Significance of PSCA as a novel prognostic marker and therapeutic target for cancer.

One of the contributing factors in the diagnosis and treatment of most cancers is the identification of their surface antigens. Cancer tissues or cells have their specific antigens. Some antigens that are present in many cancers elicit different functions. One of these antigens is the prostate stem cell antigen (PSCA) antigen, which was first identified in the prostate. PSCA is a cell surface protein that has different functions in different tissues. It can play an inhibitory role in cell proliferation as well as a tumor-inducing role. PSCA has several genetic variants involved in cancer susceptibility in some tissues, so identifying the characteristics of this antigen and its relationship with clinical features can provide more information on diagnosis and treatment of patients with cancers. Most studies on the PSCA have focused on prostate cancer. While it is also expressed in other cancers, little attention has been paid to its role as a valuable diagnostic, prognostic, and therapeutic tool in other cancers. PSCA has several genetic variants that seem to play a significant role in cancer susceptibility in some tissues, so identifying the characteristics of this antigen and its relationship and variants with clinical features can be beneficial in concomitant cancer therapy and diagnosis, as theranostic tools. In this study, we will review the alteration of the PSCA expression and its polymorphisms and evaluate its clinical and theranostics significance in various cancers.

Global trend in exosome isolation and application: an update concept in management of diseases.

Extracellular vesicles (EVs) secreted by various cells offer great potential for use in the diagnosis and treatment of disease. EVs are heterogeneous membranous vesicles. Exosomes are a subtype of EVs, 40-150 nm spherical vesicles with a lipid layer derived from endosomes. Exosomes, which are involved in signal transduction and maintain homeostasis, are released from almost all cells, tissues, and body fluids. Although several methods exist to isolate and characterize EVs and exosomes, each technique has significant drawbacks and limitations that prevent progress in the field. New approaches in the biology of EVs show great potential for isolating and characterizing EVs, which will help us better understand their biological function. The strengths and limitations of conventional strategies and novel methods (microfluidic) for EV isolation are outlined in this review. We also present various exosome isolation techniques and kits that are commercially available and assess the global market demand for exosome assays.

Recent advances in targeted drug delivery systems for resistant colorectal cancer.

Colorectal cancer (CRC) is one of the deadliest cancers in the world, the incidences and morality rate are rising and poses an important threat to the public health. It is known that multiple drug resistance (MDR) is one of the major obstacles in CRC treatment. Tumor microenvironment plus genomic instability, tumor derived exosomes (TDE), cancer stem cells (CSCs), circulating tumor cells (CTCs), cell-free DNA (cfDNA), as well as cellular signaling pathways are important issues regarding resistance. Since non-targeted therapy causes toxicity, diverse side effects, and undesired efficacy, targeted therapy with contribution of various carriers has been developed to address the mentioned shortcomings. In this paper the underlying causes of MDR and then various targeting strategies including exosomes, liposomes, hydrogels, cell-based carriers and theranostics which are utilized to overcome therapeutic resistance will be described. We also discuss implication of emerging approaches involving single cell approaches and computer-aided drug delivery with high potential for meeting CRC medical needs.

Cell-free protein synthesis: The transition from batch reactions to minimal cells and microfluidic devices.

Thanks to the synthetic biology, the laborious and restrictive procedure for producing a target protein in living microorganisms by biotechnological approaches can now experience a robust, pliant yet efficient alternative. The new system combined with lab-on-chip microfluidic devices and nanotechnology offers a tremendous potential envisioning novel cell-free formats such as DNA brushes, hydrogels, vesicular particles, droplets, as well as solid surfaces. Acting as robust microreactors/microcompartments/minimal cells, the new platforms can be tuned to perform various tasks in a parallel and integrated manner encompassing gene expression, protein synthesis, purification, detection, and finally enabling cell-cell signaling to bring a collective cell behavior, such as directing differentiation process, characteristics of higher order entities, and beyond. In this review, we issue an update on recent cell-free protein synthesis (CFPS) formats. Furthermore, the latest advances and applications of CFPS for synthetic biology and biotechnology are highlighted. In the end, contemporary challenges and future opportunities of CFPS systems are discussed.

Tumor microenvironment complexity and therapeutic implications at a glance.

The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices. Video abstract.

Toll-like receptors as novel therapeutic targets for herpes simplex virus infection.

Seropositivity for HSV reaches more than 70% within the world population, and yet no approved vaccine exists. While HSV1 is responsible for keratitis, encephalitis, and labialis, HSV2 carriers have a high susceptibility to other STD infections, such as HIV. Induction of antiviral innate immune responses upon infection depends on a family of pattern recognition receptors called Toll-like receptors (TLR). TLRs bridge innate and adaptive immunity by sensing virus infection and activating antiviral immune responses. HSV adopts smart tricks to evade innate immunity and can also manipulate TLR signaling to evade the immune system or even confer destructive effects in favor of virus replication. Here, we review mechanisms by which HSV can trick TLR signaling to impair innate immunity. Then, we analyze the role of HSV-mediated molecular cues, in particular, NF-κB signaling, in promoting protective versus destructive effects of TLRs. Finally, TLR-based therapeutic opportunities with the goal of preventing or treating HSV infection will be discussed.

A novel multi-stimuli-responsive theranostic nanomedicine based on Fe3O4@Au nanoparticles against cancer.

A novel multi-stimuli-responsive theranostic nanomedicine was designed and fabricated by the conjugation of a thiol end-capped poly(N-isopropylacrylamide-block-acrylic acid) (HS-PNIPAAm-b-PAA) onto Fe3O4@Au nanoparticles (NPs) followed by physical loading of doxorubicin hydrochloride (Dox) as a general anticancer drug. For this purpose, Fe3O4@Au NPs were fabricated through small Au nanolayer grown on larger magnetic NPs. A HS-PNIPAAm-b-PAA was synthesized through an atom transfer radical polymerization (ATRP) approach, and then conjugated with as-synthesized Fe3O4@Au NPs by Au-S bonding. The Dox loading capacity of the synthesized Fe3O4@Au/Polymer theranostic NPs was calculated to be 81%. The theranostic nanomedicine exhibited excellent in vitro drug release behavior under pH and thermal stimuli. The anticancer activity evaluation using MTT assay (against MCF7 cells) revealed that the fabricated Fe3O4@Au/Polymer has high potential as theranostic nanomedicine for cancer therapy of solid tumors. This nanosystem can also applied in photothermal therapy, hyperthermia therapy, and their combination with chemotherapy due to presence of gold and Fe3O4 nanomaterials in its structure.

Implications of resistin in type 2 diabetes mellitus and coronary artery disease: Impairing insulin function and inducing pro-inflammatory cytokines.

Diabetes mellitus is a metabolic and chronic disorder, which is very common all over the world. Many genetic and nongenetic factors are involved in the development of type 2 diabetes mellitus (T2DM). Meanwhile, the resistin gene is an important candidate in the pathogenesis of this complex condition. High levels of transcription of the resistin gene are associated with inflammation, insulin resistance, initiation and development of T2DM and atherosclerosis progression through induction of secretion of bioactive materials from adipocytes. Releasing adipose tissue-derived inflammatory cytokines is associated with inflammatory processes activation, which causes inhibition of insulin action via interference with insulin signaling, such that these disorders can contribute to insulin resistance. With the direct effect of resistin and other inflammatory mediators on vascular endothelial cells and arterial walls, the expression of cell adhesion molecules is increased. This process can lead to atherosclerosis and will result in coronary artery disease (CAD). In this review, we will explore the effects of resistin on inflammation and insulin resistance that may lead to type 2 diabetes and CAD.

Modulating tumor hypoxia by nanomedicine for effective cancer therapy.

Hypoxia, a characteristic feature of tumors, is indispensable to tumor angiogenesis, metastasis, and multi drug resistance. Hypoxic avascular regions, deeply embedded inside the tumors significantly hinder delivery of therapeutic agents. The low oxygen tension results in resistance to the current applied anti-cancer therapeutics including radiotherapy, chemotherapy, and photodynamic therapy, the efficacy of which is firmly tied to the level of tumor oxygen supply. However, emerging data indicate that nanocarriers/nanodrugs can offer substantial benefits to improve the efficacy of current therapeutics, through modulation of tumor hypoxia. This review aims to introduce the most recent advances made in nanocarrier mediated targeting of tumor hypoxia. The first part is dedicated to the approaches by which nanocarriers could be designed to target/leverage hypoxia. These approaches include i) inhibiting Hypoxia Inducer Factor (HIF-1α); ii) hypoxia activated prodrugs/linkers; and iii) obligate anaerobe mediated targeting of tumor hypoxia. The second part, details novel nanosystems proposed to modulate tumor hypoxia through tumor oxygenation. These methods seek to lessen tumor hypoxia through vascular normalization, or reoxygenation therapy. The reoxygenation of tumor could be accomplished by: i) generation of oxygen filled nanocarriers; ii) natural/artificial oxygen nanocarriers; and iii) oxygen generators. The efficacy of each approach and their potential in cancer therapy is further discussed.

Combination of nanotechnology with vascular targeting agents for effective cancer therapy.

As a young science, nanotechnology promptly integrated into the current oncology practice. Accordingly, various nanostructure particles were developed to reduce drug toxicity and allow the targeted delivery of various diagnostic and therapeutic compounds to the cancer cells. New sophisticated nanosystems constantly emerge to improve the performance of current anticancer modalities. Targeting tumor vasculature is an attractive strategy to fight cancer. Though the idea was swiftly furthered from basic science to the clinic, targeting tumor vasculature had a limited potential in patients, where tumors relapse due to the development of multiple drug resistance and metastasis. The aim of this review is to discuss the advantages of nanosystem incorporation with various vascular targeting agents, including (i) endogen anti-angiogenic agents; (ii) inhibitors of angiogenesis-related growth factors; (iii) inhibitors of tyrosine kinase receptors; (iv) inhibitors of angiogenesis-related signaling pathways; (v) inhibitors of tumor endothelial cell-associated markers; and (vi) tumor vascular disrupting agents. We also review the efficacy of nanostructures as natural vascular targeting agents. The efficacy of each approach in cancer therapy is further discussed.

Tumor rim cells: From resistance to vascular targeting agents to complete tumor ablation.

Current vascular targeting strategies pursue two main goals: anti-angiogenesis agents aim to halt sprouting and the formation of new blood vessels, while vascular disrupting agents along with coaguligands seek to compromise blood circulation in the vessels. The ultimate goal of such therapies is to deprive tumor cells out of oxygen and nutrients long enough to succumb cancer cells to death. Most of vascular targeting agents presented promising therapeutic potential, but the final goal which is cure is rarely achieved. Nevertheless, in both preclinical and clinical settings, tumors tend to grow back, featuring a highly invasive, metastatic, and extremely resistant form. This review highlights the critical significance of tumor rim cells as the main factor, determining therapy success with vascular targeting agents. We present an overview of different single and combination treatments with vascular targeting agents that enable efficient targeting of tumor rim cells and long-lasting tumor cure. Understanding the nature of tumor rim cells, how they establish, how they manage to survive of vascular targeting agents, and how they contribute in tumor refractoriness, may open new avenues to the development of beneficial strategies, capable to eliminate residual rim cells, and enable tumor ablation once and forever.

Thermal-responsive ß-cyclodextrin-based magnetic hydrogel as a de novo nanomedicine for chemo/hyperthermia treatment of cancerous cells.

A novel thermal-responsive ß-cyclodextrin-based magnetic hydrogel [ß-cyclodextrin-graft-poly(N-isopropylacrylamide)/Fe3O4 (ß-CD-g-PNIPAAm/Fe3O4)] was fabricated as a novel nanomedicine for chemo/hyperthermia treatment of cancer cells. Firstly, ß-CD was modified by maleic anhydride (MA) followed by copolymerization with NIPAAm monomer and thiol-end capped Fe3O4 nanoparticles (NPs) in the presence of a crosslinker through acrylamide-thiol polymerization system to afford a magnetic hydrogel. The saturation magnetization (δ s) value for developed hydrogel was determined to be 8.2 emu g-1. The hydrogel was physically loaded with an anticancer agent, doxorubicin hydrochloride (Dox). The encapsulation efficiency (EE) of drug into the hydrogel was obtained as 73 %. The system represented acceptable thermal-triggered drug release behavior that best fitted with Higuchi model, demonstrating the release of drug is mostly controlled by diffusion mechanism. The anticancer performance of the ß-CD-g-PNIPAAm/Fe3O4-Dox was evaluated using MCF7 cells by MTT-assay. In addition, flow cytometry analyses showed considerable cellular uptake of Dox in the cells treated with ß-CD-g-PNIPAAm/Fe3O4-Dox (∼70 %) compared to free Dox (∼28 %). As results, in time period of 48 h by combination of chemo- and hyperthermia-therapies, the developed system displayed greater anticancer efficiency than the free Dox.

Recent advances in biomimetic cell membrane-camouflaged nanoparticles for cancer therapy.

The emerging strategy of biomimetic nanoparticles (NPs) via cellular membrane camouflage holds great promise in cancer therapy. This scholarly review explores the utilization of cellular membranes derived from diverse cellular entities; blood cells, immune cells, cancer cells, stem cells, and bacterial cells as examples of NP coatings. The camouflaging strategy endows NPs with nuanced tumor-targeting abilities such as self-recognition, homotypic targeting, and long-lasting circulation, thus also improving tumor therapy efficacy overall. The comprehensive examination encompasses a variety of cell membrane camouflaged NPs (CMCNPs), elucidating their underlying targeted therapy mechanisms and delineating diverse strategies for anti-cancer applications. Furthermore, the review systematically presents the synthesis of source materials and methodologies employed in order to construct and characterize these CMCNPs, with a specific emphasis on their use in cancer treatment.

Codelivery of methotrexate and silibinin by niosome nanoparticles for enhanced chemotherapy of CT26 colon cancer cells.

Colon cancer (CC) is one of the most prevalent cancers in the world, and chemotherapy is widely applied to combat it. However, chemotherapy drugs have severe side effects and emergence of multi drug resistance (MDR) is common. This bottleneck can be overcome by niosome nanocarriers that minimize drug dose/toxicity meanwhile allow co-loading of incompatible drugs for combination therapy. In this research, silibinin (Sil) as a hydrophobic drug was loaded into the lipophilic part, and methotrexate (MTX) into the hydrophilic part of niosome by the thin film hydration (TFH) method to form Nio@MS NPs for CT26 colon cancer therapyin vitro. Our results indicated synthesis of ideal niosome nanoparticles (NPs) with spherical morphology, size of ∼100 nm, and a zeta potential of -10 mV. The IC50value for Nio@MS was determined ∼2.6 µg ml-1, which was significantly lower than MTX-Sil (∼6.86 µg ml-1), Sil (18.46 µg ml-1), and MTX (9.8 µg ml-1). Further, Nio@MS significantly reduced cell adhesion density, promoted apoptosis and increased gene expression level of caspase 3 and BAX while promoted significant downregulation of BCL2. In conclusion, the design and application of niosome to co-administer Sil and MTX can increase the drugs cytotoxicity, reduce their dose and improve anti-cancer potential by combating MDR.

A rapid protocol for synthesis of chitosan nanoparticles with ideal physicochemical features.

In this research, an innovative protocol is introduced to address crucial deficiencies in the formulation of chitosan nanoparticles (Cs NPs). While NPs show potential in drug delivery systems (DDSs), their application in the clinic is hindered by various drawbacks, such as toxicity, high material costs, and time-consuming and challenging preparation procedures. Within polymer-based NPs, Cs is a plentiful natural substance derived from the deacetylation of chitin, which can be sourced from the shells of shrimp or crab. Cs NPs can be formulated using the ionic gelation technique, which involves the use of a negatively charged agent, such as tripolyphosphate (TPP), as a crosslinking agent. Even though Cs is a cost-effective and biocompatible material, the formulation of Cs NPs with the correct size and surface electrical charge (zeta potential) presents a persistent challenge. In this study, various techniques were employed to analyze the prepared Cs NPs. The size and surface charge of the NPs were evaluated using dynamic light scattering (DLS). Morphological analysis was conducted using field emission-scanning electron microscopy (FE-SEM). The chemical composition and formation of Cs NPs were investigated using Fourier transform infrared (FTIR). The stability analysis was confirmed through X-ray diffraction (XRD) analysis. Lastly, the biocompatibility of the NPs was assessed through cell cytotoxicity evaluation using the MTT assay. Moreover, here, 11 formulations with different parameters such as reaction pH, Cs:TPP ratio, type of Cs/TPP, and ultrasonication procedure were prepared. Formulation 11 was chosen as the optimized formulation based on its high stability of more than three months, biocompatibility, nanosize of 75.6 ± 18.24 nm, and zeta potential of +26.7 mV. To conclude, the method described here is easy and reproducible and can be used for facile preparation of Cs NPs with desirable physicochemical characteristics and engineering ideal platforms for drug delivery purposes.

Exosome-mediated tumor metastasis: Biology, molecular targets and immuno-therapeutic options.

Small extracellular vesicles called exosomes play a crucial part in promoting intercellular communication. They act as intermediaries for the exchange of bioactive chemicals between cells, released into the extracellular milieu by a variety of cell types. Within the context of cancer progression, metastasis is a complex process that plays a significant role in the spread of malignant cells from their main site of origin to distant anatomical locations. This complex process plays a key role in the domain of cancer-related deaths. In summary, the trajectory of current research in the field of exosome-mediated metastasis is characterized by its unrelenting quest for more profound understanding of the molecular nuances, the development of innovative diagnostic tools and therapeutic approaches, and the unwavering dedication to transforming these discoveries into revolutionary clinical applications. This unrelenting pursuit represents a shared desire to improve the prognosis for individuals suffering from metastatic cancer and to nudge the treatment paradigm in the direction of more effective and customized interventions.

Hyaluronic Acid-Targeted Niosomes for Effective Breast Cancer Chemostarvation Therapy.

Chemotherapy is widely used for cancer therapy; however, its efficacy is limited due to poor targeting specificity and severe side effects. Currently, the next generations of delivery systems with multitasking potential have attracted significant attention for cancer therapy. This study reports on the design and synthesis of a multifunctional nanoplatform based on niosomes (NIO) coloaded with paclitaxel (PTX), a chemotherapeutic drug commonly used to treat breast cancer, and sodium oxamate (SO), a glycolytic inhibitor to enhance the cytotoxicity of anticancer drug, along with quantum dots (QD) as bioimaging agents, and hyaluronic acid (HA) coating for active targeting. HN@QPS nanoparticles with a size of ∼150 nm and a surface charge of -39.9 mV with more than 90% EE for PTX were synthesized. Codelivery of SO with PTX remarkably boosted the anticancer effects of PTX, achieving IC50 values of 1-5 and >0.5 ppm for HN@QP and HN@QPS, respectively. Further, HN@QPS treatment enhanced the apoptosis rate by more than 70% in MCF-7 breast cancer cells without significant cytotoxicity on HHF-2 normal cells. Also, quantification of mitochondrial fluorescence showed efficient toxicity against MCF-7 cells. Moreover, the cellular uptake evaluation demonstrated an improved uptake of HN@Q in MCF-7 cells. Taken together, this preliminary research indicated the potential of HN@QPS as an efficient targeted-dual drug delivery nanotheranostic against breast cancer cells.

Self-activating chitosan-based nanoparticles for sphingosin-1 phosphate modulator delivery and selective tumor therapy.

This study reports on the design and synthesis of hypoxia responsive nanoparticles (HRNPs) composed of methoxy polyethylene glycol-4,4 dicarboxylic azolinker-chitosan (mPEG-Azo-chitosan) as ideal drug delivery platform for Fingolimod (FTY720, F) delivery to achieve selective and highly enhanced TNBC therapy in vivo. Herein, HRNPs with an average size of 49.86 nm and a zeta potential of +3.22 mV were synthetized, which after PEG shedding can shift into a more positively-charged NPs (+30.3 mV), possessing self-activation ability under hypoxia situation in vitro, 2D and 3D culture. Treatment with lower doses of HRNPs@F significantly reduced MDA-MB-231 microtumor size to 15 %, induced apoptosis by 88 % within 72 h and reduced highly-proliferative 4 T1 tumor weight by 87.66 % vs. ∼30 % for Fingolimod compared to the untreated controls. To the best of our knowledge, this is the first record for development of hypoxia-responsive chitosan-based NPs with desirable physicochemical properties, and selective self-activation potential to generate highly-charged nanosized tumor-penetrating chitosan NPs. This formulation is capable of localized delivery of Fingolimod to the tumor core, minimizing its side effects while boosting its anti-tumor potential for eradication of TNBC solid tumors.

Biomimetic alginate-based electroconductive nanofibrous scaffolds for bone tissue engineering application.

Novel electrically conductive nanofibrous scaffolds were designed and fabricated through the grafting of aniline monomer onto a phenylamine-functionalized alginate (Alg-NH2) followed by electrospinning with poly(vinyl alcohol) (PVA). Performance of the prepared scaffolds in bone tissue engineering (TE) were studied in terms of physicochemical (e.g., conductivity, electroactivity, morphology, hydrophilicity, water uptake, and mechanical) and biological (cytocompatibility, in vitro biodegradability, cells attachment and proliferation, hemolysis, and protein adsorption) properties. The contact angles of the scaffolds with water drop were obtained about 50 to 60° that confirmed their excellent hydrophilicities for TE applications. Three dimensional (3D), inter-connected and uniform porous structures of the scaffolds without any bead formation was confirmed by scanning electron microscopy (SEM). Electrical conductivities of the fabricated scaffolds were obtained as 1.5 × 10-3 and 2.7 × 10-3 Scm-1. MTT assay results revealed that the scaffolds have acceptable cytocompatibilities and can enhance the cells adhesion as well as proliferation, which approved their potential for TE applications. Hemolysis rate of the developed scaffolds were quantified <2 % even at high concentration (200 µgmL-1) of samples that approved their hemocompatibilities. The scaffolds were also exhibited acceptable protein adsorption capacities (65 and 68 µgmg-1). As numerous experimental results, the developed scaffolds have acceptable potential for bone TE.

Enzymatically crosslinked magnetic starch-grafted poly(tannic acid) hydrogel for "smart" cancer treatment: An in vitro chemo/hyperthermia therapy study.

A novel strategy was designed and developed based of horseradish peroxidase (HRP)-mediated crosslinking of tyramine-functionalized starch (Tyr-St), tannic acid (TA) and phenolated-magnetic nanoparticles (Fe3O4-PhOH NPs), and simultaneous loading of doxorubicin hydrochloride (Dox) to afford a pH-responsive magnetic hydrogel-based drug delivery system (DDS) for synergistic in vitro chemo/hyperthermia therapy of human breast cancer (MCF-7) cells. The developed St-g-PTA/Fe3O4 magnetic hydrogel showed porous micro-structure with saturation magnetization (δs) value of 19.2 emu g-1 for Fe3O4 NPs content of ∼7.4 wt%. The pore sizes of the St-g-PTA/Fe3O4 hydrogel was calculated to be 2400 ± 200 nm-2. In vitro drug release experiments exhibited the developed DDS has pH-dependent drug release behavior, while at physiological pH (7.4) released only 30 % of the loaded drug after 100 h. Human serum albumin (HSA) adsorption capacities of the synthesized St/Fe3O4 and St-g-PTA/Fe3O4 magnetic hydrogels were obtained as 86 ± 2.2 and 77 ± 1.9 µgmg-1, respectively. The well-known MTT-assay approved the cytocompatibility of the developed St-g-PTA/Fe3O4 hydrogel, while the Dox-loaded system exhibited higher anti-cancer activity than those of the free Dox as verified by MTT-assay, and optical as well as florescent microscopies imaging. The synergistic chemo/hyperthermia therapy effect was also verified for the developed St-g-PTA/Fe3O4-Dox via hot water approach.