Notch Signaling Suppression by Golden Phytochemicals: Potential for Cancer Therapy.

Cancer is one of the main causes of mortality worldwide. Cancer cells are characterized by unregulated cellular processes, including proliferation, progression, and angiogenesis. The occurrence of these processes is due to the dysregulation of various signaling pathways such as NF-κB (nuclear factor-κB), Wnt/beta-catenin, Notch signaling and MAPK (mitogen-activated protein kinases). Notch signaling pathways cause the progression of various types of malignant tumors. Among the phytochemicals for cancer therapy, several have attracted great interest, including curcumin, genistein, quercetin, silibinin, resveratrol, cucurbitacin and glycyrrhizin. Given the great cellular and molecular heterogeneity within tumors and the high toxicity and side effects of synthetic chemotherapeutics, natural products with pleiotropic effects that simultaneously target numerous signaling pathways appear to be ideal substitutes for cancer therapy. With this in mind, we take a look at the current status, impact and potential of known compounds as golden phytochemicals on key signaling pathways in tumors, focusing on the Notch pathway. This review may be useful for discovering new molecular targets for safe and efficient cancer therapy with natural chemotherapeutics.

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.

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.

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.

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.

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.

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.

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.

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.

Molecular targets, therapeutic agents and multitasking nanoparticles to deal with cancer stem cells: A narrative review.

There is increasing evidence that malignant tumors are initiated and maintained by a sub-population of tumor cells that have similar biological properties to normal adult stem cells. This very small population of Cancer Stem Cells (CSC) comprises tumor initiating cells responsible for cancer recurrence, drug resistance and metastasis. Conventional treatments such as chemotherapy, radiotherapy and surgery, in addition to being potentially toxic and non-specific, may paradoxically increase the population, spread and survival of CSCs. Next-generation sequencing and omics technologies are increasing our understanding of the pathways and factors involved in the development of CSCs, and can help to discover new therapeutic targets against CSCs. In addition, recent advances in nanomedicine have provided hope for the development of optimal specific therapies to eradicate CSCs. Moreover, the use of artificial intelligence and nano-informatics can elucidate new drug targets, and help to design drugs and nanoparticles (NPs) to deal with CSCs. In this review, we first summarize the properties of CSCs and describe the signaling pathways and molecular characteristics responsible for the emergence and survival of CSCs. Also, the location of CSCs within the tumor and the effect of host factors on the creation and maintenance of CSCs are discussed. Newly discovered molecular targets involved in cancer stemness and some novel therapeutic compounds to combat CSCs are highlighted. The optimum properties of anti-CSC NPs, including blood circulation and stability, tumor accumulation and penetration, cellular internalization, drug release, endosomal escape, and aptamers designed for specific targeting of CSCs are covered. Finally, some recent smart NPs designed for therapeutic and theranostic purposes to overcome CSCs are discussed.

Multifunctional nanostructures: Intelligent design to overcome biological barriers.

Over the past three decades, nanoscience has offered a unique solution for reducing the systemic toxicity of chemotherapy drugs and for increasing drug therapeutic efficiency. However, the poor accumulation and pharmacokinetics of nanoparticles are some of the key reasons for their slow translation into the clinic. The is intimately linked to the non-biological nature of nanoparticles and the aberrant features of solid cancer, which together significantly compromise nanoparticle delivery. New findings on the unique properties of tumors and their interactions with nanoparticles and the human body suggest that, contrary to what was long-believed, tumor features may be more mirage than miracle, as the enhanced permeability and retention based efficacy is estimated to be as low as 1%. In this review, we highlight the current barriers and available solutions to pave the way for approved nanoformulations. Furthermore, we aim to discuss the main solutions to solve inefficient drug delivery with the use of nanobioengineering of nanocarriers and the tumor environment. Finally, we will discuss the suggested strategies to overcome two or more biological barriers with one nanocarrier. The variety of design formats, applications and implications of each of these methods will also be evaluated.

Prospects for hypoxia-based drug delivery platforms for the elimination of advanced metastatic tumors: From 3D modeling to clinical concepts.

Hypoxia is a unique characteristic of the solid tumor microenvironment. Hypoxia contributes to multi-drug resistance, metastasis and cancer relapse through numerous molecular pathways, but at the same time provides an opportunity for the development of novel drugs or modalities specifically targeting hypoxic tumor regions. Given the high significance of tumor hypoxia in therapeutic results, we here discuss a variety of hypoxia-adopted strategies, and their potential and utility in the treatment of deep-seated hypoxic tumor cells. We discuss the merits and demerits of these approaches, as well as their combination with other approaches such as photodynamic therapy. We also survey the currently available 3D hypoxia modeling systems, in particular organoid-based microfluidics. Finally, we discuss the potential and the current status of preclinical tumor hypoxia approaches in clinical trials for advanced cancer. We believe that multi-modal imaging and therapeutic hypoxia adopted drug delivery platforms could provide better efficacy and safety profiles, and more importantly personalized therapy. Determining the hypoxia status of tumors could offer a second chance for the clinical translation of hypoxia-based agents, such as hypoxia activated prodrugs (HAPs) from bench to bedside.

Tumor microenvironment penetrating chitosan nanoparticles for elimination of cancer relapse and minimal residual disease.

Chitosan and its derivatives are among biomaterials with numerous medical applications, especially in cancer. Chitosan is amenable to forming innumerable shapes such as micelles, niosomes, hydrogels, nanoparticles, and scaffolds, among others. Chitosan derivatives can also bring unprecedented potential to cross numerous biological barriers. Combined with other biomaterials, hybrid and multitasking chitosan-based systems can be realized for many applications. These include controlled drug release, targeted drug delivery, post-surgery implants (immunovaccines), theranostics, biosensing of tumor-derived circulating materials, multimodal systems, and combination therapy platforms with the potential to eliminate bulk tumors as well as lingering tumor cells to treat minimal residual disease (MRD) and recurrent cancer. We first introduce different formats, derivatives, and properties of chitosan. Next, given the barriers to therapeutic efficacy in solid tumors, we review advanced formulations of chitosan modules as efficient drug delivery systems to overcome tumor heterogeneity, multi-drug resistance, MRD, and metastasis. Finally, we discuss chitosan NPs for clinical translation and treatment of recurrent cancer and their future perspective.

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.

Roles of miRNAs in Colorectal Cancer: Therapeutic Implications and Clinical Opportunities.

Colorectal cancer (CRC) is one of the most disseminated diseases across the globe engaging the digestive system. Various therapeutic methods from traditional to the state-of-the-art ones have been applied in CRC patients, however, the attempts have been unfortunate to lead to a definite cure. MiRNAs are a smart group of non-coding RNAs having the capabilities of regulating and controlling coding genes. By utilizing this stock-in-trade biomolecules, not only disease's symptoms can be eliminated, there may also be a good chance for the complete cure of the disease in the near future. Herein, we provide a comprehensive review delineating the therapeutic relationship between miRNAs and CRC. To this, various clinical aspects of miRNAs which act as a tumor suppressor and/or an oncogene, their underlying cellular processes and clinical outcomes, and, in particular, their effects and expression level changes in patients treated with chemo- and radiotherapy are discussed. Finally, based on the results deducted from scientific research studies, therapeutic opportunities based on targeting/utilizing miRNAs in the preclinical as well as clinical settings are highlighted.

Co-Administration of Vadimezan and Recombinant Coagulase-NGR Inhibits Growth of Melanoma Tumor in Mice.

Purpose: Tumor vascular targeting appeared as an appealing approach to fight cancer, though, the results from the clinical trials and drugs in the market were proved otherwise. The promise of anti-angiogenic therapy as the leading tumor vascular targeting strategy was negatively affected with the discovery that tumor vascularization can occur non-angiogenic mechanisms such as co-option. An additional strategy is induction of tumor vascular infarction and ischemia. Methods: Such that we used truncated coagulase (tCoa) coupled to tumor endothelial targeting moieties to produce tCoa-NGR fusion proteins. We showed that tCoa-NGR can bypass coagulation cascade to induce selective vascular thrombosis and infarction of mild and highly proliferative solid tumors in mice. Moreover, combination therapy can be used to improve the potential of cancer vascular targeting modalities. Herein, we report combination of tCoa-NGR with vascular disrupting agent (VDA), vadimezan. Results: Our results show that synergistic work of these two agents can significantly suppress growth of B16-F10 melanoma tumors in C57/BL6 mice. Conclusion: For the first time, we used the simultaneous benefits of two strategies for inducing thrombosis and destruction of tumor vasculature as spatial co-operation. The tCoa-NGR induce thrombosis which reduces blood flow in the peripheral tumor region. And combined with the action of DMXAA, which target inner tumor mass, growth and proliferation of melanoma tumors can be significantly suppressed.

A novel bioreducible and pH-responsive magnetic nanohydrogel based on ß-cyclodextrin for chemo/hyperthermia therapy of cancer.

A new strategy for design and development of a magnetic "smart" drug delivery system (DDS) based on ß-cyclodextrin (ß-CD) and poly(2-ethyl-2-oxazoline) (PEtOx) was reported. For this purpose, a ß-CD-(I)7 was acetylated, and then EtOx monomer was grafted onto the acetylated ß-CD-(I)7 through cationic ring-opening polymerization followed by simultaneous crosslinking with amine-end capped Fe3O4 nanoparticles (Fe3O4-NH2 NPs) and cystamine to produce a ß-CD-g-(PEtOx)7/Fe3O4 as a reduction- and pH-responsive magnetic DDS. The developed magnetic nanohydrogel was loaded with doxorubicin hydrochloride (Dox), and its drug loading and encapsulation efficiencies, as well as its pH- and reduction-triggered drug release behaviors were investigated. The anticancer activity of the formulated ß-CD-g-(PEtOx)7/Fe3O4-Dox was investigated against MCF7 cells. According to the results, the formulated ß-CD-g-(PEtOx)7/Fe3O4-Dox can be considered as an efficient and "smart" DDS for cancer therapy and diagnosis due to its high drug loading value (∼ 74 %), slow and stimuli-triggered drug release behavior, and acceptable magnetic properties.

Evaluation of Anti-Tumor Potential of Lactobacillus acidophilus ATCC4356 Culture Supernatants in MCF-7 Breast Cancer.

BACKGROUND: The anti-cancer activity of some lactic acid bacterial strains is well documented in several kinds of literatures. Lactobacillus strains have received considerable attention as a beneficial microbiota. The aim of this study is to evaluate the effects of anti-tumor activities of L. acidophilus ATCC4356 culture supernatants on the MCF-7 human breast cancer cells. MATERIALS AND METHODS: The anti-cancer effects of 24h and 48h culture supernatants at various concentrations (1.25, 2.5, 5, 10 and 20 µg/ml) were determined by various in vitro and in vivo assays including MTT, tumor volume measurement as well as 99mTc-MIBI biodistribution in MCF-7 tumor bearing nude mice and histopathology test. For evaluation of the related mechanism of action, quantitative PCR was conducted. RESULTS: The 48h culture supernatants at 10 and 20 µg/ml exhibited significant in vitro inhibition of MCF-7 cell proliferation. However, this inhibition was not observed for HUVEC human endothelial normal cells. Q-PCR indicated that treatment by the supernatant led to a significant downregulation of VEGFR (~ 0.009 fold) and Bcl- 2 (~ 0.5 fold) and upregulation of p53 (~ 1.3 fold). In vivo study using MCF-7 xenograft mouse models demonstrated a reduction in tumor weight and volume by both 24h and 48h supernatants (2 mg/kg) after 15 days. According to the 99mTc-MIBI biodistribution result, treatment of MCF-7 bearing nude mice with both 24h and 48h supernatant (2mg/kg) led to a significant decrease in tumor uptake compared with the control group. CONCLUSION: These results suggest that the culture supernatants of L. acidophilus ATCC4356 at suitable concentrations can be considered as a good alternative nutraceutical with promising therapeutic indexes for breast cancer.

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.