to fruition as a potent immunotherapy agent in cancer treatment. [Display omitted] • IL-18 can boost innate and adaptive anticancer immune responses. • IL-18 as a monotherapy agent has shown poor anticancer effectiveness. • Bioengineering approaches can address the drawbacks of IL-18 as a bioadjuvant. • IL-18 can reverse the immuno-suppressive condition of the tumor microenvironment. • IL-18 can improve the effectiveness of modern anticancer therapeutics. [ABSTRACT FROM AUTHOR]

Immunotherapy using monoclonal antibodies targeting programmed death ligand-1 (PD-L1) on cancer cells as a biomarker of escape from response to immune checkpoint has demonstrated efficacy in treating many solid tumors. In addition, some of the signals, such as vascular endothelial growth factor (VEGF), bind to receptors on the surface of normal endothelial cells and encourage angiogenesis, or the formation and survival of new blood vessels. Due to the special features of nanobodies with high specificity and affinity as a powerful new tool in cancer therapy, here, a recombinant bispecific bivalent anti-PD-L1/VEGF nanobody was constructed and its functionality in inhibition of angiogenesis in vitro was investigated. Results demonstrated that bivalent anti-PD-L1/VEGF nanobody efficiently inhibited HUVEC and A431 cells proliferation and tube formation. In addition, bivalent anti-PD-L1/VEGF nanobody efficiently inhibited angiogenesis in an ex ovo Chick Chorioallantoic Membrane assay. The results indicate for the potential of bivalent anti-PD-L1/VEGF nanobody as a novel promising tool for cancer therapy. [ABSTRACT FROM AUTHOR]