Microfluidic System Consisting of a Magnetic 3D-Printed Microchannel Filter for Isolation and Enrichment of Circulating Tumor Cells Targeted by Anti-HER2/MOF@Ferrite Core-Shell Nanostructures: A Theranostic CTC Dialysis System.

Low number of circulating tumor cells (CTCs) in the blood samples and time-consuming properties of the current CTC isolation methods for processing a small volume of blood are the biggest obstacles to CTC usage in practice. Therefore, we aimed to design a CTC dialysis system with the ability to process cancer patients' whole blood within a reasonable time. Two strategies were employed for developing this dialysis setup, including (i) synthesizing novel in situ core-shell Cu ferrites consisting of the Cu-CuFe2O4 core and the MIL-88A shell, which are targeted by the anti-HER2 antibody for the efficient targeting and trapping of CTCs; and (ii) fabricating a microfluidic system containing a three-dimensional (3D)-printed microchannel filter composed of a polycaprolactone/Fe3O4 nanoparticle composite with pore diameter less than 200 µm on which a high-voltage magnetic field is focused to enrich and isolate the magnetic nanoparticle-targeted CTCs from a large volume of blood. The system was assessed in different aspects including capturing the efficacy of the magnetic nanoparticles, CTC enrichment and isolation from large volumes of human blood, side effects on blood cells, and the viability of CTCs after isolation for further analysis. Under the optimized conditions, the CTC dialysis system exhibited more than 80% efficacy in the isolation of CTCs from blood samples. The isolated CTCs were viable and were able to proliferate. Moreover, the CTC dialysis system was safe and did not cause side effects on normal blood cells. Taken together, the designed CTC dialysis system can process a high volume of blood for efficient dual diagnostic and therapeutic purposes.

Biodegradable and biocompatible subcutaneous implants consisted of pH-sensitive mebendazole-loaded/folic acid-targeted chitosan nanoparticles for murine triple-negative breast cancer treatment.

BACKGROUND: Mebendazole (MBZ) is a well-known anti-parasite drug with significant anti-cancer properties. However, MBZ exhibits low solubility, limited absorption efficacy, extensive first-pass effect, and low bioavailability. Therefore, multiple oral administration of high dose MBZ is required daily for achieving the therapeutic serum level which can cause severe side effects and patients' non-compliance. METHOD: In the present study, MBZ-loaded/folic acid-targeted chitosan nanoparticles (CS-FA-MBZ) were synthesized, characterized, and used to form cylindrical subcutaneous implants for 4T1 triple-negative breast tumor (TNBC) treatment in BALB/c mice. The therapeutic efficacy of the CS-FA-MBZ implants was investigated after subcutaneous implantation in comparison with Control, MBZ (40 mg/kg, oral administration, twice a week for 2 weeks), and CS-FA implants, according to 4T1 tumors' growth progression, metastasis, and tumor-bearing mice survival time. Also, their biocompatibility was evaluated by blood biochemical analyzes and histopathological investigation of vital organs. RESULTS: The CS-FA-MBZ implants were completely degraded 15 days after implantation and caused about 73.3%, 49.2%, 57.4% decrease in the mean tumors' volume in comparison with the Control (1050.5 ± 120.7 mm3), MBZ (552.4 ± 76.1 mm3), and CS-FA (658.3 ± 88.1 mm3) groups, respectively. Average liver metastatic colonies' number per microscope field at the CS-FA-MBZ group (2.3 ± 0.7) was significantly (P < 0.05) lower than the Control (9.6 ± 1.7), MBZ (5.0 ± 1.5), and CS-FA (5.2 ± 1) groups. In addition, the CS-FA-MBZ treated mice exhibited about 52.1%, 27.3%, and 17% more survival days after the cancer cells injection in comparison with the Control, MBZ, and CS-FA groups, respectively. Moreover, the CS-FA-MBZ implants were completely biocompatible based on histopathology and blood biochemical analyzes. CONCLUSION: Taking together, CS-FA-MBZ implants were completely biodegradable and biocompatible with high therapeutic efficacy in a murine TNBC model.

Immunoprotective effect of an in silico designed multiepitope cancer vaccine with BORIS cancer-testis antigen target in a murine mammary carcinoma model.

In our previous study, immunoinformatic tools were used to design a novel multiepitope cancer vaccine based on the most immunodominant regions of BORIS cancer-testis antigen. The final vaccine construct was an immunogenic, non-allergenic, and stable protein consisted of multiple cytotoxic T lymphocytes epitopes, IFN-γ inducing epitopes, and B cell epitopes according to bioinformatic analyzes. Herein, the DNA sequence of the final vaccine construct was placed into the pcDNA3.1 vector as a DNA vaccine (pcDNA3.1-VAC). Also, the recombinant multiepitope peptide vaccine (MPV) was produced by a transfected BL21 E. coli strain using a recombinant pET-28a vector and then, purified and screened by Fast protein liquid chromatography technique (FPLC) and Western blot, respectively. The anti-tumor effects of prophylactic co-immunization with these DNA and protein cancer vaccines were evaluated in the metastatic non-immunogenic 4T1 mammary carcinoma in BALB/c mice. Co-immunization with the pcDNA3.1-VAC and MPV significantly (P < 0.001) increased the serum levels of the MPV-specific IgG total, IgG2a, and IgG1. The splenocytes of co-immunized mice exhibited a significantly higher efficacy to produce interleukin-4 and interferon-γ and proliferation in response to MPV in comparison with the control. The prophylactic co-immunization regime caused significant breast tumors' growth inhibition, tumors' weight decrease, inhibition of metastasis formation, and enlarging tumor-bearing mice survival time, without any considerable side effects. Taking together, this cancer vaccine can evoke strong immune response against breast tumor and inhibits its growth and metastasis.

Diagnostic and prognostic value of stem cell factor plasma level in glioblastoma multiforme patients.

BACKGROUND: Investigation of novel blood-circulating agents as potential biomarkers for glioblastoma multiforme (GBM) patients' diagnosis and monitoring has gained lots of attention, due to limitations of imaging modalities and invasive tissue biopsy procedures. The present study aims to assess the diagnostic and prognostic values of preoperative stem cell factor (SCF) plasma level in GBM patients. METHODS: Preoperative plasma samples from 58 GBM patients and 20 patients with nonglial tumors and 30 healthy controls were obtained. SCF levels were measured by employing the enzyme-linked immunosorbent assay test and the values were compared between these three groups. Then, the association of SCF plasma level and tumor volume, progression-free survival (PFS), and overall survival (OS) for the GBM patients were evaluated. RESULTS: Mean preoperative SCF plasma level of the GBM patients (2.80 ± 1.52 ng/ml) was significantly higher (p < 0.0001) than the healthy controls (0.80 ± 0.24 ng/ml) and patients with nonglial tumor (1.41 ± 0.76 ng/ml). Receiver operating characteristic analysis revealed that the preoperative SCF plasma level could distinguish the GBM patients from healthy controls and patients with nonglial tumors with the area under curve values of 0.915 and 0.790, respectively. However, no significant association was observed between the GBM patients' preoperative SCF plasma levels and tumors' volume (Spearman Rho correlation coefficient, 0.1847; 95% CI, p = 0.1652). The GBM patients were divided into two subgroups based on mean preoperative SCF plasma levels (2.80 ng/ml). No significant difference was observed between the patients' PFS (p = 0.3792) and OS (p = 0.1469) at these two subgroups. CONCLUSION: Taking together, the SCF plasma level can serve as a novel diagnostic blood-circulating biomarker for patients with GBM. However, its plasma level is not correlated with GBM patients' tumor volume, PFS, or OS.

Pathogenic role of the SP/ NK1R system in GBM cells through inhibiting the thioredoxin system.

OBJECTIVES: Glioblastoma multiforme (GBM), a highly aggressive Grade IV brain tumor, is a significant public health issue due to its poor prognosis and incurability. Neuropeptide substance P (SP) plays a critical role in GBM tumor growth and development via activation of neurokinin-1receptor (NK1R). Moreover, SP is a pro-oxidant factor contributing to oxidative stress in various cell types. However, the link between SP and oxidative stress in cancer cells is not fully investigated. Here, we aimed to identify the effects of SP and NK1R antagonist, aprepitant, on the redox status of GBM cells. MATERIALS AND METHODS: Resazurin assay was employed to determine the effect of aprepitant on viability of U87 glioblastoma cells. 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assay was employed to measure the levels of intracellular reactive oxygen species (ROS). A quantitative real-time polymerase chain reaction was applied to measure the expression of proteins of the thioredoxin system. Commercial kits (ZellBio GmbH) were also used to measure the enzymatic activity of these proteins. RESULTS: We found that SP increased ROS level in U87 GBM cells, and aprepitant significantly reduced this effect. Furthermore, we found that SP could also affect the thioredoxin system, a central antioxidant enzyme defense system. SP reduced both expression and enzymatic activity of the thioredoxin system's proteins, Trx and thioredoxin reductase (TrxR) and these effects were significantly reduced by aprepitant. CONCLUSION: Our results indicated that SP activation of NK1R represented a link between oxidative stress and GBM and highlighted the need for further validations in future studies.

Efficacy of co-immunization with the DNA and peptide vaccines containing SYCP1 and ACRBP epitopes in a murine triple-negative breast cancer model.

Multiepitope cancer vaccines have gained lots of attention for prophylactic and therapeutic purposes in cancer patients. In our previous study, multiepitope DNA and peptide cancer vaccines consisted of the most immunodominant epitopes of ACRBP and SYCP1 antigens were designed by bioinformatic tools. In this study, the effect of prophylactic co-immunization with these DNA and peptide cancer vaccines in the 4T1 breast cancer animal model was assessed. Serum levels of the peptide-specific IgG total, IgG2a and IgG1 were measured by enzyme-linked immunosorbent assay (ELISA). Also, the efficacy of the immunized mice splenocytes' for producing interleukin-4 (IL-4) and interferon-γ (IFN-γ) was evaluated. The co-immunization caused a significant (P < .05) increase in the serum levels of IgG1 and IgG2a. The co-immunized mice splenocytes exhibited significantly enhanced IL-4 (6.6-fold) and IFN-γ (19-fold) production. Also, their lymphocytes exhibited higher proliferation rate (3-fold) and granzyme B production (6.5-fold) in comparison with the control. The prophylactic co-immunization significantly decreased the breast tumors' volume (78%) and increased the tumor-bearing mice survival time (37.5%) in comparison with the control. Taking together, prophylactic co-immunization with these multiepitope DNA and peptide cancer vaccines can activate the immune system against breast cancer. However, further experiments are needed to evaluate their efficacy from different angles.

Exploring the out of sight antigens of SARS-CoV-2 to design a candidate multi-epitope vaccine by utilizing immunoinformatics approaches.

SARS-CoV-2 causes a severe respiratory disease called COVID-19. Currently, global health is facing its devastating outbreak. However, there is no vaccine available against this virus up to now. In this study, a novel multi-epitope vaccine against SARS-CoV-2 was designed to provoke both innate and adaptive immune responses. The immunodominant regions of six non-structural proteins (nsp7, nsp8, nsp9, nsp10, nsp12 and nsp14) of SARS-CoV-2 were selected by multiple immunoinformatic tools to provoke T cell immune response. Also, immunodominant fragment of the functional region of SARS-CoV-2 spike (400-510 residues) protein was selected for inducing neutralizing antibodies production. The selected regions' sequences were connected to each other by furin-sensitive linker (RVRR). Moreover, the functional region of ß-defensin as a well-known agonist for the TLR-4/MD complex was added at the N-terminus of the vaccine using (EAAAK)3 linker. Also, a CD4 + T-helper epitope, PADRE, was used at the C-terminal of the vaccine by GPGPG and A(EAAAK)2A linkers to form the final vaccine construct. The physicochemical properties, allergenicity, antigenicity, functionality and population coverage of the final vaccine construct were analyzed. The final vaccine construct was an immunogenic, non-allergen and unfunctional protein which contained multiple CD8 + and CD4 + overlapping epitopes, IFN-γ inducing epitopes, linear and conformational B cell epitopes. It could form stable and significant interactions with TLR-4/MD according to molecular docking and dynamics simulations. Global population coverage of the vaccine for HLA-I and II were estimated 96.2% and 97.1%, respectively. At last, the final vaccine construct was reverse translated to design the DNA vaccine. Although the designed vaccine exhibited high efficacy in silico, further experimental validation is necessary.

A Novel Bilayer Wound Dressing Composed of a Dense Polyurethane/Propolis Membrane and a Biodegradable Polycaprolactone/Gelatin Nanofibrous Scaffold.

One-layer wound dressings cannot meet all the clinical needs due to their individual characteristics and shortcomings. Therefore, bilayer wound dressings which are composed of two layers with different properties have gained lots of attention. In the present study, polycaprolactone/gelatin (PCL/Gel) scaffold was electrospun on a dense membrane composed of polyurethane and ethanolic extract of propolis (PU/EEP). The PU/EEP membrane was used as the top layer to protect the wound area from external contamination and dehydration, while the PCL/Gel scaffold was used as the sublayer to facilitate cells' adhesion and proliferation. The bilayer wound dressing was investigated regarding its microstructure, mechanical properties, surface wettability, anti-bacterial activity, biodegradability, biocompatibility, and its efficacy in the animal wound model and histopathological analyzes. Scanning electron micrographs exhibited uniform morphology and bead-free structure of the PCL/Gel scaffold with average fibers' diameter of 237.3 ± 65.1 nm. Significant anti-bacterial activity was observed against Staphylococcal aureus (5.4 ± 0.3 mm), Escherichia coli (1.9 ± 0.4 mm) and Staphylococcus epidermidis (1.0 ± 0.2 mm) according to inhibition zone test. The bilayer wound dressing exhibited high hydrophilicity (51.1 ± 4.9°), biodegradability, and biocompatibility. The bilayer wound dressing could significantly accelerate the wound closure and collagen deposition in the Wistar rats' skin wound model. Taking together, the PU/EEP-PCL/Gel bilayer wound dressing can be a potential candidate for biomedical applications due to remarkable mechanical properties, biocompatibility, antibacterial features, and wound healing activities.

Utilizing 808 nm laser for sensitizing of melanoma tumors to megavoltage radiation therapy.

Melanotic melanoma has high content of melanin and laser can destroy melanin-containing cells through thermal effect. In this study, the therapeutic effect of 808 nm laser therapy was investigated on B16-F10 melanoma tumor growth and tumor-bearing mice survival time. In addition, as laser can destroy melanin as the main cause of melanoma radioresistance, the effect of laser administration to enhance radiation therapy efficacy at B16-F10 cancer cells was evaluated in vitro and in vivo. Laser therapy (1 W/cm2 × 4 min) could cause significant (P < 0.05) inhibition of melanoma tumors' growth (~ 61%) and about three times increase of the tumor-bearing mice survival time in comparison with no-treatment group. In addition, the mice which were treated with 1 W/cm2 × 4 min laser administration plus 6 Gy megavoltage radiation therapy exhibited ~ 68% lesser tumors' volume and 27 days increase of survival time in comparison with 6 Gy irradiated tumor-bearing mice. Also, significantly higher (P < 0.05) tumor necrosis percentage was observed at the histopathological slides of 1 W/cm2 × 4 min laser + RT treated mice tumors (57 ± 12%) in comparison with radiation therapy group (31 ± 10%). Therefore, not only laser therapy can inhibit melanoma tumors' growth per se but also its combination with radiation therapy can cause a significant enhancement of radiation therapy efficacy. The laser administration can be used as a radiosensitizing method for melanotic melanoma radiation therapy.

Spirulina extract enriched for Braun-type lipoprotein (Immulina®) for inhibition of 4T1 breast tumors' growth and metastasis.

Spirulina platensis extracts have exhibited considerable anti-cancer effects. To investigate the efficacy of the Spirulina extract enriched for Braun-type lipoprotein (Immulina®) for breast cancer treatment, 4T1 breast tumor-bearing mice were treated with 40 mg/kg Immulina® daily and the tumors' growth and metastasis were assessed. Also, CD4, CD8, and CD56 staining were performed to investigate the Immulina® effect on the immune cells' recruitment to the tumors by immunohistochemistry. Immulina® could significantly (P < 0.001) inhibit 4T1 breast tumors' growth. Immulina®-treated group exhibited a 63% decrease in the tumors' volume in comparison with control (P < 0.001). Also, Immulina® could significantly (P < 0.001) decrease metastatic burden at the vital organs as 68% and 61% decrease in the liver and lungs metastatic colonies were observed, respectively. Also, Immulina® could increase mean survival time of the tumor-bearing mice for 29 days. The Spirulina-treated mice tumors contained significantly more infiltrated NK, CD4+, and CD8+ T lymphocytes in comparison with control. Taking together, Immulina® can be a safe anti-cancer supplement with the ability to cause direct apoptosis to the cancer cells and activate the immune system against tumor. This supplement with natural origin seems to have bright future to help breast cancer patients.

C-phycocyanin: a natural product with radiosensitizing property for enhancement of colon cancer radiation therapy efficacy through inhibition of COX-2 expression.

Different chemical and nanomaterial agents have been introduced for radiosensitizing purposes. However, many researchers believe these agents are far away from clinical application due to side effects and limited knowledge about their behavior in the human body. In this study, C-phycocyanin (C-PC) was used as a natural radiosensitizer for enhancement of radiation therapy (RT) efficacy. C-PC treatment's effect on the COX-2 expression of cancer cells was investigated by flow cytometry, western blot, qRT-PCR analyses in vitro and in vivo. Subsequently, the radiosensitizing effect of C-PC treatment was investigated by MTT and clonogenic cell survival assays for CT-26, DLD-1, HT-29 colon cancer cell lines and the CRL-1831 as normal colonic cells. In addition, the C-PC treatment effect on the radiation therapy efficacy was evaluated according to CT-26 tumor's growth progression and immunohistochemistry analyses of Ki-67 labeling index. C-PC treatment (200 µg/mL) could significantly enhance the radiation therapy efficacy in vitro and in vivo. Synergistic interaction was detected at C-PC and radiation beams co-treatment based on Chou and Talalay formula (combination index <1), especially at 200 µg/mL C-PC and 6 Gy radiation dosages. The acquired DEF of C-PC treatment was 1.39, 1.4, 1.63, and 1.05 for CT-26, DLD-1, HT-29, and CRL-1831 cells, respectively. Also, C-PC + RT treated mice exhibited 35.2% lower mean tumors' volume and about 6 days more survival time in comparison with the RT group (P < 0.05). In addition, C-PC + RT group exhibited 54% lower Ki-67 index in comparison with the RT group. Therefore, C-PC can exhibit high radiosensitizing effects. However, the potential cardiovascular risks of C-PC as a COX-2 inhibitor should be evaluated with extensive preclinical testing before developing this agent for clinical trials.

Modeling farmers' responsible environmental attitude and behaviour: a case from Iran.

There is an increasing concern over the environmental degradation caused by agricultural activities especially in developing countries which mostly linked to farmer's behavior. Thus, this study aimed to model the responsible attitude and behavior of Iranian farmers in respect to environment. The Theory of Planned Behavior (TPB) was used as a basis for identification of the main determinants of the farmers' responsible environmental behavior. A survey of 400 farmers in the Hamedan Province, selected through a multistage stratified random sampling method. Data was gathered using a questionnaire which its validity and reliability were confirmed by a panel of agricultural and environmental experts and calculated Cronbach's alpha (0.65 ≤ α ≤ 0.80), respectively. Data were analyzed using structural equation modeling (SEM) to evaluate the strength of relationship between the constructs and test the overall model fit. Results of study showed that "using animal manure in the farms" was the most important behavior which farmers are responsibly doing to respect their environment but their least attention is given to "disposing cans and bottles after spraying." Also, the fitness indices of the model revealed that the TPB partially supported the farmers' responsible environmental behavior as perceived behavioral control and environmental attitude positively influenced the farmers' responsible environmental behavior but there was not observed any significant influence by subjective norm. Among the additional incorporated constructs, environmental awareness, ethical commitment, and environmental concern significantly had a positive influence on farmers' behavior by mediating role of the environmental attitude. The inclusion of new constructs in the TPB model was supported through improving the predictive power of the modified model in predicting farmers' responsible environmental behavior.

Immunization using male germ cells and gametes as rich sources of cancer/testis antigens for inhibition of 4T1 breast tumors' growth and metastasis in BALB/c mice.

Recently cancer/testis antigens (CTA) have gained lots of attention as targets of immune therapy. However, the therapeutic efficacy of the CTAs single-antigen vaccines is not satisfying due to tumor heterogenicity. Therefore, many studies have focused on the enhancement of their efficacy by utilizing rich sources of tumor-associated antigens for anti-cancer vaccination. In the present study, the testicular germ cells and sperm cells as well-known sources of cancer/testis antigens were investigated for anti-4T1 breast cancer vaccination in BALB/c mice. The testicular germ cells (TGCs) and sperm cells were isolated from male BALB/c mice. The definite number of cells were homogenized and mixed with Bacillus Calmette-Guerin (BCG) for vaccination of female BALB/c mice. The treatment groups underwent 3 times of immunizations with one-week intervals and one week after the last injection, all groups were injected with 4T1 cancer cells. The TGCs + BCG (259.7 ±â€¯39 mm3) and Sperm + BCG (426 ±â€¯52 mm3) groups exhibited a significant decrease in the tumors' volume in comparison with BCG (641.3 ±â€¯102 mm3) and no-treatment (788.1 ±â€¯117 mm3) groups. Therefore, the TGCs + BCG immunized mice had the smallest tumors in comparison with all groups (P < 0.05). Also, the vital organs of TGCs + BCG (lungs: 6.8 ±â€¯2, liver: 10.1 ±â€¯2) immunized mice exhibited lowest metastatic burden in comparison with the Sperm + BCG (lungs: 13.5 ±â€¯3, liver: 21.1 ±â€¯4), BCG (lungs: 24.3 ±â€¯4, liver: 33 ±â€¯4), and no-treatment (lungs: 26.5 ±â€¯6, liver: 37.3 ±â€¯3) groups. These observations were inconsistent with the tumor-bearing mice survival evaluations as the TGCs + BCG group had longer mean survival time (79.6 ±â€¯12 days) in comparison with other groups (no-treatment: 49.8 ±â€¯8, BCG: 50.5 ±â€¯10, BCG + Sperm: 64.6 ±â€¯7 days). Therefore, TGCs can be a potential source of antigens for the anti-breast cancer immunization and more investigations are necessary.

In silico analysis of transmembrane protein 31 (TMEM31) antigen to design novel multiepitope peptide and DNA cancer vaccines against melanoma.

Multiepitope cancer vaccines are announcing themselves as the future of melanoma treatment. Herein, high immunogenic regions of transmembrane protein 31 (TMEM31) antigen were selected according to cytotoxic T lymphocytes' (CTL) epitopes and major histocompatibility complex (MHC) binding affinity through in silico analyses. The 32-62, 77-105, and 125-165 residues of the TMEM31 were selected as the immunodominant fragments. They were linked together by RVRR and HEYGAEALERAG motifs to improve epitopes separation and presentation. In addition, to activate helper T lymphocytes (HTL), Pan HLA DR-binding epitope (PADRE) peptide sequence and tetanus toxin fragment C (TTFrC) were incorporated into the final construct. Also, the Beta-defensin conserved domain was utilized in the final construct as a novel adjuvant for Toll-like receptor 4/myeloid differentiation factor (TLR4-MD) activation. The CTL epitopes, cleavage sites, post-translational modifications, TAP transport efficiency, and B cells epitopes were predicted for the peptide vaccine. The final construct contained multiple CTL and B cell epitopes. In addition, it showed 93.55% and 99.13% population coverage in the world for HLA I and HLA II, respectively. According to these preliminary results, the multiepitope cancer vaccine can be an appropriate choice for further experimental investigations.

Investigation of different targeting decorations effect on the radiosensitizing efficacy of albumin-stabilized gold nanoparticles for breast cancer radiation therapy.

Gold nanoparticles (GNPs) radiosensitizing effect strongly depends on the tumor targeting efficacy. The aim of this study is to identify the most ideal targeting decoration for BSA-GNPs according to tumor targeting and biodistribution. Therefore, three well-known targeting agents (folic acid, glucose, and glutamine) were utilized for BSA-GNPs decoration. Glucose-BSA-GNPs, glutamine-BSA-GNPs, and folic acid-BSA-GNPs were synthesized and then, characterized by Fourier-transform infrared spectroscopy and UV-Spectrometry. Then, the GNPs were intravenously injected 10 mg/kg to 4T1 breast tumor-bearing mice to evaluate biodistribution and radiosensitizing effects. Folic acid and glutamine decorations could significantly increase tumor targeting efficacy of BSA-GNPs as 2.1 and 2.4 times increase of gold accumulation was detected in comparison with BSA-GNPs. They exhibited the highest radiosensitizing efficacy and caused about 33% decrease in tumors volume in comparison with BSA-GNPs after 6 Gy radiation therapy. All the GNPs were completely biocompatible. Although, glutamine-BSA-GNPs and folic acid-BSA-GNPs could significantly enhance the tumor targeting and radiosensitizing efficacy of BSA-GNPs, did not exhibit any significant advantage over each other. Therefore, glutamine and folic acid decoration of BSA-GNPs can significantly increase the tumor targeting and therapeutic efficacy as radiosensitizer.

Alive attenuated Salmonella as a cargo shuttle for smart carrying of gold nanoparticles to tumour hypoxic regions.

In the present study, alive attenuated Salmonella typhi Ty21a was introduced as a vehicle for smart delivery of gold nanoparticles to the tumours' hypoxic regions. At the first step, the uptakes of gold nanoparticles with seven different decorations by S. typhi Ty21a was investigated using flow cytometry and inductively coupled plasma optical emission spectroscopy. The analyses demonstrated that folic acid functionalised gold nanoparticles (FA-GNPs) are the best candidates for producing the Golden Bacteria (GB). Subsequently, the GB and FA-GNPs efficacies for tumour targeting were investigated after intravenous injection to CT-26 tumour-bearing mice. The GB exhibited more GNPs delivery to the tumour in comparison with FA-GNPs. Moreover, GB injection causes more delivery of GNPs to the tumours' central regions in comparison with tumours' periphery. This trend is completely in reverse for FA-GNPs injected group. The ratios of peripheral to central regions' gold concentration of the tumours were 1.95 ± 0.13 and 0.61 ± 0.10 for FA-GNPs and GB groups, respectively. This observation demonstrates higher accumulation of gold nanoparticles in the centre of the tumour due to their active delivery by the S. typhi Ty21a to the deeps of tumours.

Ultra-small but ultra-effective: Folic acid-targeted gold nanoclusters for enhancement of intracranial glioma tumors' radiation therapy efficacy.

The aim of the present study is to investigate folic acid and BSA decorated gold nanoclusters (FA-AuNCs) effect on the enhancement of intracranial C6 glioma tumors radiation therapy (RT) efficacy. Inductively coupled plasma optical emission spectrometry (ICP-OES) measurements exhibited about 2.5 times more FA-AuNCs uptake by C6 cancer cells (32.8 ng/106 cells) than the normal cells. FA-AuNCs had significantly higher concentration in the brain tumors (8.1 µg/mg) in comparison with surrounding normal brain tissue (4.3 µg/mg). Moreover, FA-AuNCs exhibited dose enhancement factor (DEF) of 1.6. The glioma-bearing rats' survival times were almost doubled at radiation therapy + FA-AuNCs (25.0 ±â€¯1.5 days) in comparison with no-treatment group (12.8 ±â€¯0.7 days). The Ki-67 labeling index was 48.89% ±â€¯9.93 for control, 29.98% ±â€¯8.32 for RT, and 11.53% ±â€¯7.65 for RT + FA-AuNCs. Therefore, FA-AuNCs can be effective radiosensitizers for intracranial glioma tumors RT.

AS1411 aptamer-targeted gold nanoclusters effect on the enhancement of radiation therapy efficacy in breast tumor-bearing mice.

AIM: Herein, the AS1411 aptamer-targeted ultrasmall gold nanoclusters (GNCs) were assessed at different aspects as a radiosensitizer. MATERIALS & METHODS: AS1411 aptamer-conjugated gold nanoclusters (Apt-GNCs) efficacy was evaluated at cancer cells targeting, radiosensitizing effect, tumor targeting, and biocompatibility in breast tumor-bearing mice. RESULTS: Flow cytometry and fluorescence microscopy exhibited more cellular uptake for Apt-GNCs in comparison with GNCs. In addition, inductively coupled plasma optical emission spectrometry results demonstrated its effective tumor targeting as the tumors' gold content for GNCs and Apt-GNCs were 8.53 and 15.33 µg/g, respectively. Apt-GNCs significantly enhanced radiotherapy efficacy as mean tumors' volume decreased about 39% and 9 days increase in the mice survival was observed. Both GNCs and Apt-GNCs were biocompatible. CONCLUSION: The Apt-GNCs is a novel and efficient  radiosensitizer.