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.

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.

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.

Horizontal Gene Transfer: From Evolutionary Flexibility to Disease Progression.

Flexibility in the exchange of genetic material takes place between different organisms of the same or different species. This phenomenon is known to play a key role in the genetic, physiological, and ecological performance of the host. Exchange of genetic materials can cause both beneficial and/or adverse biological consequences. Horizontal gene transfer (HGT) or lateral gene transfer (LGT) as a general mechanism leads to biodiversity and biological innovations in nature. HGT mediators are one of the genetic engineering tools used for selective introduction of desired changes in the genome for gene/cell therapy purposes. HGT, however, is crucial in development, emergence, and recurrence of various human-related diseases, such as cancer, genetic-, metabolic-, and neurodegenerative disorders and can negatively affect the therapeutic outcome by promoting resistant forms or disrupting the performance of genome editing toolkits. Because of the importance of HGT and its vital physio- and pathological roles, here the variety of HGT mechanisms are reviewed, ranging from extracellular vesicles (EVs) and nanotubes in prokaryotes to cell-free DNA and apoptotic bodies in eukaryotes. Next, we argue that HGT plays a role both in the development of useful features and in pathological states associated with emerging and recurrent forms of the disease. A better understanding of the different HGT mediators and their genome-altering effects/potentials may pave the way for the development of more effective therapeutic and diagnostic regimes.

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.

Static DNA Nanostructures For Cancer Theranostics: Recent Progress In Design And Applications.

Among the various nano/biomaterials used in cancer treatment, the beauty and benefits of DNA nanocomposites are outstanding. The specificity and programmability of the base pairing of DNA strands, together with their ability to conjugate with different types of functionalities have realized unsurpassed potential for the production of two- and three-dimensional nano-sized structures in any shape, size, surface chemistry and functionality. This review aims to provide an insight into the diversity of static DNA nanodevices, including DNA origami, DNA polyhedra, DNA origami arrays and bioreactors, DNA nanoswitch, DNA nanoflower, hydrogel and dendrimer as young but promising platforms for cancer theranostics. The utility and potential of the individual formats in biomedical science and especially in cancer therapy will be discussed.

Dynamic DNA nanostructures in biomedicine: Beauty, utility and limits.

DNA composite materials are at the forefront, especially for biomedical science, as they can increase the efficacy and safety of current therapies and drug delivery systems. The specificity and predictability of the Watson-Crick base pairing make DNA an excellent building material for the production of programmable and multifunctional objects. In addition, the principle of nucleic acid hybridization can be applied to realize mobile nanostructures, such as those reflected in DNA walkers that sort and collect cargo on DNA tracks, DNA robots performing tasks within living cells and/or DNA tweezers as ultra-sensitive biosensors. In this review, we present the diversity of dynamic DNA nanostructures functionalized with different biomolecules/functional units, imaging smart biomaterials capable of sensing, interacting, delivery and performing complex tasks within living cells/organisms.

Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer.

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including angiogenic switch, immune escape, cancer stem cells, extracellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer and discuss the implications of such approaches in cancer treatment.

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.

Effects of nano-encapsulated curcumin-chrysin on telomerase, MMPs and TIMPs gene expression in mouse B16F10 melanoma tumour model.

Due to the high rate of drug resistance among malignant melanoma cases, it seems necessary to introduce an efficient pharmaceutical approach to melanoma treatment. For this purpose, Curcumin (Cur) and Chrysin (Chr), two natural anti-cancers, were co-encapsulated in PLGA-PEG nanoparticles (NPs), characterized by DLS, FTIR and FE-SEM and investigated for their effects on MMPs, TIMPs and TERT genes expression in C57B16 mice bearing B16F10 melanoma tumours. The results showed that the expression of MMP-9, MMP-2 and TERT genes were significantly decreased in all treated groups compared to the control. This reduction had the highest amount in CurChr NPs group and then CurChr group for each three genes. Likewise, the expression of TIMP-1 and TIMP-2 genes was significantly increased in all treated groups, compared to the control. Combination groups showed the highest rise in expression of these two genes and the observed increase was greater in nano groups. Moreover, the highest melanoma tumour growth inhibition was detected for CurChr NPs, followed by CurChr = Cur NPs > Cur > Chr NP > Chr. Overall, it is speculated that the nano-combination of Cur and Chr into polymeric NPs with a one-step fabricated co-delivery system may be a promising and convenient approach to improve their efficiency in melanoma cancer therapy.

NGR (Asn-Gly-Arg)-targeted delivery of coagulase to tumor vasculature arrests cancer cell growth.

Induction of selective thrombosis and infarction in tumor-feeding vessels represents an attractive strategy to combat cancer. Here we took advantage of the unique coagulation properties of staphylocoagulase and genetically engineered it to generate a new fusion protein with novel anti-cancer properties. This novel bi-functional protein consists of truncated coagulase (tCoa) and an NGR (GNGRAHA) motif that recognizes CD13 and αvß3 integrin receptors, targeting it to tumor endothelial cells. Herein, we report that tCoa coupled by its C-terminus to an NGR sequence retained its normal binding activity with prothrombin and avß3 integrins, as confirmed in silico and in vitro. Moreover, in vivo biodistribution studies demonstrated selective accumulation of FITC-labeled tCoa-NGR fusion proteins at the site of subcutaneously implanted PC3 tumor xenografts in nude mice. Notably, systemic administration of tCoa-NGR to mice bearing 4T1 mouse mammary xenografts or PC3 human prostate tumors resulted in a significant reduction in tumor growth. These anti-tumor effects were accompanied by massive thrombotic occlusion of small and large tumor vessels, tumor infarction and tumor cell death. From these findings, we propose tCoa-NGR mediated tumor infarction as a novel and promising anti-cancer strategy targeting both CD13 and integrin αvß3 positive tumor neovasculature.

Tumor target amplification: Implications for nano drug delivery systems.

Tumor cells overexpress surface markers which are absent from normal cells. These tumor-restricted antigenic signatures are a fundamental basis for distinguishing on-target from off-target cells for ligand-directed targeting of cancer cells. Unfortunately, tumor heterogeneity impedes the establishment of a solid expression pattern for a given target marker, leading to drastic changes in quality (availability) and quantity (number) of the target. Consequently, a subset of cancer cells remains untargeted during the course of treatment, which subsequently promotes drug-resistance and cancer relapse. Since target inefficiency is only problematic for cancer treatment and not for treatment of other pathological conditions such as viral/bacterial infections, target amplification or the generation of novel targets is key to providing eligible antigenic markers for effective targeted therapy. This review summarizes the limitations of current ligand-directed targeting strategies and provides a comprehensive overview of tumor target amplification strategies, including self-amplifying systems, dual targeting, artificial markers and peptide modification. We also discuss the therapeutic and diagnostic potential of these approaches, the underlying mechanism(s) and established methodologies, mostly in the context of different nanodelivery systems, to facilitate more effective ligand-directed cancer cell monitoring and targeting.

An overview on Vadimezan (DMXAA): The vascular disrupting agent.

Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA (ASA404) or Vadimezan, a flavone-acetic acid-based drug, is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however, proposed direct and indirect mechanisms of action for DMXAA comprises (i) inducing apoptosis in endothelial cells; (ii) hemorrhagic necrosis and ischemia in tumor; (iii) release of serotonin (5-HT); (vi) stimulation of innate immune system; (v) production of inflammatory cytokines, for example TNF, IL-6, GCSF, KC, IP-10, and MCP-1; (vi) activation of NFκB and p38 (MAPK); (vii) production of nitric oxide; and (viii) reducing tumor energetics and membrane turnover. Despite the remarkable results from preclinical and phase I/II, DMXAA has failed in phase III clinical trials. The reason for this surprising discrepancy, among others, was discovered to be STING receptor variations between mice and humans. In this review, the development, the mechanisms of DMXAA action, the clinical trials, the combination therapy, and the future of this drug will be 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.

RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice.

Induction of thrombosis in tumor vasculature represents an appealing strategy for combating cancer. Herein, we combined unique intrinsic coagulation properties of staphylocoagulase with new acquired functional potentials introduced by genetic engineering, to generate a novel bi-functional fusion protein consisting of truncated coagulase (tCoa) bearing an RGD motif on its C-terminus for cancer therapy. We demonstrated that free coagulase failed to elicit any significant thrombotic activity. Conversely, RGD delivery of coagulase retained coagulase activity and afforded favorable interaction of fusion proteins with prothrombin and αvß3 endothelial cell receptors, as verified by in silico, in vitro, and in vivo experiments. Although free coagulase elicited robust coagulase activity in vitro, only targeted coagulase (tCoa-RGD) was capable of producing extensive thrombosis, and subsequent infarction and massive necrosis of CT26 mouse colon, 4T1 mouse mammary and SKOV3 human ovarian tumors in mice. Additionally, systemic injections of lower doses of tCoa-RGD produced striking tumor growth inhibition of CT26, 4T1 and SKOV3 solid tumors in animals. Altogether, the nontoxic nature, unique shortcut mechanism, minimal effective dose, wide therapeutic window, efficient induction of thrombosis, local effects and susceptibility of human blood to coagulase suggest tCoa-RGD fusion proteins as a novel and promising anticancer therapy for human trials.

The effect of chrysin-loaded nanofiber on wound healing process in male rat.

Wound healing is an inflammatory process. Chrysin, a natural flavonoid found in honey, has been recently investigated to have anti-inflammatory and antioxidant effects. In this work, the effects of chrysin-loaded nanofiber on the expressions of genes that are related to wound healing process such as P53, TIMPs, MMPs, iNOS, and IL-6 in an animal model study were evaluated. The electrospinning method was used for preparation the different concentrations of chrysin-loaded PCL-PEG nanofiber (5%, 10%, and 20% [w/w]) and characterized by FTIR and SEM. The wound healing effects of chrysin-loaded PCL-PEG nanofiber were in vivo investigated in rats, and the expressions of genes related to wound healing process were evaluated by real-time PCR. The study results showed chrysin-loaded PLC-PEG compared to chrysin ointment and control groups significantly increase IL-6, MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 (p < .05). On the other hand, nanofibers containing chrysin significantly decreased p53 and iNOS expression compared to chrysin ointment and control groups (p < .05). According to the results, chrysin-loaded PCL-PEG-PCL nanofibers have positive effects on the expression of the genes that have pivotal role in wound healing.

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.

The herbal medicine Melissa officinalis extract effects on gene expression of p53, Bcl-2, Her2, VEGF-A and hTERT in human lung, breast and prostate cancer cell lines.

INTRODUCTION: Earlier, we verified that Melissa officinalis extract (MOE) elicits potent antiproliferative effects on different human cancer cells. To gain insights into the molecular mechanisms accounting for the cytotoxic effects of MOE, we assessed the expression patterns of several prominent molecules with therapeutic potential in cancer by Quantitative PCR (Q-PCR). METHODS: A549, MCF-7 and PC3 cancer cells were grown in complete RPMI 1640 and seeded in 24 well micro plates. After incubation for 72h, 100µg/ml of MOE was added and the cells were further incubated for 72h. Afterwards, the cells were subjected to RNA extraction for the means of Q-PCR. RESULTS: Our results indicated that in PC3 cancer cells, MOE resulted in a significant downregulation of VEGF-A (0.0004 fold), Bcl-2 (0.001 fold), Her2 (0.02 fold), and hTERT (0.023 fold) compared to the untreated control. In addition, VEGF-A and hTERT mRNA were significantly downregulated in MCF-7 and A549 cancer cells, as well. Notably, high anti-angiogenic activity was closely associated with a high anti-telomerase activity of MOE in studying cancer cells. The decrease in VEGF-A expression was significantly superior than that of hTERT downregulation, as PC3 cancer cells with the highest hTERT down regulation (0.023) presented the highest anti VEGF activity (0.0004 fold), whereas MCF-7 cells with the lowest hTERT inhibition (0.213) showed the lowest VEGF inhibition(0.0435) among the three studied cancer cells. We noticed that the modulation of VEGF-A and hTERT gene expression can be considered as a common target, accounting for the therapeutic potential of MOE on human breast, lung and prostate cancer cells. CONCLUSION: Altogether, it is suggested that the potent antiproliferative activity of the hydroalcoholic extract of Melissa officinalis is somehow explainable by its high potency to inhibit expression of the prominent oncogenes Bcl2, Her2, VEGF-A and hTERT in prostate cancer. In tumors with functional p53, including MCF-7 and A549 cancer cells, the role of p53, Bcl2 and Her2 is less significant. It appears that MOE exerts its antiproliferative effects in these cancer cells partly via concurrent downregulation of VEGF-A and hTERT. Additional studies are needed to clarify the role of other active molecules in cancer cells harboring functional p53.

The Effect of Chrysin Loaded PLGA-PEG on Metalloproteinase Gene Expression in Mouse 4T1 Tumor Model.

Despite the advances in medicine, cancer remains as one of the leading causes of the death worldwide. Through our previous study, the Chrysin loaded PGLA/PEG has been synthesized, and its physico-chemical properties were characterized. The aim of the present study was to evaluate the Chrysin loaded PGLA/PEG nanoparticle therapeutic effects on TIMP-1, TIMP-2, MMP-2, MMP-9 and PI3k expression in Mouse 4T1 breast tumor model.30 mice were enrolled in the current study, and the mice were randomly divided into 3 groups: untreated (n=10), Chrysin treatment (n=10) and Chrysin-loaded PLGA/PEG-based treatment (n=10). 1064T1 mammary carcinoma cells subcutaneously inoculated in the flank on mice orthotopically. After the treatments, the primary tumors were isolated from the Mice under anesthesia. For RNA extraction, the isolated tissues were frozen in -70°C. RNA extraction was performed by using RNA extraction kit. The expression of TIMP-1, TIMP-2, MMP-2 and MMP-9 were measured by the real time PCR.The study results showed the expression of TIMP-1 and TIMP-2 in Chrysin-loaded PLGA/PEG treatment groups was higher than Chrysin receiving one. Also, the results showed that the MMP-9 and MMP-2 expressions were reduced after Chrysin loaded PLGA/PEG treatment. The reduction of the mentioned genes was greater in Chrysin-loaded PLGA/PEG treatment group in comparison with Chrysin receiving group.According to our present study, expression of the mentioned genes after treatments, Chrysin; especially, Chrysin-loaded PLGA/PEG could be proposed as a new component in the cancer therapy for reducing the progression and metastasis.