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Yousefpour P, Atyabi F, Vasheghani-Farahani E, Movahedi M, Dinarvand R. Int J Nanomedicine. 2011;6:1977—1990. The authors have advised Figure 9D on page 1986 is incorrect. Due to an error at the time of figure assembly Figure 9B and D were duplicated. The correct Figure 9 is shown below. Figure 9 Fluorescence microscopy of cellular uptake of (A) trastuzumab-decorated chitosan-doxorubicin conjugated nanoparticles by SKOV-3 cell line, (B) trastuzumab-decorated chitosan-doxorubicin conjugated nanoparticles by MCF-7 cell line, (C) chitosan-doxorubicin conjugated nanoparticles by SKOV-3 cell line, and (D) chitosan-doxorubicin conjugated nanoparticles by MCF-7 cell line. (E) SKOV-3 cells and (F) MCF-7 cells in cell culture medium served as negative controls. The authors previously requested a corrigendum to correct this error soon after publication but it was not actioned due to communication issues between the journal and authors. The authors have now contacted the journal again several years later to request the same corrigendum in relation to the same error. The authors apologize for the error and advise it does not affect the results of the paper.

Azam Shamsian,1,2 Mohammad Reza Sepand,3 Marziye Javaheri Kachousangi,1,2 Tahereh Dara,4 Seyed Nasser Ostad,3 Fatemeh Atyabi,1,2 Mohammad Hossein Ghahremani1,3 1Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 4Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranCorrespondence: Mohammad Hossein GhahremaniDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, New Building, Room 2-318, Tehran 1417614411, IranTel/Fax +982166959102Email mhghahremani@tums.ac.irBackground: Among various theories for the origin of cancer, the “stemness phenotype model” suggests a dynamic feature for tumor cells in which non-cancer stem cells (non-CSCs) can inter-convert to CSCs. Differentiation with histone-deacetylase inhibitor, vorinostat (SAHA), can induce stem cells to differentiate as well as enforces non-CSCs to reprogram to CSCs. To avoid this undesirable effect, one can block the Wnt-βcatenin pathway. Thus, a dual delivery system of SAHA and a Wnt-βcatenin blocker will be beneficial in the induction of differentiation of CSCs. Protein corona (PC) formation in nanoparticle has a biologic milieu, and despite all problematic properties, it can be employed as a medium for dual loading of the drugs.Materials and Methods: We prepared sphere gold nanoparticles (GNPs) with human plasma protein corona loaded with SAHA as differentiating agent and PKF118-310 (PKF) as a Wnt-βcatenin antagonist. The MCF7 breast cancer stem cells were treated with NPs and the viability and differentiation were evaluated by Western blotting and sphere formation assay.Results: We found that both drugs loaded onto corona-capped GNPs had significant cytotoxicity in comparison to bare GNP-corona. Data demonstrated an increase in stem cell population and upregulation of mesenchymal marker, Snail by SAHA-loaded GNPs treatment; however, the combination of PKF loaded GNPs along with SAHA-loaded GNPs resulted in a reduction of stem cell populations and Snail marker. We have shown that in MCF7 and its CSCs simultaneous treatment with SAHA and PKF118-310 induced differentiation and inhibition of Snail induction.Conclusion: Our study reveals the PC-coated GNPs as a biocompatible career for both hydrophilic (PKF) and hydrophobic (SAHA) agents which can decrease breast cancer stem cell populations along with reduced stemness state regression.Keywords: co-delivery, HDAC inhibitor, Wnt, cancer stem cell, protein corona

Talaie F, Azizi E, Dinarvand R, Atyabi F. Int J Nanomedicine. 2011;6:1963‒1975. The Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. Concerns were raised regarding the alleged duplication of images in Figures 3 and 7. Specifically, Figure 3A, chitosan nanoparticles, appears to have been duplicated with a similar image for Figure 3C, DOX-NAC-C nanoparticles. Figure 7B 1, FBS-free RPMI, appears to have been duplicated with a similar image for Figure 7B 7, NAP-C. Figure 7B 4, NAC-C, appears to have been duplicated with a similar image for Figure 7B 10, Chitosan. The authors responded to our queries but were unable to provide a satisfactory explanation for the duplicated images and the Editor requested for the article to be retracted. The authors were notified of this decision. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Barbari GR, Dorkoosh FA, Amini M, et al. Int J Nanomedicine. 2017;12:3471–3483 The Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. Concerns were raised regarding the alleged duplication of features within the image shown in Figure 4. The first author responded to our queries but was unable to provide the original images for Figure 4. The first author explained they were responsible for the preparation of the SEM images and wishes to apologize to the readers and other authors for any errors that may have been introduced to the image which led to the retraction of the paper. However, all the authors accept responsibility for the integrity of the reported research and agree with the decision to retract the article. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Faezeh Vakhshiteh,1 Fatemeh Atyabi,1,2 Seyed Nasser Ostad3 1Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Abstract: Mesenchymal stem cells (MSCs) are multipotent stromal cells present in various adult tissues. Several studies suggest that MSCs secrete exosomes that perform as mediators in the tumor niche and play several roles in tumorigenesis, angiogenesis, and metastasis. In contrast, there are other studies supporting the tumor-suppressing effects of MSC-derived exosomes. Therefore, the exact association of MSC exosomes and tumor cells remains open to debate. This review aimed to demonstrate the present knowledge of MSC-derived exosomes in cancer research and to illustrate current approaches to make use of modified exosomes as a platform in therapeutic strategies in cancer. Keywords: mesenchymal stem cells, exosome, drug delivery, exosome engineering, cancer therapy

Maliheh Hajiramezanali,1 Fatemeh Atyabi,2,3 Mona Mosayebnia,1 Mehdi Akhlaghi,4 Parham Geramifar,4 Amir Reza Jalilian,4 Seyed Mohammad Mazidi,5 Hassan Yousefnia,6 Soraya Shahhosseini,7 Davood Beiki4 1Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 3Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 4Research Center for Nuclear Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran; 5Radiation Application Research School, Nuclear Science and Technology Research Institute (NSTRI), Tehran, Iran; 6Material and Nuclear Fuel Research School, Nuclear Science and Technology Research Institute (NSTRI), Tehran, Iran; 7Department of Radiopharmacy and Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran Introduction: Nowadays, nanoparticles (NPs) have attracted much attention in biomedical imaging due to their unique magnetic and optical characteristics. Superparamagnetic iron oxide nanoparticles (SPIONs) are the prosperous group of NPs with the capability to apply as magnetic resonance imaging (MRI) contrast agents. Radiolabeling of targeted SPIONs with positron emitters can develop dual positron emission tomography (PET)/MRI agents to achieve better diagnosis of clinical conditions.Methods: In this work, N,N,N-trimethyl chitosan (TMC)-coated magnetic nanoparticles (MNPs) conjugated to S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA) as a radioisotope chelator and bombesin (BN) as a targeting peptide (DOTA–BN–TMC–MNPs) were prepared and validated using fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), thermogravimetric analysis (TGA), vibrating sample magnetometer (VSM), and powder X-ray diffraction (PXRD) tests. Final NPs were radiolabeled with gallium-68 (68Ga) and evaluated in vitro and in vivo as a potential PET/MRI probe for breast cancer (BC) detection.Results: The DOTA–BN–TMC–MNPs with a particle size between 20 and 30 nm were efficiently labeled with 68Ga (radiochemical purity higher than 98% using thin layer chromatography (TLC)). The radiolabeled NPs showed insignificant toxicity (>74% cell viability) and high affinity (IC50=8.79 µg/mL) for the gastrin-releasing peptide (GRP)-avid BC T-47D cells using competitive binding assay against 99mTc–hydrazinonicotinamide (HYNIC)–gamma-aminobutyric acid (GABA)–BN (7–14). PET and MRI showed visible uptake of NPs by T-47D tumors in xenograft mouse models.Conclusion: 68Ga–DOTA–BN–TMC–MNPs could be a potential diagnostic probe to detect BC using PET/MRI technique. Keywords: superparamagnetic iron oxide nanoparticles, trimethyl chitosan, bombesin, gallium-68, PET/MRI

Akram Assali,1 Omid Akhavan,2 Fatemeh Mottaghitalab,1 Mohsen Adeli,3 Rassoul Dinarvand,1 Shayan Razzazan,4 Ehsan Arefian,5 Masoud Soleimani,6 Fatemeh Atyabi1 1Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Physics, Sharif University of Technology, Tehran, Iran; 3Department of Biology, Chemistry, Pharmacy, Institute of Chemistry and Biochemistry, Freie University Berlin, Berlin, Germany; 4Department of Electrical Engineering, Amirkabir University of Technology, Tehran, Iran; 5Molecular Virology Lab, Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran; 6Hematology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran Introduction: MicroRNA-101 (miR-101) is an intense cancer suppressor with special algorithm to target a wide range of pathways and genes which indicates the ability to regulate apoptosis, cellular stress, metastasis, autophagy, and tumor growth. Silencing of some genes such as Stathmin1 with miR-101 can be interpreted as apoptotic accelerator and autophagy suppressor. It is hypothesized that hybrid microRNA (miRNA) delivery structures based on cationized graphene oxide (GO) could take superiority of targeting and photothermal therapy to suppress the cancer cells.Materials and methods: In this study, GO nanoplatforms were covalently decorated with polyethylene glycol (PEG) and poly-L-arginine (P-L-Arg) that reduced the surface of GO and increased the near infrared absorption ~7.5-fold higher than nonreduced GO.Results: The prepared nanoplatform [GO-PEG-(P-L-Arg)] showed higher miRNA payload and greater internalization and facilitated endosomal scape into the cytoplasm in comparison with GO-PEG. Furthermore, applying P-L-Arg, as a targeting agent, greatly improved the selective transfection of nanoplatform in cancer cells (MCF7, MDA-MB-231) in comparison with immortalized breast cells and fibroblast primary cells. Treating cancer cells with GO-PEG-(P-L-Arg)/miR-101 and incorporating near infrared laser irradiation induced 68% apoptosis and suppressed Stathmin1 protein.Conclusion: The obtained results indicated that GO-PEG-(P-L-Arg) would be a suitable targeted delivery system of miR-101 transfection that could downregulate autophagy and conduct thermal stress to activate apoptotic cascades when combined with photothermal therapy. Keywords: miR-101, cationized graphene oxide, poly-L-arginine, apoptosis, autophagy, photothermal therapy

Ghullam Reza Barbari,1 Farid Dorkoosh,1 Mohsen Amini,2 Nika Bahari Javan,1 Mohammad Sharifzadeh,3 Fateme Atyabi,1 Saeed Balalaie,4 Niyousha Rafiee Tehrani,5 Morteza Rafiee Tehrani1 1Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Medicinal Chemistry, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 4Department of Chemistry, Khajeh Nasir Toosi University, Tehran, Iran; 5School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Background: Despite years of experience and rigorous research, injectable insulin is the sole trusted treatment method to control the blood glucose level in diabetes type 1 patients, but injection of insulin is painful and poses a lot of stress to the patients, especially children, therefore, development of a non-injectable formulation of insulin is a major breakthrough in the history of medicine and pharmaceutical sciences. Methods: In this study, a novel peptide grafted derivative of chitosan (CPP-g- chitosan) is synthesized and its potential for oral delivery of proteins and peptides is evaluated. Drug-loaded nanoparticles were developed from this derivative using ionic gelation method with application of sodium tripolyphosphate (TPP) as a cross-linking agent. Human insulin was used as the model protein drug and release kinetic was studied at gastrointestinal pH. Finally the developed nanoparticles were filled into very tiny enteric protective capsules and its effects on blood glucose level are evaluated in laboratory animals. Results: Presence of the positively charged cell-penetrating peptide moiety in the structure of chitosan polymer had slight inhibitory effects on the release of insulin from the nanoparticles in simulated gastric fluid (pH 1.2) comparing to native chitosan. The nanoparticles were positively charged in gastrointestinal pH with size ranging from 180 nm to 326 nm. The polypeptide grafted to chitosan is a novel analog of Penetratin, presenting both the hydrophilic and hydrophobic characteristics altering the release behavior of the nanoparticles and significantly increase the absorption of insulin into the rat epithelium comparing to nanoparticles from simple chitosan. In-vivo results in diabetic rat proved that this nanoparticulate system can significantly lower the blood glucose levels in diabetic rats and remain effective for a duration of 9–11 hours. Conclusion: The results indicate that nanoparticles developed from this new peptide conjugated derivative of chitosan are very promising for oral delivery of proteins and peptides. Keywords: peptide grafted, oral delivery, cell-penetrating peptide, penetratin

Ghullam Reza Barbari,1 Farid Abedin Dorkoosh,1 Mohsen Amini,2 Mohammad Sharifzadeh,3 Fateme Atyabi,1 Saeed Balalaie,4 Niyousha Rafiee Tehrani,5 Morteza Rafiee Tehrani1 1Department of Pharmaceutics, 2Department of Medicinal Chemistry, 3Department of Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, 4Department of Chemistry, Khaje Nasiroddin University, 5Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Abstract: A simple and reproducible water-in-oil (W/O) nanoemulsion technique for making ultrasmall (

Barbari GR, Dorkoosh F, Amini M, et al. Synthesis and characterization of a novel peptide-grafted Cs and evaluation of its nanoparticles for the oral delivery of insulin, in vitro, and in vivo study. Int J Nanomed. 2018;13:5127–5138.The Editor in Chief and Publisher of International Journal of Nanomedicine wish to retract the published article. The journal was notified of the potential duplication of images in Figure 4 and Figure 5 of the published article. It was observed that Figure 5 was an inverted version of Figure 4. The authors were asked for an explanation but were unable to provide a satisfactory response or provide the original raw data for the images. It was determined the first author, Ghullam Reza Barbari, was solely responsible for preparing the images, however all the authors had approved of the final article for publication.The Editor in Chief determined the results and findings of the article were no longer valid and advised a retraction was the only course of action.The authors wish to apologise for this error.Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Abstract Background: The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a protective antigen and a major virulence factor of this bacteria. Stimulating the immune system for helicobacter infection treatment could have an important role. The aim of study is to assess the effect of recombinant Neutrophil activating protein (Hp-NapA) of helicobacter pylori on proliferation and viability of peritoneal macrophages from BALB/c mice. Materials and Methods: In this experimental study, recombinant Hp-NapA of helicobacter pylori was produced in vitro. Mice peritoneal macrophages were purified and cultured. Different concentrations of recombinant Hp-NapA was used for macrophages stimulation. MTT assay was performed to assess the viability and proliferation of macrophages. Results: The results elucidated that the increasing effect of stimulation with recombinant Hp-NapA was significant at the dose of 30 µg/ml(p=0.01). The rate of viabitity was significantly higher than control group at the doses of 30 and 60 µg/ml and in the concurrency series of recombinant protein with lipopolysaccharid, there was a statistically significarit increase in proliferation at just these doses. Conclusion: According to our findings, recombinant Hp-NapA has a positive effect on proliferation, viability and function of peritoneal macrophages. Therefore, it is proposed that recombinant Hp-NapA can be studied as an immunomodulator for immunotherapy.

Hosniyeh Hosseinzadeh1, Fatemeh Atyabi1, Rassoul Dinarvand1, Seyed Naser Ostad21Nanotechnology Research Centre, 2Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranAbstract: Nanoparticles have proven to be an effective delivery system with few side effects for anticancer drugs. In this study, gemcitabine-loaded nanoparticles have been prepared by an ionic gelation method using chitosan and Pluronic® F-127 as a carrier. Prepared nanoparticles were characterized using dynamic light scattering, Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), scanning electron microscopy, and transmission electron microscopy. Different parameters such as concentration of sodium tripolyphosphate, chitosan, Pluronic, and drug on the properties of the prepared nanoparticles were evaluated. In vitro drug release was studied in phosphate-buffered saline (PBS; pH = 7.4). The cytotoxicity of the nanoparticles was assayed in the HT-29 colon cancer cell line. The mucoadhesion behavior of the nanoparticles was also studied by mucus glycoprotein assay. The prepared nanoparticles had a spherical shape with positive charge and a mean diameter ranging between 80 to 170 nm. FT-IR and DSC studies found that the drug was dispersed in its amorphous form due to its potent interaction with nanoparticle matrix. Maximum drug encapsulation efficiency was achieved at 0.4 mg/mL gemcitabine while maximum drug loading was 6% obtained from 0.6 mg/mL gemcitabine. An in vitro drug release study at 37°C in PBS (pH = 7.4) exhibited a controlled release profile for chitosan–Pluronic® F-127 nanoparticles. A cytotoxicity assay of gemcitabine-loaded nanoparticles showed an increase in the cytotoxicity of gemcitabine embedded in the nanoparticles in comparison with drug alone. The mucoadhesion study results suggest that nanoparticles could be considered as an efficient oral formulation for colon cancer treatment.Keywords: chitosan, nanoparticles, ionic gelation, gemcitabine, mucoadhesion, oral drug delivery, anticancer

Tahereh Sadat Jafarzadeh Kashi1, Solmaz Eskandarion1,2, Mehdi Esfandyari-Manesh3,4, Seyyed Mahmoud Amin Marashi5, Nasrin Samadi6, Seyyed Mostafa Fatemi1,7, Fatemeh Atyabi2,3, Saeed Eshraghi8, Rassoul Dinarvand2,31Dental Materials Department, Faculty of Dentistry, 2Department of Pharmaceutics, 3Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 4Department of Chemistry, Amirkabir University of Technology, Tehran, 5Department of Microbiology and Immunology, Faculty of Medicine, Babol University of Medical Sciences, Babol, 6Drug and Food Control Department, Faculty of Pharmacy, 7Research Center of Science and Technology in Medicine, 8Department of Microbiology, Tehran University of Medical Sciences, Tehran, IranBackground: Low drug entrapment efficiency of hydrophilic drugs into poly(lactic-co-glycolic acid) (PLGA) nanoparticles is a major drawback. The objective of this work was to investigate different methods of producing PLGA nanoparticles containing minocycline, a drug suitable for periodontal infections.Methods: Different methods, such as single and double solvent evaporation emulsion, ion pairing, and nanoprecipitation were used to prepare both PLGA and PEGylated PLGA nanoparticles. The resulting nanoparticles were analyzed for their morphology, particle size and size distribution, drug loading and entrapment efficiency, thermal properties, and antibacterial activity.Results: The nanoparticles prepared in this study were spherical, with an average particle size of 85–424 nm. The entrapment efficiency of the nanoparticles prepared using different methods was as follows: solid/oil/water ion pairing (29.9%) > oil/oil (5.5%) > water/oil/water (4.7%) > modified oil/water (4.1%) > nano precipitation (0.8%). Addition of dextran sulfate as an ion pairing agent, acting as an ionic spacer between PEGylated PLGA and minocycline, decreased the water solubility of minocycline, hence increasing the drug entrapment efficiency. Entrapment efficiency was also increased when low molecular weight PLGA and high molecular weight dextran sulfate was used. Drug release studies performed in phosphate buffer at pH 7.4 indicated slow release of minocycline from 3 days to several weeks. On antibacterial analysis, the minimum inhibitory concentration and minimum bactericidal concentration of nanoparticles was at least two times lower than that of the free drug.Conclusion: Novel minocycline-PEGylated PLGA nanoparticles prepared by the ion pairing method had the best drug loading and entrapment efficiency compared with other prepared nanoparticles. They also showed higher in vitro antibacterial activity than the free drug.Keywords: nanoparticle, PEGylation, PLGA, ion pairing, minocycline, antibacterial

Fatemeh Talaei1, Ebrahim Azizi2, Rassoul Dinarvand3, Fatemeh Atyabi31Novel Drug Delivery Systems Lab, 2Molecular Research Lab, Department of Pharmacology and Toxicology, 3Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranAbstract: Thiolated chitosan has high transfection and mucoadhesive properties. We investigated the potential of two recently synthesized polymers: NAC-C (N-acetyl cysteine-chitosan) and NAP-C (N-acetyl penicillamine-chitosan) in anticancer drug delivery targeting epidermal growth factor receptor (EGFR). Doxorubicin (DOX) and antisense oligonucleotide (ASOND)-loaded polymer nanoparticles were prepared in water by a gelation process. Particle characterization, drug loading, and drug release were evaluated. To verify drug delivery efficiency in vitro experiments on a breast cancer cell line (T47D) were performed. EGFR gene and protein expression was analyzed by real time quantitative polymerase chain reaction and Western blotting, respectively. A loading percentage of 63% ± 5% for ASOND and 70% ± 5% for DOX was achieved. Drug release data after 15 hours showed that ASOND and DOX were completely released from chitosan-based particles while a lower and more sustained release of only 22% ± 8% was measured for thiolated particles. In a cytosol simulated release medium/reducing environment, such as found intracellularly, polymer-based nanoparticles dissociated, liberating approximately 50% of both active substances within 7 hours. ASOND-loaded polymer nanoparticles had higher stability and high mucoadhesive properties. The ASOND-loaded thiolated particles significantly suppressed EGFR gene expression in T47D cells compared with ASOND-loaded chitosan particles and downregulated EGFR protein expression in cells. This study could facilitate future investigations into the functionality of NAP-C and NAC-C polymers as an efficient ASOND delivery system in vitro and in vivo.Keywords: thiolated chitosan, nanoparticles, doxorubicin, antisense oligonucleotide, epidermal growth factor receptor, T47D breast cancer cells, controlled release

Mona Noori Koopaei1, Rassoul Dinarvand1,2, Mohsen Amini3, Hojatollah Rabbani4, Shaghayegh Emami4, Seyed Nasser Ostad5, Fatemeh Atyabi1,21Novel Drug Delivery Laboratory, Faculty of Pharmacy, 2Nanotechnology Research Center, 3Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 4Monoclonal Antibody Research Center, Avesina Research Institute, ACECR, Tehran, Iran; 5Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Science, Tehran, IranBackground: The objective of this study was to develop pegylated poly lactide-co-glycolide acid (PLGA) immunonanocarriers for targeting delivery of docetaxel to human breast cancer cells.Methods: The polyethylene glycol (PEG) groups on the surface of the PLGA nanoparticles were functionalized using maleimide groups. Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2) antigens of cancer cells, used as the targeting moiety, was attached to the maleimide groups on the surface of pegylated PLGA nanoparticles. Nanoparticles prepared by a nanoprecipitation method were characterized for their size, size distribution, surface charge, surface morphology, drug-loading, and in vitro drug release profile.Results: The average size of the trastuzumab-decorated nanoparticles was 254 ± 16.4 nm and their zeta potential was -11.5 ± 1.4 mV. The average size of the nontargeted PLGA nanoparticles was 183 ± 22 nm and their zeta potential was -2.6 ± 0.34 mV. The cellular uptake of nanoparticles was studied using both HER2-positive (SKBR3 and BT-474) and HER2-negative (Calu-6) cell lines.Conclusion: The cytotoxicity of the immunonanocarriers against HER2-positive cell lines was significantly higher than that of nontargeted PLGA nanoparticles and free docetaxel.Keywords: nanoparticles, drug targeting, immunonanocarriers, trastuzumab, docetaxel, PLGA, HER2 receptor

Parisa Yousefpour1, Fatemeh Atyabi2, Ebrahim Vasheghani-Farahani3, Ali-Akbar Mousavi Movahedi1, Rassoul Dinarvand21Department of Biotechnology, Faculty of Science, University of Tehran, 2Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, 3Biotechnology Group, Department of Chemical Engineering, Faculty of Engineering, Tarbiat Modares University, Tehran, IranBackground: Targeting drugs to their sites of action to overcome the systemic side effects associated with most antineoplastic agents is still a major challenge in pharmaceutical research. In this study, the monoclonal antibody, trastuzumab, was used as a targeting agent in nanoparticles carrying the antitumor drug, doxorubicin, specifically to its site of action.Methods: Chitosan-doxorubicin conjugation was carried out using succinic anhydride as a crosslinker. Trastuzumab was conjugated to self-assembled chitosan-doxorubin conjugate (CS-DOX) nanoparticles (particle size, 200 nm) via thiolation of lysine residues and subsequent linking of the resulted thiols to chitosan. Conjugation was confirmed by gel permeation chromatography, differential scanning calorimetry, Fourier transform infrared spectroscopy, and 1H nuclear magnetic resonance spectroscopy studies. Dynamic light scattering, transmission electron microscopy, and zeta potential determination were used to characterize the nanoparticles.Results: CS-DOX conjugated nanoparticles had a spherical shape and smooth surface with a narrow size distribution and core-shell structure. Increasing the ratio of doxorubicin to chitosan in the conjugation reaction gave rise to a higher doxorubicin content but lower conjugation efficiency. Trastuzumab-decorated nanoparticles (CS-DOX-mAb) contained 47 µg/mg doxorubicin and 33.5 µg/mg trastuzumab. Binding of trastuzumab to the nanoparticles was further probed thermodynamically by isothermal titration calorimetry. Fluorescence microscopy demonstrated enhanced and selective uptake of CS-DOX-mAb by Her2+ cancer cells compared with nontargeted CS-DOX nanoparticles and free drug.Conclusion: Antibody-conjugated nanoparticles were shown to discriminate between Her2+ and Her2- cells, and thus have the potential to be used in active targeted drug delivery, with reduction of drug side effects in Her2+ breast and ovarian cancers.Keywords: chitosan, doxorubicin, self-assembled nanoparticles, active targeting, trastuzumab

Azade Taheri1, Rassoul Dinarvand1,2, Faranak Salman Nouri1, Mohammad Reza Khorramizadeh3, Atefeh Taheri Borougeni4, Pooria Mansoori5, Fatemeh Atyabi1,21Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical sciences, Tehran, Iran; 3Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; 4Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Tehran University of Medical Sciences, Tehran, Iran; 5Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IranAbstract: Biotin molecules could be used as suitable targeting moieties in targeted drug delivery systems against tumors. To develop a biotin targeted drug delivery system, we employed human serum albumin (HSA) as a carrier. Methotrexate (MTX) molecules were conjugated to HSA. MTX-HSA nanoparticles (MTX-HSA NPs) were prepared from these conjugates by cross-linking the HSA molecules. Biotin molecules were then conjugated on the surface of MTX-HSA NPs. The anticancer efficacy of biotin targeted MTX-HSA NPs was evaluated in mice bearing 4T1 breast carcinoma. A single dose of biotin targeted MTX-HSA NPs showed stronger in vivo antitumor activity than non-targeted MTX-HSA NPs and free MTX. By 7 days after treatment, average tumor volume in the biotin targeted MTX-HSA NPs-treated group decreased to 17.6% of the initial tumor volume when the number of attached biotin molecules on MTX-HSA-NPs was the highest. Average tumor volume in non-targeted MTX-HSA NPs-treated mice grew rapidly and reached 250.7% of the initial tumor volume. Biotin targeted MTX-HSA NPs increased the survival of tumor-bearing mice to 47.5 ± 0.71 days and increased their life span up to 216.7%. Mice treated with biotin targeted MTX-HSA NPs showed slight body weight loss (8%) 21 days after treatment, whereas non-targeted MTX-HSA NPs treatment at the same dose caused a body weight loss of 27.05% ± 3.1%.Keywords: biotin, targeted drug delivery, in vivo anticancer delivery, human serum albumin, methotrexate, conjugates

Parisa Yousefpour1,2, Fatemeh Atyabi1, Ebrahim Vashegani Farahani3, Ramin Sakhtianchi1, Rassoul Dinarvand11Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Biotechnology, Faculty of Science, University of Tehran, Tehran, Iran 3Department of Chemical Engineering, Tarbiat Modares University, Tehran, IranAbstract: This study deals with the preparation and investigation of a nanoscale delivery system for the anticancer drug doxorubicin (DOX) using its complexation with polyanionic carbohydrate dextran sulfate (DS). Dynamic light scattering, SEM, and zeta potential determination were used to characterize nanocomplexes. DOX-DS complexation was studied in the presence of ethanol as a hydrogen-bond disrupting agent, NaCl as an electrostatic shielding agent, and chitosan as a positively charged polymer. Thermodynamics of DOX-DS interaction was studied using isothermal titration calorimetry (ITC). A dialysis method was applied to investigate the release profile of DOX from DOX-DS nanocomplexes. Spherical and smooth-surfaced DOX-DS nanocomplexes (250–500 nm) with negative zeta potential were formed at a DS/DOX (w/w) ratio of 0.4–0.6, with over 90% drug encapsulation efficiency. DOX when complexed with DS showed lower fluorescence emission and 480 nm absorbance plus a 15 nm bathometric shift in its visible absorbance spectrum. Electrostatic hydrogen bonding and π-π stacking interactions are the main contributing interactions in DOX-DS complexation. Thermal analysis of DOX-DS complexation by ITC revealed that each DOX molecule binds with 3 DS glycosyl monomers. Drug release profile of nanocomplexes showed a fast DOX release followed by a slow sustained release, leading to release of 32% of entrapped DOX within 15 days. DOX-DS nanocomplexes may serve as a drug delivery system with efficient drug encapsulation and also may be taken into consideration in designing DOX controlled-release systems.Keywords: chitosan, dextran, doxorubicin, nanocomplex, anticancer, drug delivery

Haleh Bakhshandeh1, Masoud Soleimani2, Saied Shah Hosseini3, Hassan Hashemi3, Iman Shabani4, Abbas Shafiee5, Amir Houshang Behesht Nejad6, Mohammad Erfan1, Rassoul Dinarvand7, Fatemeh Atyabi71Department of Pharmaceutics, School of Pharmacy, Shaheed Beheshti Medical University, Tehran, Iran; 2Hematology Department, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran; 3Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran; 4Nanotechnology and Tissue Engineering Department, Stem Cell Technology Research Center, Tehran, Iran; 5Stem Cell Biology Department, Stem Cell Technology Research Center, Tehran, Iran; 6Ophthalmology Department, Tehran University of Medical Sciences, Tehran, Iran; 7Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranAbstract: The study aimed to fabricate and characterize a 2-part artificial cornea as a substitute for penetrating keratoplasty in patients with corneal blindness. The peripheral part of the artificial cornea consisted of plasma-treated electrospun poly (ε-caprolactone) (PCL) nanofibers, which were attached to a hydrogel disc of polyvinyl alcohol (PVA) as a central optical part. The physical properties of the prepared artificial cornea, including morphology, mechanical properties, light transmittance, and contact angle, were assessed. Cell attachment and proliferation studies were performed on rabbit limbal stem cells. The SEM image of the polymeric system showed that the peripheral part formed a highly porous scaffold that could facilitate tissue biointegration. Assessment of the mechanical properties of the peripheral nanofibrous part and the hydrogel optical part showed suitable elasticity. Young’s modulus values of the electrospun PCL skirt and PVA hydrogel core were 7.5 and 5.3 MPa, respectively, which is in line with the elasticity range of natural human cornea (0.3–7 MPa). The light transmittance of the central part was >85% when measured in the 400–800 nm wavelength range. The plasma-treated PCL nanofibrous scaffold promoted limbal stem cell adhesion and proliferation within 10 days. These results confirmed that the polymeric artificial cornea showed suitable physical properties and good biocompatibility and epithelialization ability.Keywords: two part artificial cornea, nanofibers, electrospun, poly (ε-caprolactone), polyvinyl alcohol hydrogel, limbal stem cells

Z Sobhani1, R Dinarvand1,2, F Atyabi1,2, M Ghahremani3, M Adeli4,51Department of Pharmaceutics, 2Nanotechnology Research Center, 3Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran; 4Department of Chemistry, Sharif University of Technology, Tehran; 5Department of Chemistry, Faculty of Science, Lorestan University, Khoramabad, IranAbstract: Potential applications of carbon nanotubes have attracted many researchers in the field of drug delivery systems. In this study, multiwalled carbon nanotubes (MWNTs) were first functionalized using hyperbranched poly citric acid (PCA) to improve their hydrophilicity and functionality. Then, paclitaxel (PTX), a potent anticancer agent, was conjugated to the carboxyl functional groups of poly citric acid via a cleavable ester bond to obtain a MWNT-g-PCA-PTX conjugate. Drug content of the conjugate was about 38% (w/w). The particle size of MWNT-g-PCA and MWNT-g-PCA-PTX was approximately 125 and 200 nm, respectively. Atomic force microscopy and transmission electron microscopy images showed a curved shape for MWNT-g-PCA and MWNT-g-PCA-PTX, which was in contrast with the straight or linear conformation expected from carbon nanotubes. It seems that the high hydrophilicity of poly citric acid and high hydrophobicity of MWNTs led to conformational changes from a linear state to a curved state. Paclitaxel can be released from the MWNT-g-PCA-PTX conjugates faster at pH 6.8 and 5.0 than at pH 7.4, which was suitable for the release of the drug in tumor tissues and tumor cells. In vitro cytotoxicity studies were evaluated in the A549 and SKOV3 cell lines. MWNT-g-PCA had an insignificant cytotoxic effect on both cell lines. MWNT-g-PCA-PTX had more of a cytotoxic effect than the free drug over a shorter incubation time (eg, 24 hours versus 48 hours), which suggests improved cell penetration of MWNT-g-PCA-PTX. Therefore, paclitaxel conjugated to MWNT-g-PCA is promising for cancer therapeutics.Keywords: multiwalled carbon nanotubes, functionalization, anticancer, drug delivery, nanoparticles

R Dinarvand1,2, N Sepehri1, S Manoochehri1, H Rouhani1, F Atyabi1,21Department of Pharmaceutics, Faculty of Pharmacy, 2Nanotechnology Research Centre, Tehran University of Medical Sciences, Tehran, IranAbstract: The effectiveness of anticancer agents may be hindered by low solubility in water, poor permeability, and high efflux from cells. Nanomaterials have been used to enable drug delivery with lower toxicity to healthy cells and enhanced drug delivery to tumor cells. Different nanoparticles have been developed using different polymers with or without surface modification to target tumor cells both passively and/or actively. Polylactide-co-glycolide (PLGA), a biodegradable polyester approved for human use, has been used extensively. Here we report on recent developments concerning PLGA nanoparticles prepared for cancer treatment. We review the methods used for the preparation and characterization of PLGA nanoparticles and their applications in the delivery of a number of active agents. Increasing experience in the field of preparation, characterization, and in vivo application of PLGA nanoparticles has provided the necessary momentum for promising future use of these agents in cancer treatment, with higher efficacy and fewer side effects.Keywords: nanotechnology, polymeric nanocarriers, targeting, anticancer agents, surface modification