Targeted poly(L-glutamic acid)-based hybrid peptosomes co-loaded with doxorubicin and USPIONs as a theranostic platform for metastatic breast cancer.

Peptosomes, as a vesicular polypeptide-based system and a versatile carrier for co-delivery of hydrophilic and hydrophobic materials, provide great delivery opportunities due to the intrinsic biocompatibility and biodegradability of the polypeptides backbone. In the current study, a novel poly(L-glutamic acid)-block-polylactic acid di-block copolymer (PGA-PLA) was synthesized in two steps. Firstly, γ-benzyl L-glutamate-N-carboxy anhydride (BLG-NCA) and 3,6-dimethyl-1,4-dioxane-2,5-dione were polymerized using N-hexylamine and benzyl alcohol as initiators to produce poly(γ-benzyl L-glutamate (PBLG) and polylactic acid. Then, PBLG was deprotected to produce PGA. Secondly, PGA was conjugated to the benzyl-PLGA to fabricate PGA-PLA diblock copolymer. The synthesized diblock copolymer was used for the encapsulation of doxorubicin, as hydrophilic anticancer and ultra-small superparamagnetic iron oxide nanoparticles (USPIONs) as hydrophobic contrast agent within aqueous core and bilayer of vesicular peptosome, respectively via double emulsion method. The prepared peptosomes (Pep@USPIONs-DOX) controlled the release of DOX (<15 % of the encapsulated DOX release up to 240 h of incubation at the physiological conditions) while increasing the stability and solubility of the hydrophobic USPIONs. Then, AS1411 DNA aptamer was decorated on the surface of the PGA-PLA peptosomes (Apt-Pep@USPIONs-DOX). The prepared targeted and non-targeted platforms showed spherical morphology with hydrodynamic sizes of 265 ± 52 and 229 ± 44 nm respectively. In vitro cellular cytotoxicity and cellular uptake were studied in nucleolin positive (4T1) and nucleolin negative (CHO) cell lines. Cellular uptake of the targeted formulation was greater than that of non-targeted peptosome, while cellular internalization of these peptosomes was identical in CHO cells. Moreover, targeted peptosomes showed greater toxicity than non-targeted peptosome in 4T1 cell line. The prepared theranostic targeted peptosomes demonstrated improved capability in terms of survival rate, biodistribution, tumor suppression efficiency, and MR imaging in the 4T1 tumor-bearing mice.

Synthesis of doxorubicin-loaded peptosomes hybridized with gold nanorod for targeted drug delivery and CT imaging of metastatic breast cancer.

BACKGROUND: Cancer nanomedicines based on synthetic polypeptides have attracted much attention due to their superior biocompatibility and biodegradability, stimuli responsive capability through secondary conformation change, adjustable functionalities for various cargos such as peptides, proteins, nucleic acids and small therapeutic molecules. Recently, a few nanoformulations based on polypeptides comprising NK105, NC6004, NK911, CT2103, have entered phase I-III clinical trials for advanced solid tumors therapy. In the current study, we prepared polypeptide-based vesicles called peptosome via self-assembly of amphiphilic polypeptide-based PEG-PBLG diblock copolymer. RESULTS: In this regard, poly(γ-benzyl L-glutamate (PBLG) was synthesized via ring opening polymerization (ROP) of γ-benzyl L-glutamate-N-carboxyanhydride (BLG-NCA) using N-hexylamine as initiator. Then amine-terminated PBLG was covalently conjugated to heterofuctional maleimide PEG-carboxylic acid or methyl-PEG-carboxylic acid. The PEG-PBLG peptosomes were prepared through double emulsion method for the co-delivery of doxorubicin.HCl and gold nanorods as hydrophilic and hydrophobic agents in interior compartment and membrane of peptosomes, respectively (Pep@MUA.GNR-DOX) that DOX encapsulation efficiency and loading capacity were determined 42 ± 3.6 and 1.68 ± 3.6. Then, theranostic peptosomes were decorated with thiol-functionalized EpCAM aptamer throught thiol-maleimide reaction producing Apt-Pep@MUA.GNR-DOX for targeted delivery. The non-targeted and targeted peptosomes showed 165.5 ± 1.1 and 185 ± 4.7 nm diameters, respectively while providing sustained, controlled release of DOX. Furthermore, non-targeted and targeted peptosomes showed considerable serum stability. In vitro study on MCF-7 and 4T1 cells showed significantly higher cytotoxicity for Apt-Pep@MUA.GNR-DOX in comparison with Pep@MUA.GNR-DOX while both system did not show any difference in cytotoxicity against CHO cell line. Furthermore, Apt-Pep@MUA.GNR-DOX illustrated higher cellular uptake toward EpCAM-overexpressing 4T1 cells compared to Pep@MUA.GNR-DOX. In preclinical stage, therapeutic and diagnostic capability of the prepared Pep@MUA.GNR-DOX and Apt-Pep@MUA.GNR-DOX were investigated implementing subcutaneous 4T1 tumor model in BALB/c mice. The obtained data indicated highest therapeutic index for Apt-Pep@MUA.GNR-DOX compared to Pep@MUA.GNR-DOX and free DOX. Moreover, the prepared system showed capability of CT imaging of tumor tissue in 4T1 tumorized mice through tumor accumulation even 24 h post-administration. CONCLUSION: In this regard, the synthesized theranostic peptosomes offer innovative hybrid multipurpose platform for fighting against breast cancer.

Three-dimensional (3D) Visualization Educational Modeling for Ophthalmology Residents' Training: Viewpoints.

Background: Three-dimensional models are used to guide residents and physicians in accessing specific anatomical areas and types of fractures and better diagnosis of anomalies. These models are useful for illuminating complex anatomical areas, such as orbit, especially limited space with sensitive access. The aim of this study was to design a three-dimensional visualization educational modeling for ophthalmology residents' training. Methods: This study is a product-oriented application that uses radiological images of anatomy, anomalies, and orbital fractures based on actual CT scans of patients. These CT scans were carefully selected from the Picture Archiving and Communication System of Ghaem Hospital of Mashhad University of Medical Sciences. Results: To produce twelve 3D models, the CT scan files were converted to 3D printer output. Then, the models were presented to residents at a training session by an ophthalmologist. These models created all major fractures associated with the orbit area and most disorders, anomalies of this area and several normal anatomical. The features of 3D models were mentioned. The strengths and weaknesses of the educational modeling, the level of satisfaction with the use of three-dimensional models, suggestions and criticisms were assessed qualitatively by the residents. Satisfaction was reported 100% by residents. Suggestions for future 3D models were presented, and the only criticism was fear of exams and grades. Conclusion: Real-size 3D modeling help to understand the spatial and mental imagery of anatomy and orbital pathology and to touch different anatomical areas creates a clear image in the minds of residents, especially in the orbit.

Improving anti-cancer drug delivery performance of magnetic mesoporous silica nanocarriers for more efficient colorectal cancer therapy.

BACKGROUND: Improving anti-cancer drug delivery performance can be achieved through designing smart and targeted drug delivery systems (DDSs). For this aim, it is important to evaluate overexpressed biomarkers in the tumor microenvironment (TME) for optimizing DDSs. MATERIALS AND METHODS: Herein, we designed a novel DDS based on magnetic mesoporous silica core-shell nanoparticles (SPION@MSNs) in which release of doxorubicin (DOX) at the physiologic pH was blocked with gold gatekeepers. In this platform, we conjugated heterofunctional polyethylene glycol (PEG) onto the outer surface of nanocarriers to increase their biocompatibility. At the final stage, an epithelial cell adhesion molecule (EpCAM) aptamer as an active targeting moiety was covalently attached (Apt-PEG-Au@NPs-DOX) for selective drug delivery to colorectal cancer (CRC) cells. The physicochemical properties of non-targeted and targeted nanocarriers were fully characterized. The anti-cancer activity, cellular internalization, and then the cell death mechanism of prepared nanocarriers were determined and compared in vitro. Finally, tumor inhibitory effects, biodistribution and possible side effects of the nanocarriers were evaluated in immunocompromised C57BL/6 mice bearing human HT-29 tumors. RESULTS: Nanocarriers were successfully synthesized with a mean final size diameter of 58.22 ± 8.54 nm. Higher cytotoxicity and cellular uptake of targeted nanocarriers were shown in the EpCAM-positive HT-29 cells as compared to the EpCAM-negative CHO cells, indicating the efficacy of aptamer as a targeting agent. In vivo results in a humanized mouse model showed that targeted nanocarriers could effectively increase DOX accumulation in the tumor site, inhibit tumor growth, and reduce the adverse side effects. CONCLUSION: These results suggest that corporation of a magnetic core, gold gatekeeper, PEG and aptamer can strongly improve drug delivery performance and provide a theranostic DDS for efficient CRC therapy.

Bone defect healing is induced by collagen sponge/polyglycolic acid.

We have evaluated the capability of a collagen/poly glycolic acid (PGA) scaffold in regeneration of a calvarial bone defects in rabbits. 4 bone critical size defects (CSD) were created in the calvarial bone of each rabbit. The following 4 treatment modalities were tested (1) a collagen/PGA scaffold (0.52% w/w); (2) the collagen/PGA scaffold (0.52% w/w) seeded with adipose-derived mesenchymal stem cells (AD-MSCs, 1 × 106 cells per each defect); (3) AD-MSCs (1 × 106 cells) no scaffold material, and (4) blank control. The rabbits were then divided into 3 random groups (of 5) and the treatment outcomes were evaluated at 4, 8 and 12 weeks. New bone formation was histologically assessed. Experimental groups were analyzed by CT scan and real-time PCR. Histological analysis of bone defects treated with collagen/PGA alone exhibited significant fibrous connective tissue formation at the 12 weeks of treatments (P ≤ 0.05). There was no significant difference between collagen/PGA alone and collagen/PGA + AD-MSCs groups. The results were confirmed by CT scan data showing healing percentages of 34.20% for the collage/PGA group alone as compared to the control group and no difference with collagen/PGA containing AD-MSCs (1 × 106 cells). RT-PCR analysis also indicated no significant differences between collagen/PGA and collagen/PGA + AD-MSC groups, although both scaffold containing groups significantly express ALP and SIO rather than groups without scaffolds. Although there was no significant difference between the scaffolds containing cells with non-cellular scaffolds, our results indicated that the Collagen/PGA scaffold itself had a significant effect on wound healing as compared to the control group. Therefore, the collagen/PGA scaffold seems to be a promising candidate for research in bone regeneration.

Diagnostic accuracy of cone-beam computed tomography in the evaluation of chronic rhinosinusitis.

INTRODUCTION: This study assessed the agreement of cone-beam computed tomography (CBCT) scan and sinus endoscopy findings and attempted to find a diagnostic accuracy of CBCT in patients with chronic rhinosinusitis (CRS). METHODS: Forty-two patients with CRS referred to the Aria and 22 Bahman Hospitals in Mashhad, Iran, during the year 2011 were included in this cross-sectional study. Paranasal sinus CBCT scanning and endoscopy were performed in all patients. The sensitivity, specificity, positive and negative predictive values (PPV and NPV), and accuracy of CBCT were determined, and the agreement between CBCT and endoscopy findings was evaluated. RESULTS: In most of our findings, except for infundibulum thickening, there was a strong agreement between CBCT and paranasal sinus endoscopy, with a kappa coefficient >0.80 (p < 0.05). The sensitivity, specificity, PPV, NPV, and accuracy of CBCT were >80% for most of the findings, except for infundibulum thickening and septal deviation. CONCLUSION: CBCT has nearly the same diagnostic accuracy as sinus endoscopy. The accuracy of CBCT scanning is high, and CBCT findings are well correlated with sinus endoscopy findings. Considering its high accuracy and lower costs and radiation doses, CBCT may be a proper alternative method for diagnostic sinus endoscopy in the assessment of CRS in patients with a contraindication for sinus endoscopy.

Hybridized quantum dot, silica, and gold nanoparticles for targeted chemo-radiotherapy in colorectal cancer theranostics.

Multimodal nanoparticles, utilizing quantum dots (QDs), mesoporous silica nanoparticles (MSNs), and gold nanoparticles (Au NPs), offer substantial potential as a smart and targeted drug delivery system for simultaneous cancer therapy and imaging. This method entails coating magnetic GZCIS/ZnS QDs with mesoporous silica, loading epirubicin into the pores, capping with Au NPs, PEGylation, and conjugating with epithelial cell adhesion molecule (EpCAM) aptamers to actively target colorectal cancer (CRC) cells. This study showcases the hybrid QD@MSN-EPI-Au-PEG-Apt nanocarriers (size ~65 nm) with comprehensive characterizations post-synthesis. In vitro studies demonstrate the selective cytotoxicity of these targeted nanocarriers towards HT-29 cells compared to CHO cells, leading to a significant reduction in HT-29 cell survival when combined with irradiation. Targeted delivery of nanocarriers in vivo is validated by enhanced anti-tumor effects with reduced side effects following chemo-radiotherapy, along with imaging in a CRC mouse model. This approach holds promise for improved CRC theranostics.

Synthesis of folate targeted theranostic cubosomal platform for co-delivery of bismuth oxide and doxorubicin to melanoma in vitro and in vivo.

Liquid crystalline nanoparticles (LCNPs) have gained much attention in cancer nanomedicines due to their unique features such as high surface area, storage stability, and sustained-release profile. In the current study, a novel LCNP for co-encapsulation of Bi2O3 and hydrophilic doxorubicin (DOX) was fabricated and functionalized with folic acid (FA) to achieve efficient tumor targeting toward CT-scan imaging and chemotherapy of melanoma in vitro and in vivo. LCNPs Bi2O3 NPs were prepared using glycerol monooleate-pluronic F-127 (GMO/PF127/water). Firstly, GMO/water were homogenized to prepare LC gel. Then, the stabilizer aqueous solution (PF127/Bi2O3/DOX) was added to the prepared LC gel and homogenized using homogenization and ultrasonication. The formulated NPs exhibited superior stability with encapsulation efficiency. High cytotoxicity and cellular internalization of the FA-Bi2O3-DOX-NPs were observed in comparison with Bi2O3-DOX-NPs and the free DOX in folate-receptor (FR) overexpressing cells (B16F10) in vitro. Moreover, ideal tumor suppression with increased survival rate were observed in tumorized mice treated with FA-Bi2O3-DOX-NPs compared to those treated with non-targeted one. On the other hand, the CT-imaging ability of the Bi2O3-DOX-NPs was tested inB16F10 tumor-bearing mice. The obtained data indicated a high potential of the developed targeted theranostic FA-Bi2O3-DOX-NPs for diagnostics and treatment of melanoma.

Synthesis of targeted doxorubicin-loaded gold nanorod -mesoporous manganese dioxide core-shell nanostructure for ferroptosis, chemo-photothermal therapy in vitro and in vivo.

In the current study, a core-shell inorganic nanostructure comprising a gold nanorod core and -mesoporous manganese dioxide shell was synthesized. Then, the mesoporous manganese dioxide shell was loaded with doxorubicin (DOX) and then coated with pluronic F127 and pluronic F127-folic acid conjugate (1.5:1 wt ratio of pluronic F127: pluronic F127-folic acid conjugate) to prepare targeted final platform. In this design, mesoporous manganese dioxide acted as a reservoir for DOX loading, anti-hypoxia, and MRI contrast agent, while the gold nanorod core acted as a photothermal and CT scan imaging agent. DOX was encapsulated in the mesoporous manganese dioxide shell with a loading capacity and loading efficiency of 19.8 % ± 0.2 and 99.0 % ± 0.9, respectively. The in vitro release experiment showed the impact of glutathione (GSH), mildly acidic pH, and laser irradiating toward accelerated stimuli-responsive DOX release. The ·OH production of the prepared platform was verified by methylene blue (MB) decomposition reaction. Furthermore, thermal imaging exhibited the ability of the prepared platform to convert the NIR irradiation to heat. In vitro cytotoxicity tests on the folate receptor-positive 4 T1 cell line revealed the remarkable cytotoxicity of the targeted formulation compared to the nontargeted formulation (statistically significant). The MTT experiment demonstrated that exposure to laser 808 irradiation enhanced cytotoxicity of the targeted formulation (p < 0.0001). The production of ROS in 4 T1 cells following treatment with the targeted formulation was demonstrated by the dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay. Furthermore, in vivo investigations by implementing subcutaneous 4 T1 tumorized female BABL/c mice indicated that the prepared platform was an effective system in suppressing tumor growth by combining chemotherapy with PTT (photothermal therapy). Additionally, simultanous PTT and anti-hypoxic activity of this system showed potent tumor growth suppression impact. The percent of tumor size reduction in mice treated with FA-F127-DOX@Au-MnO2 + 808 nm laser compared to the control group was 99.7 %. The results of the biodistribution investigation showed tumor accumulation and modified pharmacokinetics of the targeted system. Lastly, 6 and 24 h post-intravenous injection, CT-scan and MR imagings capability of the prepared platform was verified in preclinical stage. The prepared multipurpose system introduces great opportunity to provide multiple treatment strategy along with multimodal imaging capability in a single platform for breast cancer treatment.

Targeted doxorubicin-loaded core-shell copper peroxide-mesoporous silica nanoparticles for combination of ferroptosis and chemotherapy of metastatic breast cancer.

In the current study, a tumor microenvironment responsive (TME-responsive) copper peroxide-mesoporous silica core-shell structure with H2O2 self-supplying ability was fabricated for targeted ferroptosis/chemotherapy against metastatic breast cancer. At the first stage, copper peroxide nanodot was synthesized and subsequently coated with mesoporous organosilica shell. After (3-Aminopropyl) triethoxysilane (APTMS) functionalization of the organosilica shell, doxorubicin (DOX) was loaded in the mesoporous structure of the nanoparticles and then, heterofunctional COOH-PEG-Maleimide was decorated on the surface through EDC/NHS chemistry. Afterward, thiol-functionalized AS1411 aptamer was conjugated to the maleimide groups of the PEGylated nanoparticles. In vitro study illustrated ROS generation of the system in the treated 4 T1 cell. Cellular uptake and cytotoxicity experiments showed enhanced internalization and cytotoxicity of the targeted system comparing to non-targeted one. The in vivo study on ectopic 4 T1 tumor induced in Female BALB/c mice showed ideal therapeutic effect of Apt-PEG-Silica-DOT@DOX with approximately 90 % tumor suppression in comparison with 50 % and 25 % tumor suppression for PEG-Silica-DOT@DOX and PEG-Silica-DOT. Moreover, Apt-PEG-Silica-DOT@DOX provide favorable characteristics for biosafety issues concerning the rate of survival and loss of body weight. The prepared platform could serve as a multifunctional system with smart behavior in drug release, tumor accumulation and capable for ferroptosis/chemotherapy against breast cancer.

Preparation of targeted theranostic red blood cell membranes-based nanobubbles for treatment of colon adenocarcinoma.

OBJECTIVES: Designing and fabrication of theranostic systems based on nanoscale gaseous vesicular systems, named nanobubbles (NBs), attracted enormous interest in recent years. Biomimetic vesicular platform (V-RBC-M) can improve the pharmacokinetics of the prepared platform due to augmented circulation half-life, desirable biodegradability and biocompatibility and reduced immunogenicity. METHODS: V-RBC-M were used for the encapsulation of lipophilic camptothecin (CPT) in the bilayer of vesicles through top-down method, followed by filling the core of V-RBC-M with inert SF6 gas to fabricate NBs with ultrasonic contrast enhancement capability (SF6-NB-CPT). In the next step, targeted NBs were formed via decoration of MUC1 aptamer on the surface of NBs (Apt-SF6-NB-CPT). RESULTS: The designed bio-NBs indicated high encapsulation efficiency and the sustained release of CPT at pH 7.4. In vitro study demonstrated higher cellular uptake and cytotoxicity of Apt-SF6-NB-CPT compared to SF6-NB-CPT in MUC1-overexpressing cells (C26). In vivo antitumor efficacy of the prepared NBs on C26 bearing BALB/c mice showed greater therapeutic efficacy and survival rate for Apt-SF6-NB-CPT. In this regard, SF6-NB-CPT showed 58% tumor growth suppression while Apt-SF6-NB-CPT system provided 95% tumor growth suppression. Furthermore, echogenic capability of SF6-NB-CPT was demonstrated through in vitro and in vivo ultrasonic imaging. CONCLUSIONS: Our finding demonstrated that the prepared targeted NBs are a promising theranostic platform with effective therapeutic and diagnotic potentials.

Surface engineering of hollow gold nanoparticle with mesenchymal stem cell membrane and MUC-1 aptamer for targeted theranostic application against metastatic breast cancer.

Mesenchymal stem cell membrane (MSCM)-coated biomimetic doxorubicin-loaded hollow gold nanoparticles were fabricated and decorated with MUC1 aptamer in order to provide smart theranostic platform. The prepared targeted nanoscale biomimetic platform was extensively characterized and evaluated in terms of selective delivery of DOX and CT-scan imaging. The fabricated system illustrated spherical morphology with 118 nm in diameter. Doxorubicin was loaded into the hollow gold nanoparticles through physical absorption technique with encapsulation efficiency and loading content of 77%±10 and 31%±4, respectively. The in vitro release profile demonstrated that the designed platform could respond to acidic environment, pH 5.5 and release 50% of the encapsulated doxorubicin during 48 h, while 14% of the encapsulated doxorubicin was released in physiological condition, pH 7.4 up to 48 h. The in vitro cytotoxicity experiments on 4T1 as MUC1 positive cell line illustrated that the targeted formulation could significantly increase mortality at 0.468 and 0.23 µg/ml of equivalent DOX concentration compared to non-targeted formulation while this cytotoxicity was not observed in CHO as MUC1 negative cell line. Furthermore, in vivo experiments showed high tumor accumulation of the targeted formulation even 24 h after intravenous injection which induced effective tumor growth suppression against 4T1 tumor bearing mice. On the other hand, existence of hollow gold in this platform provided CT scan imaging capability of the tumor tissue in 4T1 tumor bearing mice up to 24 h post-administration. The obtained results indicated that the designed paradigm are promising and safe theranostic system for fighting against metastatic breast cancer.

Using magnetic mesoporous silica nanoparticles armed with EpCAM aptamer as an efficient platform for specific delivery of 5-fluorouracil to colorectal cancer cells.

Background: Theranostic nanoparticles with both imaging and therapeutic capacities are highly promising in successful diagnosis and treatment of advanced cancers. Methods: Here, we developed magnetic mesoporous silica nanoparticles (MSNs) loaded with 5-fluorouracil (5-FU) and surface-decorated with polyethylene glycol (PEG), and epithelial cell adhesion molecule (EpCAM) aptamer (Apt) for controlled release of 5-FU and targeted treatment of colorectal cancer (CRC) both in vitro and in vivo. In this system, Au NPs are conjugated onto the exterior surface of MSNs as a gatekeeper for intelligent release of the anti-cancer drug at acidic conditions. Results: Nanocarriers were prepared with a final size diameter of 78 nm, the surface area and pore size of SPION-MSNs were calculated as 636 m2g-1, and 3 nm based on the BET analysis. The release of 5-FU from nanocarriers was pH-dependent, with an initial rapid release (within 6 h) followed by a sustained release for 96 h at pH 5.4. Tracking the cellular uptake by flow cytometry technique illustrated more efficient and higher uptake of targeted nanocarriers in HT-29 cells compared with non-targeted formula. In vitro results demonstrated that nanocarriers inhibited the growth of cancer cells via apoptosis induction. Furthermore, the targeted NPs could significantly reduce tumor growth in immunocompromised C57BL/6 mice bearing HT-29 tumors, similar to those injected with free 5-FU, while inducing less side effects. Conclusion: These findings suggest that application of Apt-PEG-Au-NPs@5-FU represents a promising theranostic platform for EpCAM-positive CRC cells, although further experiments are required before it can be practiced in the clinic.

Synthesis of manganese-incorporated polycaplactone-poly (glyceryl methacrylate) theranostic smart hybrid polymersomes for efficient colon adenocarcinoma treatment.

In the current study, a multifunctional nanoscale vesicular system (polymersome) with the ability to accumulate in the site of action, control drug release and integrate diagnostic and therapeutic functions was developed. The theranostic polymersome was engineered as a promising dual-functional nanoplatform, which can be used for tumor therapy and magnetic resonance imaging (MRI). In this regard, the amphiphilic diblock copolymer of poly(ε-caprolactone)-block-poly(glyceryl methacrylate)[(PCL-b-PGMA)] was synthesized by combined ring-opening polymerization (ROP), and reversible addition-fragmentation chain-transfer (RAFT) polymerization techniques followed by hydrolysis of the pendant oxiran rings to hydroxyl groups. Because of the amphiphilic properties and desirable hydrophobic/hydrophilic balance of the synthesized copolymer, it could self-assemble to form a polymersomal structure in an aqueous environment (with diameters about 100-145 nm). The hydrophilic anticancer drug, doxorubicin (DOX) and hydrophobic paramagnetic Mn (phenanthroline)2 complex, being well-represented on T1-weighted magnetic resonance imaging (MRI), were encapsulated in the hydrophilic core (33%±2.3 efficiency) and hydrophobic bilayer membrane (100 %efficient) of a polymersome system, respectively to provide PCL-PGMA@Mn(phen)2/DOX NPs. It was found that adding aptamer AS1411 to NPs surfaces enhanced their specificity and selectivity towards colorectal cancer cells expressing nucleolin (HT29 and C26). In vivo evaluation after intravenous administration of the prepared platform was performed using subcutaneous C26 tumor-bearing Balb/C mice. The obtained results demonstrated that the prepared targeted platform provided a reduced systemic toxicity in terms of body weight loss and mortality while showing efficient tumor regression. Furthermore, the prepared theranostic platform afforded MRI imaging capability for tumor monitoring. It could be concluded that the biocompatible PCL-PGMA magnetic DOX-loaded polymersomes could serve as a versatile multifunctional system for simultaneous tumor imaging and therapy.

Synthesis of a targeted, dual pH and redox-responsive nanoscale coordination polymer theranostic against metastatic breast cancer in vitro and in vivo.

BACKGROUND: Nanoscale coordination polymers (nCP) have exhibited a great potential in designing of the theranostic platforms in the latest years. However, they have low selectivity for cancerous tissues and require to be modified for becoming effective cancer therapeutics. In this study, a novel nanoscale pH and redox-responsive coordination polymer with high selectivity was synthesized. METHODS: The nCP was synthesized by iron(III) chloride and dithiodiglycolic acid. After loading the prepared nCP with doxorubicin (DOX), nCP was coated with an amphiphilic copolymer composed of α-tocopheryl succinate-polyethylene glycol (VEP). Next, AS1411 aptamer was decorated on the VEP shell of the DOX-loaded nCP (Apt-VEP-nCP@DOX) to provide a guided drug delivery platform. RESULTS: The prepared platform demonstrated high DOX loading capacity and pH and redox-responsive DOX release. Apt-VEP-nCP@DOX displayed greater DOX internalization and toxicity toward breast cancer cells of 4T1 and MCF7 compared with that of non-targeted VEP-nCP@DOX. Also, the intravenous injection of Apt-VEP-nCP@DOX (a single dose) considerably suppressed the 4T1 tumor growth in vivo. Moreover, Apt-VEP-nCP@DOX showed outstanding magnetic resonance (MR) imaging capability for 4T1 adenocarcinoma diagnosis in ectopic 4T1 tumor model in mice. CONCLUSIONS: The developed innovative intelligent Apt-VEP-nCP@DOX could serve as a safe and biocompatible theranostic platform appropriate for further translational purposes against breast cancer.

3D Printed Models for Teaching Orbital Anatomy, Anomalies and Fractures.

PURPOSE: The aim of this study was to determine the efficacy of using 3D printing models in the learning process of orbital anatomy and pathology by ophthalmology residents. METHODS: A quasi-experimental study was performed with 24 residents of ophthalmology at Mashhad University of Medical Sciences. Each stratum was randomized into two groups. The educational booklets were distributed, and various forms of orbital 3D models were printed from orbital computed tomography (CT) scans. Knowledge enhancement on the topics was measured by comparing pretest and posttest scores. RESULTS: Thirteen residents who were trained using traditional methods were deemed the control group; while 11 residents who were trained using the 3D printed models were classed as the intervention group. The control group was younger than the intervention group (P = 0.047). The results showed that there was a statistically significant difference in the total posttest scores between the two groups. Based on the repeated measures of the analysis of variance (ANOVA), score variables were significant between the two groups (P = 0.008). Interestingly, the use of the 3D educational model was more effective and statistically significant with the year one residents as compared to the year two residents (P = 0.002). CONCLUSION: This study is the first one in Iran quantifying the effects of learning using 3D printed models in medical education. In fact, 3D modeling training is seemingly effective in teaching ophthalmic residents. As residents have never encountered such technology before, their experience using 3D models proved to be satisfactory and had a surprising positive effect on the learning process through visual training.

Evaluation of DWI and ADC Sequences' Diagnostic Values in Benign and Malignant Pulmonary Lesions.

OBJECTIVE: The gold standard for the diagnosis of lung cancer is conducting a histopathologic study. It is also diagnosed based on some features of a computed tomography (CT) scan. Imposed radiation is a prominent side effect of a CT scan. Diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC) images have currently been used in the diagnosis of different lesions, including those of the brain and breast, and their uses in lung lesions are being evaluated. In this study, to find a safe, sensitive, and specific method, we aimed to assess DWI imaging to replace the CT scan and the positron emission tomography scan. MATERIAL AND METHODS: A total of 29 patients were enrolled in the study. In b800 images in DWI, spinal cord and lesion signals were measured, and the lesion-to-cord-signal ratio (LCR) was calculated. The ADC value was measured in a quantitative way. Lesions were also graded qualitatively in b800 DWI sequences. RESULTS: There was a significant difference between malignant and benign lesions in terms of DWI grading in b800 images (p<0.001). There was a significant difference between ADC means of a malignant and benign lesion (p=0.003). The mean LCR for malignant lung lesions was significantly higher than that of the benign ones (p<0.001). Considering Grade 3 as the cutoff in DWI grading results in sensitivity, specificity, and accuracy of 89%, 90%, and 89.6%, respectively. For ADC values, sensitivity, specificity, and accuracy of 79%, 80%, and 79.3%, respectively, were obtained when the cutoff was 1.027×10-3 sec/mm2. The sensitivity of 84%, the specificity of 90%, and the accuracy of 86.2% were calculated for the LCR in a cutoff of 0.983. In this study, all three parameters had an area under the curve of ≥0.8, meaning that these variables were valuable for the differentiation of benign and malignant lesions. CONCLUSION: Diffusion-weighted magnetic resonance imaging is a noninvasive tool, with no contrast agent and requiring ionizing radiations, which could be used for the qualitative, quantitative, and semiquantitative assessment of pulmonary lesions.

Synthesis of multimodal polymersomes for targeted drug delivery and MR/fluorescence imaging in metastatic breast cancer model.

The objective of the current study is to design and delivery of targeted PEG-PCL nanopolymersomes encapsulated with Gadolinium based Quantum Dots (QDs) and Doxorubicin (DOX) as magnetic resonance-florescence imaging and anti-cancer agent. Diagnostic and therapeutic efficiency of the prepared theranostic formulation was evaluated in vitro and in vivo. Hydrophobic QDs based on indium-copper-gadolinium-zinc sulfide were synthesized and characterized extensively. Hydrophobic QDs and hydrophilic DOX were loaded in PEG-PCL polymersomes through double emulsion method. Drug release pattern was studied in both citrate (pH 5.4) and phosphate (pH 7.4) buffer during 10 days. Both fluorescence and magnetic properties of bare QDs and prepared formulations were studied entirely. AS1411 DNA aptamer was covalently attached to the surface of polymersomal formulation in order to prepare targeted drug delivery system. Cellular cytotoxicity and cellular uptake analysis were performed in both nucleolin positive (MCF7 and 4T1) and nucleolin negative (CHO) cell lines. After in vitro evaluations, anti-tumor efficiency and diagnostic capability of the formulation was investigated in 4T1 tumor baring mice. Scanning emission electron microscopy (SEM) confirmed spherical shape and around 100 nm size of prepared formulations. Transmission electron microscopy (HRTEM) showed crystal shape of QDs with size of 2-3 nm. Drug release study obtained controlled release of encapsulated DOX and stability of formulation in physiologic condition. MTT and flow cytometry results demonstrated that AS1411 aptamer could enhance both toxicity and cellular uptake in nucleolin overexpressing cell lines (P < 0.05). Moreover, aptamer targeted formulation could increase survival rate and tumor inhibitory growth effect in 4T1 tumor baring mice (P < 0.05). Our results verify that aptamer targeted polymersomes loaded with non-toxic QDs as a diagnostic agent and DOX as an anti-cancer drug, could provide a theranostic platform with the purpose of optimization of treatment process and minimization of systemic side effects.

A new approach to automatic fetal brain extraction from MRI using a variational level set method.

BACKGROUND AND PURPOSE: Appropriate images extracted from the MRI of mothers' wombs can be of great help in the medical diagnosis of fetal abnormalities. As maternal tissue may appear in such images, affecting visualization of myelination of the fetal brain, it is not possible to use methods routinely used for extraction of adult brains for fetal brains. The aim of the present study was to use a variational level set approach to extract fetal brain from T2-weighted MR images of the womb. METHODS: Coronal T2-weighted images were acquired using fast MRI protocols (to avoid artifacts). The database includes 105 MR images from eight subjects. After correcting the inhomogeneity of the images, the fetal eyes were located, and from that information, the location of the fetus brain was automatically determined. Then, the variational level set was used for fetus brain extraction. The results were analyzed by a clinical specialist (radiologist) and the similarity (Dice and Jaccard coefficients), sensitivity and specificity were calculated. RESULTS AND CONCLUSIONS: The means of the statistical analysis for the Dice and Jaccard coefficients, sensitivity and specificity, were 99.56%, 96.89%, 95.71%, and 97.96%, respectively. Thus, extraction of fetal brain from MR images was confirmed, both statistically and visually through cross-validation.