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A Novel Brain Tumor Detection and Coloring Technique from 2D MRI Images. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12115744] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The early automated identification of brain tumors is a difficult task in MRI images. For a long time, continuous research efforts have floated a new idea of replacing different grayscale anatomic regions of diagnostic images with appropriate colors that could overcome the problems being faced by radiologists. The colorization of grayscale images is challenging for enhancing various regions’ contrasts by transforming grayscale images into high-contrast color images. This study investigates standard solutions in discriminating between normal and abnormal regions by assigning colors to grayscale human brain MR images to differentiate different kinds of tissues. The proposed approach is influenced by connected component and index-based colorization methods for applying colors to different regions and abnormal areas. It is an automated approach that varies its inputs using luminance and pixel matrix values and provides the possible outcome. After segmentation, a specific algorithm is devised to colorize the region-of-interest (ROI) areas, which distinguishes and applies colors to differentiate the regions. Results show that implementing the watershed-based area segmentation method and ROI selection method based on the morphological operation helps identify tissues during processing. Moreover, the colorization approach based on luminance and pixel matrix after segmentation and ROI selection is beneficial due to better PSNR and SSIM values and visible contrast improvement. Our proposed algorithm works with less processing overhead and uses less time than those of the industry’s previously used color transfer method.
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Rizvi SFA, Ali A, Ahmad M, Mu S, Zhang H. Multifunctional self-assembled peptide nanoparticles for multimodal imaging-guided enhanced theranostic applications against glioblastoma multiforme. NANOSCALE ADVANCES 2021; 3:5959-5967. [PMID: 36132681 PMCID: PMC9419261 DOI: 10.1039/d1na00597a] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 08/20/2021] [Indexed: 05/15/2023]
Abstract
The synthesis of self-assembled peptide nanoparticles using a facile one-pot synthesis approach is gaining increasing attention, allowing therapy in combination with diagnosis. Their drawback is limited diagnostic potential, which can be improved after necessary modifications and efficacious functionalization. Herein, a cyclic heptapeptide having the Arg-Gly-Asp-Lys-Leu-Ala-Lys sequence was modified by conjugation of the ε-amino group of the terminal lysine residue with diethylenetriamine pentaacetic acid (DTPA) as a bifunctional chelating agent (BFC) for radiolabeling with a γ-emitting radionuclide (99mTc, half-life 6.01 h; energy 140 keV). Further, the free amino group of the middle lysine residue was successfully conjugated with near-infrared fluorescence (NIRF) dye Cyanine5.5 N-succinimidyl ester (Ex/Em = 670/701 nm) by a co-assembly method to form newly designed novel NIRF dye conjugated self-assembled peptide-DTPA (Cy5.5@SAPD) nanoparticles. The fluorescent nanoparticle formation was confirmed by using a fluorescence spectrophotometer (Ex/Em = 650/701 nm), and the transmission electron microscope (TEM) images showed a size of ∼ 40 nm with a lattice fringe distance of 0.294 nm. Cytotoxicity and confocal laser scanning microscopy (CLSM) studies showed that these nanoparticles possess a high affinity for the αvβ3-integrin receptor overexpressed on brain tumor glioblastoma with an EC50 = 20 μM. Moreover, these nanoparticles were observed to have potential to internalize into U87MG cells more prominently than HEK-293 cancer cells and induce apoptosis. The apoptosis assay showed 79.5% apoptotic cells after 24 h treatment of Cy5.5@SAPD nanoparticles. Additionally, these nanoparticles were also radiolabeled with 99mTc for the single photon emission computed tomography (SPECT) imaging study in tumor-bearing female Balb/c mice. The excellent imaging feature of Cy5.5@SAPD-99mTc nanoparticles as a multimodal (SPECT/NIRF) diagnostic probe, as well as noteworthy therapeutic potential was observed. The results suggested that our newly designed novel dual-targeting dual-imaging nanoparticles may serve as an admirable theranostic probe to treat brain tumor glioblastoma multiforme.
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Affiliation(s)
- Syed Faheem Askari Rizvi
- College of Chemistry and Chemical Engineering, Lanzhou University Lanzhou-730000 Gansu Province P. R. China +86-931-8912058 +86-931-8912582
- Department of Nuclear Medicine, Institute of Nuclear Medicine and Oncology (INMOL) Lahore-54000 Punjab Pakistan
| | - Azam Ali
- College of Chemistry and Chemical Engineering, Lanzhou University Lanzhou-730000 Gansu Province P. R. China +86-931-8912058 +86-931-8912582
| | - Munir Ahmad
- Department of Nuclear Medicine, Institute of Nuclear Medicine and Oncology (INMOL) Lahore-54000 Punjab Pakistan
| | - Shuai Mu
- College of Chemistry and Chemical Engineering, Lanzhou University Lanzhou-730000 Gansu Province P. R. China +86-931-8912058 +86-931-8912582
| | - Haixia Zhang
- College of Chemistry and Chemical Engineering, Lanzhou University Lanzhou-730000 Gansu Province P. R. China +86-931-8912058 +86-931-8912582
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Rizvi SFA, Shahid S, Mu S, Zhang H. Hybridization of tumor homing and mitochondria-targeting peptide domains to design novel dual-imaging self-assembled peptide nanoparticles for theranostic applications. Drug Deliv Transl Res 2021; 12:1774-1785. [PMID: 34535874 DOI: 10.1007/s13346-021-01066-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2021] [Indexed: 01/05/2023]
Abstract
A novel hybridized dual-targeting peptide-based nanoprobe was successfully designed by using the cyclic heptapeptide. This peptide has Arg-Gly-Asp-Lys-Leu-Ala-Lys sequence, in which the RGD homing motif and KALK mitochondria-targeting motif were linked via amide bond. The designed peptide probe was further modified through covalent linkage to induce dual-imaging functionality, and self-assembled to form spherical nanoparticles. The novel Cy5.5-SAPD-99mTc nanoparticles were tested for in vitro cytotoxicity, cellular uptake, and apoptosis-inducing functionalities. The cellular internalization, enhanced cytotoxicity and selective receptor binding capabilities against U87MG cells, excellent dual-imaging potential, improved apoptosis-inducing feature by damaging mitochondria, and in vivo preclinical investigations suggested that our newly designed novel hybridized peptide-based dual-imaging nanoparticles may serve as an admirable theranostic probe to treat brain tumor glioblastoma multiforme. This study describes the development of dual-targeting self-assembled peptide nanoparticles followed by modifications using NIRF dye and radiolabeled with 99mTc for dual-imaging and enhanced therapeutic efficacy against brain tumor.
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Affiliation(s)
- Syed Faheem Askari Rizvi
- College of Chemistry and Chemical Engineering, Gansu Province, Lanzhou University, Lanzhou-730000, People's Republic of China
| | - Samiah Shahid
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore-54000, Punjab, Pakistan
| | - Shuai Mu
- College of Chemistry and Chemical Engineering, Gansu Province, Lanzhou University, Lanzhou-730000, People's Republic of China
| | - Haixia Zhang
- College of Chemistry and Chemical Engineering, Gansu Province, Lanzhou University, Lanzhou-730000, People's Republic of China.
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Wu S, Helal-Neto E, Matos APDS, Jafari A, Kozempel J, Silva YJDA, Serrano-Larrea C, Alves Junior S, Ricci-Junior E, Alexis F, Santos-Oliveira R. Radioactive polymeric nanoparticles for biomedical application. Drug Deliv 2021; 27:1544-1561. [PMID: 33118416 PMCID: PMC7599028 DOI: 10.1080/10717544.2020.1837296] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nowadays, emerging radiolabeled nanosystems are revolutionizing medicine in terms of diagnostics, treatment, and theranostics. These radionuclides include polymeric nanoparticles (NPs), liposomal carriers, dendrimers, magnetic iron oxide NPs, silica NPs, carbon nanotubes, and inorganic metal-based nanoformulations. Between these nano-platforms, polymeric NPs have gained attention in the biomedical field due to their excellent properties, such as their surface to mass ratio, quantum properties, biodegradability, low toxicity, and ability to absorb and carry other molecules. In addition, NPs are capable of carrying high payloads of radionuclides which can be used for diagnostic, treatment, and theranostics depending on the radioactive material linked. The radiolabeling process of nanoparticles can be performed by direct or indirect labeling process. In both cases, the most appropriate must be selected in order to keep the targeting properties as preserved as possible. In addition, radionuclide therapy has the advantage of delivering a highly concentrated absorbed dose to the targeted tissue while sparing the surrounding healthy tissues. Said another way, radioactive polymeric NPs represent a promising prospect in the treatment and diagnostics of cardiovascular diseases such as cardiac ischemia, infectious diseases such as tuberculosis, and other type of cancer cells or tumors.
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Affiliation(s)
- Shentian Wu
- Department of Radiotherapy Center, Maoming People's Hospital, Maoming City, China
| | - Edward Helal-Neto
- Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro, Brazil
| | | | - Amir Jafari
- Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro, Brazil.,Department of Medical Nanotechnology in the Faculty of Advanced Technology in Medicine, Iran University of Medical Science, Tehran, Iran
| | - Ján Kozempel
- Faculty of Nuclear Sciences and Physical Engineering (FJFI), Czech Technical University in Prague (ČVUT), Prague, Czech Republic
| | | | | | - Severino Alves Junior
- Department of Fundamental Chemistry, Federal University of Pernambuco, Recife, Brazil
| | - Eduardo Ricci-Junior
- Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Frank Alexis
- School of Biological Sciences and Engineering, Yachay Tech University, Urcuquí, Ecuador
| | - Ralph Santos-Oliveira
- Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro, Brazil.,Laboratory of Radiopharmacy and Nanoradiopharmaceuticals, Zona Oeste State University, Rio de Janeiro, Brazil
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Mikulová MB, Mikuš P. Advances in Development of Radiometal Labeled Amino Acid-Based Compounds for Cancer Imaging and Diagnostics. Pharmaceuticals (Basel) 2021; 14:167. [PMID: 33669938 PMCID: PMC7924883 DOI: 10.3390/ph14020167] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/13/2021] [Accepted: 02/18/2021] [Indexed: 02/08/2023] Open
Abstract
Radiolabeled biomolecules targeted at tumor-specific enzymes, receptors, and transporters in cancer cells represent an intensively investigated and promising class of molecular tools for the cancer diagnosis and therapy. High specificity of such biomolecules is a prerequisite for the treatment with a lower burden to normal cells and for the effective and targeted imaging and diagnosis. Undoubtedly, early detection is a key factor in efficient dealing with many severe tumor types. This review provides an overview and critical evaluation of novel approaches in the designing of target-specific probes labeled with metal radionuclides for the diagnosis of most common death-causing cancers, published mainly within the last three years. Advances are discussed such traditional peptide radiolabeling approaches, and click and nanoparticle chemistry. The progress of radiolabeled peptide based ligands as potential radiopharmaceuticals is illustrated via novel structure and application studies, showing how the molecular modifications reflect their binding selectivity to significant onco-receptors, toxicity, and, by that, practical utilization. The most impressive outputs in categories of newly developed structures, as well as imaging and diagnosis approaches, and the most intensively studied oncological diseases in this context, are emphasized in order to show future perspectives of radiometal labeled amino acid-based compounds in nuclear medicine.
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Affiliation(s)
- Mária Bodnár Mikulová
- Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32 Bratislava, Slovakia;
| | - Peter Mikuš
- Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32 Bratislava, Slovakia;
- Toxicological and Antidoping Center (TAC), Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32 Bratislava, Slovakia
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Izci M, Maksoudian C, Manshian BB, Soenen SJ. The Use of Alternative Strategies for Enhanced Nanoparticle Delivery to Solid Tumors. Chem Rev 2021; 121:1746-1803. [PMID: 33445874 PMCID: PMC7883342 DOI: 10.1021/acs.chemrev.0c00779] [Citation(s) in RCA: 256] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Indexed: 02/08/2023]
Abstract
Nanomaterial (NM) delivery to solid tumors has been the focus of intense research for over a decade. Classically, scientists have tried to improve NM delivery by employing passive or active targeting strategies, making use of the so-called enhanced permeability and retention (EPR) effect. This phenomenon is made possible due to the leaky tumor vasculature through which NMs can leave the bloodstream, traverse through the gaps in the endothelial lining of the vessels, and enter the tumor. Recent studies have shown that despite many efforts to employ the EPR effect, this process remains very poor. Furthermore, the role of the EPR effect has been called into question, where it has been suggested that NMs enter the tumor via active mechanisms and not through the endothelial gaps. In this review, we provide a short overview of the EPR and mechanisms to enhance it, after which we focus on alternative delivery strategies that do not solely rely on EPR in itself but can offer interesting pharmacological, physical, and biological solutions for enhanced delivery. We discuss the strengths and shortcomings of these different strategies and suggest combinatorial approaches as the ideal path forward.
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Affiliation(s)
- Mukaddes Izci
- NanoHealth
and Optical Imaging Group, Translational Cell and Tissue Research
Unit, Department of Imaging and Pathology, KU Leuven, Herestraat 49, B3000 Leuven, Belgium
| | - Christy Maksoudian
- NanoHealth
and Optical Imaging Group, Translational Cell and Tissue Research
Unit, Department of Imaging and Pathology, KU Leuven, Herestraat 49, B3000 Leuven, Belgium
| | - Bella B. Manshian
- Translational
Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Herestraat 49, B3000 Leuven, Belgium
| | - Stefaan J. Soenen
- NanoHealth
and Optical Imaging Group, Translational Cell and Tissue Research
Unit, Department of Imaging and Pathology, KU Leuven, Herestraat 49, B3000 Leuven, Belgium
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Iqbal Z, Arafa ESA, Kanwal Z, Murtaza G. Smart solution of severe problems: Radiolabeled nanocarriers for cancer imaging and therapy. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2020.102205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Novy Z, Stepankova J, Hola M, Flasarova D, Popper M, Petrik M. Preclinical Evaluation of Radiolabeled Peptides for PET Imaging of Glioblastoma Multiforme. Molecules 2019; 24:molecules24132496. [PMID: 31288488 PMCID: PMC6651196 DOI: 10.3390/molecules24132496] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/02/2019] [Accepted: 07/07/2019] [Indexed: 01/09/2023] Open
Abstract
In this study, we have compared four 68Ga-labeled peptides (three Arg-Gly-Asp (RGD) peptides and substance-P) with two 18F-tracers clinically approved for tumor imaging. We have studied in vitro and in vivo characteristics of selected radiolabeled tracers in a glioblastoma multiforme tumor model. The in vitro part of the study was mainly focused on the evaluation of radiotracers stability under various conditions. We have also determined in vivo stability of studied 68Ga-radiotracers by analysis of murine urine collected at various time points after injection. The in vivo behavior of tested 68Ga-peptides was evaluated through ex vivo biodistribution studies and PET/CT imaging. The obtained data were compared with clinically used 18F-tracers. 68Ga-RGD peptides showed better imaging properties compared to 18F-tracers, i.e., higher tumor/background ratios and no accumulation in non-target organs except for excretory organs.
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Affiliation(s)
- Zbynek Novy
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic.
| | - Jana Stepankova
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic
| | - Michaela Hola
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic
| | - Dominika Flasarova
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic
| | - Miroslav Popper
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic
| | - Milos Petrik
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic.
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Sun N, Zhao L, Zhu J, Li Y, Song N, Xing Y, Qiao W, Huang H, Zhao J. 131I-labeled polyethylenimine-entrapped gold nanoparticles for targeted tumor SPECT/CT imaging and radionuclide therapy. Int J Nanomedicine 2019; 14:4367-4381. [PMID: 31354266 PMCID: PMC6580422 DOI: 10.2147/ijn.s203259] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 04/14/2019] [Indexed: 01/02/2023] Open
Abstract
Purpose: Polyethylenimine (PEI) has been widely used as a versatile template to develop multifunctional nanosystems for disease diagnosis and treatment. In this study, we manufactured iodine-131 (131I)-labeled PEI-entrapped gold nanoparticles (Au PENPs) as a novel nanoprobe for single-photon emission computed tomography/computed tomography (SPECT/CT) imaging and radionuclide therapy. Materials and methods: PEI was PEGylated and sequentially conjugated with Buthus martensii Karsch chlorotoxin (BmK CT, a tumor-specific ligand which can selectively bind to MMP2), 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO), and fluorescein isothiocyanate to form the multifunctional PEI template for entrapment of Au NPs. Then, the PEI surface was radiolabeled with 131I via HPAO to produce the novel nanoprobe (BmK CT-Au PENPs-131I). Results: The synthesized multifunctional Au PENPs before and after 131I radiolabeling were well-characterized as follows: structure, X-ray attenuation coefficient, colloid stability, cytocompatibility, and radiochemical stability in vitro. Furthermore, BmK CT-Au PENPs-131I were suitable for targeted SPECT/CT imaging and radionuclide therapy of tumor cells in vitro and in a xenograft tumor model in vivo. Conclusion: The developed multifunctional Au PENPs are a promising theranostic platform for targeted imaging and treatment of different MMP2-overexpressing tumors.
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Affiliation(s)
- Na Sun
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200080, People’s Republic of China
| | - Lingzhou Zhao
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200080, People’s Republic of China
| | - Jingyi Zhu
- State Key Laboratory of Material-Oriented Chemical Engineering, School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing211816, People’s Republic of China
| | - Yujie Li
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200080, People’s Republic of China
| | - Ningning Song
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200080, People’s Republic of China
| | - Yan Xing
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200080, People’s Republic of China
| | - Wenli Qiao
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200080, People’s Republic of China
| | - He Huang
- State Key Laboratory of Material-Oriented Chemical Engineering, School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing211816, People’s Republic of China
| | - Jinhua Zhao
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200080, People’s Republic of China
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Song Y, Li W, Meng S, Zhou W, Su B, Tang L, Zhao Y, Wu X, Yin D, Fan M, Zhou C. Dual integrin αvβ 3 and NRP-1-Targeting Paramagnetic Liposome for Tumor Early Detection in Magnetic Resonance Imaging. NANOSCALE RESEARCH LETTERS 2018; 13:380. [PMID: 30483904 PMCID: PMC6258593 DOI: 10.1186/s11671-018-2797-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 11/13/2018] [Indexed: 06/09/2023]
Abstract
Enhanced MRI (magnetic resonance imaging) plays a vital role in the early detection of tumor but with low specificity. Molecular imaging of angiogenesis could efficiently deliver contrast agents to the tumor site by specific targeted carriers. We designed and synthesized dual-targeted paramagnetic liposomes functionalized with two angiogenesis-targeting ligands, the αVβ3 integrin-specific RGD (Arg-Gly-Asp) and the neuropilin-1 (NRP-1) receptor-specific ATWLPPR (Ala-Thr-Trp-Leu-Pro-Pro-Arg) (A7R). These liposomes were proved to be in the nanoparticle range and demonstrated to effectively encapsulate paramagnetic MRI contrast agents Gd-DTPA (gadolinium-diethylenetriamine pentaacetic acid). T1 relaxivity of various liposome formulations was lower than pure Gd-DTPA but with no statistically significant difference. In vitro cellular uptake and competitive inhibition assay showed the higher binding affinity of dual-targeted liposomes to HUVECs (human umbilical vein endothelial cells) and A549 cells compared with pure Gd-DTPA, non-targeted, and single-targeted liposomes, which was proved to be mediated by the binding of RGD/ανβ3-integrin and A7R/NRP1. For MR imaging of mice bearing A549 cells in vivo, dual-targeted liposomes reached the highest SER (signal enhancement rate) value with a significant difference at all experimental time points. It was about threefold increase compared to pure Gd-DTPA and non-targeted liposomes and was 1.5-fold of single-targeted liposomes at 2 h post injection. The SER was lowered gradually and decreased only by 40% of the peak value in 6 h. Dual-targeted liposomes were likely to exert a synergistic effect and the specificity of delivering Gd-DTPA to the tumor site. Therefore, dual-ανβ3-integrin-NRP1-targeting paramagnetic liposome with a RGD-ATWLPPR heterodimeric peptide might be a potent system for molecular imaging of tumor.
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Affiliation(s)
- Yin Song
- Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, No. 507, Zheng Min Road, Shanghai, 200433 People’s Republic of China
| | - Wei Li
- Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, No. 507, Zheng Min Road, Shanghai, 200433 People’s Republic of China
| | - Shuyan Meng
- Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, No. 507, Zheng Min Road, Shanghai, 200433 People’s Republic of China
| | - Wei Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, No. 507, Zheng Min Road, Shanghai, 200433 People’s Republic of China
| | - Bo Su
- Central Laboratory, Shanghai Pulmonary Hospital, Tongji University, Shanghai, 200433 China
| | - Liang Tang
- Central Laboratory, Shanghai Pulmonary Hospital, Tongji University, Shanghai, 200433 China
| | - Yinmin Zhao
- Central Laboratory, Shanghai Pulmonary Hospital, Tongji University, Shanghai, 200433 China
| | - Xiaoyan Wu
- Department of Radiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China
| | - Dazhi Yin
- Shanghai Key Laboratory of Magnetic Resonance and Department of Physics, East China Normal University, Shanghai, 200062 China
| | - Mingxia Fan
- Shanghai Key Laboratory of Magnetic Resonance and Department of Physics, East China Normal University, Shanghai, 200062 China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, No. 507, Zheng Min Road, Shanghai, 200433 People’s Republic of China
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Elgohary MM, Helmy MW, Mortada SM, Elzoghby AO. Dual-targeted nano-in-nano albumin carriers enhance the efficacy of combined chemo/herbal therapy of lung cancer. Nanomedicine (Lond) 2018; 13:2221-2224. [DOI: 10.2217/nnm-2018-0097] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Aim: A Nano-in-Nano approach was exploited to facilitate incorporation of the chemotherapeutic drug etoposide (ETP) as nanosuspension, synergistically with berberine (BER) into hydrophilic albumin nanoparticles (HSA NPs).Methods: For maximal tumor targeting, HSA was modified with mannose and phenyl-boronic acid. Furthermore, different crosslinkers were investigated for sustained release of water soluble BER from HSA NPs. Results: The elaborated dual-targeted HSA NPs (216.2 nm) were spherical with high BER and ETP entrapment efficiency (69.5 and 87.6%, respectively) and loading (10.52 and 14.04%, respectively). The NPs exhibited sequential release pattern for both ETP and BER (51.55 and 34.33% over 72 h, respectively). Phenyl-boronic acid/mannose-HSA NPs demonstrated powerful cytotoxicity against A549 lung cancer cells (IC50: 12.4 μg/ml) correlated to enhanced cellular internalization. Dual-targeted NPs displayed 9.77-fold higher caspase-3 level and 3.5-fold lower VEGF level than positive control mice. Conclusion: Dual-targeted Nano-in-Nano albumin carriers could be beneficial for parenteral ETP/BER delivery to lung cancer.
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Affiliation(s)
- Mayada M Elgohary
- Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
- Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
| | - Maged W Helmy
- Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
| | - Sana M Mortada
- Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
| | - Ahmed O Elzoghby
- Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
- Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
- Division of Engineering in Medicine, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA
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13
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Magro RD, Cox A, Zambelli V, Mancini S, Masserini M, Re F. The ability of liposomes, tailored for blood–brain barrier targeting, to reach the brain is dramatically affected by the disease state. Nanomedicine (Lond) 2018; 13:585-594. [DOI: 10.2217/nnm-2017-0317] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Aim: To investigate if and how the ability of liposomes, previously designed for Alzheimer's therapy, to reach the brain changes in aging/pathological conditions with respect to the healthy state. Methods: Biodistribution and pharmacokinetics of liposomes in young or aged healthy mice and in an Alzheimer's mouse model were measured by radiochemical techniques. The expression of brain receptors and structural proteins was evaluated by Western blot. Results: At equal blood levels, the amount and integrity of liposomes in the brain were dramatically lower in Alzheimer's or aged mice, with respect to young animals. These differences are likely attributable to molecular alterations in the brain vasculature. Conclusion: Brain alterations in pathology or aging should be considered in the design of drug delivery systems for brain targeting.
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Affiliation(s)
- Roberta Dal Magro
- School of Medicine & Surgery, Nanomedicine Center NANOMIB, Milan Center for Neuroscience (NeuroMi), University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy
| | - Alysia Cox
- School of Medicine & Surgery, Nanomedicine Center NANOMIB, Milan Center for Neuroscience (NeuroMi), University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy
| | - Vanessa Zambelli
- School of Medicine & Surgery, Nanomedicine Center NANOMIB, Milan Center for Neuroscience (NeuroMi), University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy
| | - Simona Mancini
- School of Medicine & Surgery, Nanomedicine Center NANOMIB, Milan Center for Neuroscience (NeuroMi), University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy
| | - Massimo Masserini
- School of Medicine & Surgery, Nanomedicine Center NANOMIB, Milan Center for Neuroscience (NeuroMi), University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy
| | - Francesca Re
- School of Medicine & Surgery, Nanomedicine Center NANOMIB, Milan Center for Neuroscience (NeuroMi), University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy
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Ehlerding EB, Sun L, Lan X, Zeng D, Cai W. Dual-Targeted Molecular Imaging of Cancer. J Nucl Med 2018; 59:390-395. [PMID: 29301927 PMCID: PMC5868496 DOI: 10.2967/jnumed.117.199877] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 12/17/2017] [Indexed: 01/03/2023] Open
Abstract
Molecular imaging is critical to personalized and precision medicine. Although singly targeted imaging probes are making an impact both clinically and preclinically, molecular imaging strategies using bispecific probes have enabled improved visualization of cancer in recent years through synergistic targeting of two ligands. In this Focus on Molecular Imaging review, we outline how peptide-, antibody-, and nanoparticle-based platforms have affected this emerging strategy, providing examples and pointing out areas in which the greatest clinical impact may be realized.
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Affiliation(s)
- Emily B Ehlerding
- Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Lingyi Sun
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dexing Zeng
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Weibo Cai
- Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin
- Department of Radiology, University of Wisconsin-Madison, Madison, Wisconsin; and
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin
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15
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Tumor target amplification: Implications for nano drug delivery systems. J Control Release 2018; 275:142-161. [PMID: 29454742 DOI: 10.1016/j.jconrel.2018.02.020] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 02/13/2018] [Accepted: 02/14/2018] [Indexed: 12/14/2022]
Abstract
Tumor cells overexpress surface markers which are absent from normal cells. These tumor-restricted antigenic signatures are a fundamental basis for distinguishing on-target from off-target cells for ligand-directed targeting of cancer cells. Unfortunately, tumor heterogeneity impedes the establishment of a solid expression pattern for a given target marker, leading to drastic changes in quality (availability) and quantity (number) of the target. Consequently, a subset of cancer cells remains untargeted during the course of treatment, which subsequently promotes drug-resistance and cancer relapse. Since target inefficiency is only problematic for cancer treatment and not for treatment of other pathological conditions such as viral/bacterial infections, target amplification or the generation of novel targets is key to providing eligible antigenic markers for effective targeted therapy. This review summarizes the limitations of current ligand-directed targeting strategies and provides a comprehensive overview of tumor target amplification strategies, including self-amplifying systems, dual targeting, artificial markers and peptide modification. We also discuss the therapeutic and diagnostic potential of these approaches, the underlying mechanism(s) and established methodologies, mostly in the context of different nanodelivery systems, to facilitate more effective ligand-directed cancer cell monitoring and targeting.
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16
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da Silva AL, Cruz FF, Rocco PRM, Morales MM. New perspectives in nanotherapeutics for chronic respiratory diseases. Biophys Rev 2017; 9:793-803. [PMID: 28914424 PMCID: PMC5662054 DOI: 10.1007/s12551-017-0319-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 08/14/2017] [Indexed: 12/12/2022] Open
Abstract
According to the World Health Organization (WHO), hundreds of millions of people of all ages and in all countries suffer from chronic respiratory diseases, with particular negative consequences such as poor health-related quality of life, impaired work productivity, and limitations in the activities of daily living. Chronic obstructive pulmonary disease, asthma, occupational lung diseases (such as silicosis), cystic fibrosis, and pulmonary arterial hypertension are the most common of these diseases, and none of them are curable with current therapies. The advent of nanotechnology holds great therapeutic promise for respiratory conditions, because non-viral vectors are able to overcome the mucus and lung remodeling barriers, increasing pharmacologic and therapeutic potency. It has been demonstrated that the extent of pulmonary nanoparticle uptake depends not only on the physical and chemical features of nanoparticles themselves, but also on the health status of the organism; thus, the huge diversity in nanotechnology could revolutionize medicine, but safety assessment is a challenging task. Within this context, the present review discusses some of the major new perspectives in nanotherapeutics for lung disease and highlights some of the most recent studies in the field.
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Affiliation(s)
- Adriana Lopes da Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Centro de Ciências da Saúde, Avenida Carlos Chagas Filho, s/n, Bloco G, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil
| | - Fernanda Ferreira Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Patricia Rieken Macedo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Marcelo Marcos Morales
- Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Centro de Ciências da Saúde, Avenida Carlos Chagas Filho, s/n, Bloco G, Ilha do Fundão, Rio de Janeiro, RJ, 21941-902, Brazil.
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17
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Kulhari H, Telukutla SR, Pooja D, Shukla R, Sistla R, Bansal V, Adams DJ. Peptide grafted and self-assembled poly(γ-glutamic acid)-phenylalanine nanoparticles targeting camptothecin to glioma. Nanomedicine (Lond) 2017. [DOI: 10.2217/nnm-2017-0067] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To synthesize cRGDfK peptide conjugated poly(γ-glutamic acid)-phenylalanine nanoparticles to improve the therapeutic efficacy of camptothecin (CPT) against glioblastoma multiforme. Methods: Peptide-conjugated, drug-loaded nanoparticles (cRGDfK-conjugated camptothecin-loaded PGA–PA nanoparticles [RCPN]) were prepared and physico-chemically characterized using different techniques. Nanoparticles were evaluated for in vitro anticancer activity, cellular uptake, induction of apoptosis and wound healing cell migration against U87MG human glioblastoma cells. Results: RCPN, with a particle size of <100 nm and 65% CPT encapsulation efficiency, exhibited a dose- and time-dependent cytotoxicity to glioblastoma cells. Compared with native CPT or unconjugated nanoparticles, RCPN induced apoptosis, increased reactive oxygen species generation and inhibited U87MG cell migration. Conclusion: cRGDfK-mediated and amphiphilic copolymer-based nanomedicines represent a new approach for improved delivery of anticancer drugs to and treatment of glioblastoma multiforme.
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Affiliation(s)
- Hitesh Kulhari
- Ian Potter NanoBioSensing Facility, NanoBiotechnology Research Laboratory, School of Science, RMIT University, Melbourne, VIC 3001, Australia
- Health Innovations Research Institute, RMIT University, Melbourne, VIC 3083, Australia
- IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana 500607, India
- Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana 500607, India
| | - Srinivasa R Telukutla
- Ian Potter NanoBioSensing Facility, NanoBiotechnology Research Laboratory, School of Science, RMIT University, Melbourne, VIC 3001, Australia
- IICT-RMIT Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana 500607, India
- Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana 500607, India
| | - Deep Pooja
- Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana 500607, India
| | - Ravi Shukla
- Ian Potter NanoBioSensing Facility, NanoBiotechnology Research Laboratory, School of Science, RMIT University, Melbourne, VIC 3001, Australia
- Health Innovations Research Institute, RMIT University, Melbourne, VIC 3083, Australia
| | - Ramakrishna Sistla
- Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana 500607, India
| | - Vipul Bansal
- Ian Potter NanoBioSensing Facility, NanoBiotechnology Research Laboratory, School of Science, RMIT University, Melbourne, VIC 3001, Australia
- Health Innovations Research Institute, RMIT University, Melbourne, VIC 3083, Australia
| | - David J Adams
- Health Innovations Research Institute, RMIT University, Melbourne, VIC 3083, Australia
- Illawarra Health & Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522, Australia
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18
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Chen XQ, Liu M, Wang RF, Yan P, Zhang CL, Ma C, Zhao Q, Yin L, Zhao GY, Guo FQ. Noninvasive imaging of c(RGD) 2 -9R as a potential delivery carrier for transfection of siRNA in malignant tumors. J Labelled Comp Radiopharm 2017; 60:385-393. [PMID: 28423195 DOI: 10.1002/jlcr.3514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 03/31/2017] [Accepted: 04/11/2017] [Indexed: 12/17/2022]
Abstract
The purpose of our study was to develop and evaluate a novel integrin αv β3 -specific delivery carrier for transfection of siRNA in malignant tumors. We adopted arginine-glycine-aspartate (RGD) motif as a tissue target for specific recognition of integrin αν β3 . A chimaeric peptide was synthesized by adding nonamer arginine residues (9-arginine [9R]) at the carboxy terminus of cyclic-RGD dimer, designated as c(RGD)2 -9R, to enable small interfering RNA (siRNA) binding. To test the applicability of the delivery carrier in vivo, c(RGD)2 -9R was labeled with radionuclide of technetium-99m. Biodistribution and γ-camera imaging studies were performed in HepG2 xenograft-bearing nude mice. As results, an optimal 10:1 molar ratio of 99m Tc-c(RGD)2 -9R to siRNA was indicated by the electrophoresis on agarose gels. 99m Tc-c(RGD)2 -9R/siRNA remained stable under a set of conditions in vitro. For in vivo study, tumor radioactivity uptake of 99m Tc-c(RGD)2 -9R/siRNA in nude mice bearing HepG2 xenografts was significantly higher than that of control probe (P < .05). The xenografts were clearly visualized at 4 hours till 6 hours noninvasively after intravenous injection of 99m Tc-c(RGD)2 -9R/siRNA, while the xenografts were not visualized at any time after injection of control probe. It was concluded that c(RGD)2 -9R could be an effective siRNA delivery carrier. Technetium-99m radiolabeled-delivery carrier represents a potential imaging strategy for RNAi-based therapy.
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Affiliation(s)
- Xue Qi Chen
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Meng Liu
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Rong Fu Wang
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Ping Yan
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Chun Li Zhang
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Chao Ma
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Qian Zhao
- Department of Nuclear Medicine, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Lei Yin
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Guang Yu Zhao
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Feng Qin Guo
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
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Levine RM, Kokkoli E. Dual-ligand α5β1 and α6β4 integrin targeting enhances gene delivery and selectivity to cancer cells. J Control Release 2017; 251:24-36. [DOI: 10.1016/j.jconrel.2017.02.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 01/20/2017] [Accepted: 02/15/2017] [Indexed: 12/18/2022]
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An Overview of Multimodal Neuroimaging Using Nanoprobes. Int J Mol Sci 2017; 18:ijms18020311. [PMID: 28157157 PMCID: PMC5343847 DOI: 10.3390/ijms18020311] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 01/26/2017] [Indexed: 01/14/2023] Open
Abstract
Nanomaterials have gained tremendous significance as contrast agents for both anatomical and functional preclinical bio-imaging. Contrary to conventional medical practices, molecular imaging plays an important role in exploring the affected cells, thus providing precision medical solutions. It has been observed that incorporating nanoprobes improves the overall efficacy of the diagnosis and treatment processes. These nano-agents and tracers are therefore often incorporated into preclinical therapeutic and diagnostic applications. Multimodal imaging approaches are well equipped with nanoprobes to explore neurological disorders, as they can display more than one type of characteristic in molecular imaging. Multimodal imaging systems are explored by researchers as they can provide both anatomical and functional details of tumors and affected tissues. In this review, we present the state-of-the-art research concerning multimodal imaging systems and nanoprobes for neuroimaging applications.
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21
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Belykh E, Martirosyan NL, Yagmurlu K, Miller EJ, Eschbacher JM, Izadyyazdanabadi M, Bardonova LA, Byvaltsev VA, Nakaji P, Preul MC. Intraoperative Fluorescence Imaging for Personalized Brain Tumor Resection: Current State and Future Directions. Front Surg 2016; 3:55. [PMID: 27800481 PMCID: PMC5066076 DOI: 10.3389/fsurg.2016.00055] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 09/12/2016] [Indexed: 12/29/2022] Open
Abstract
INTRODUCTION Fluorescence-guided surgery is one of the rapidly emerging methods of surgical "theranostics." In this review, we summarize current fluorescence techniques used in neurosurgical practice for brain tumor patients as well as future applications of recent laboratory and translational studies. METHODS Review of the literature. RESULTS A wide spectrum of fluorophores that have been tested for brain surgery is reviewed. Beginning with a fluorescein sodium application in 1948 by Moore, fluorescence-guided brain tumor surgery is either routinely applied in some centers or is under active study in clinical trials. Besides the trinity of commonly used drugs (fluorescein sodium, 5-aminolevulinic acid, and indocyanine green), less studied fluorescent stains, such as tetracyclines, cancer-selective alkylphosphocholine analogs, cresyl violet, acridine orange, and acriflavine, can be used for rapid tumor detection and pathological tissue examination. Other emerging agents, such as activity-based probes and targeted molecular probes that can provide biomolecular specificity for surgical visualization and treatment, are reviewed. Furthermore, we review available engineering and optical solutions for fluorescent surgical visualization. Instruments for fluorescent-guided surgery are divided into wide-field imaging systems and hand-held probes. Recent advancements in quantitative fluorescence-guided surgery are discussed. CONCLUSION We are standing on the threshold of the era of marker-assisted tumor management. Innovations in the fields of surgical optics, computer image analysis, and molecular bioengineering are advancing fluorescence-guided tumor resection paradigms, leading to cell-level approaches to visualization and resection of brain tumors.
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Affiliation(s)
- Evgenii Belykh
- Department of Neurosurgery, St. Joseph’s Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA
- School of Life Sciences, Arizona State University, Tempe, AZ, USA
- Laboratory of Neurosurgery, Irkutsk Scientific Center of Surgery and Traumatology, Irkutsk, Russia
- Irkutsk State Medical University, Irkutsk, Russia
| | - Nikolay L. Martirosyan
- Department of Neurosurgery, St. Joseph’s Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA
- School of Life Sciences, Arizona State University, Tempe, AZ, USA
| | - Kaan Yagmurlu
- Department of Neurosurgery, St. Joseph’s Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA
| | - Eric J. Miller
- University of Arizona College of Medicine – Phoenix, Phoenix, AZ, USA
| | - Jennifer M. Eschbacher
- Department of Neurosurgery, St. Joseph’s Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA
| | - Mohammadhassan Izadyyazdanabadi
- Department of Neurosurgery, St. Joseph’s Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA
- School of Life Sciences, Arizona State University, Tempe, AZ, USA
| | - Liudmila A. Bardonova
- Department of Neurosurgery, St. Joseph’s Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA
- Laboratory of Neurosurgery, Irkutsk Scientific Center of Surgery and Traumatology, Irkutsk, Russia
- Irkutsk State Medical University, Irkutsk, Russia
| | - Vadim A. Byvaltsev
- Laboratory of Neurosurgery, Irkutsk Scientific Center of Surgery and Traumatology, Irkutsk, Russia
- Irkutsk State Medical University, Irkutsk, Russia
| | - Peter Nakaji
- Department of Neurosurgery, St. Joseph’s Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA
| | - Mark C. Preul
- Department of Neurosurgery, St. Joseph’s Hospital and Medical Center, Barrow Neurological Institute, Phoenix, AZ, USA
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22
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Lu W, Hong H, Cai W. Radio-nanomaterials for biomedical applications: state of the art. EUROPEAN JOURNAL OF NANOMEDICINE 2016; 8:151-170. [PMID: 27482194 PMCID: PMC4963156 DOI: 10.1515/ejnm-2016-0011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The incorporation of radioactive isotope(s) into conventional nanomaterials can bring extra properties which are not possessed by original materials. The resulting radioactive nanomaterials (radio-nanomaterials), with added physical/chemical properties, can be used as important tools for different biomedical applications. In this review, our goal is to provide an up-to-date overview on these applications using radio-nanomaterials. The first section illustrates the utilization of radionanomaterials for understanding of in vivo kinetics of their parent nano-materials. In the second section, we focus on two primary applications of radio-nanomaterials: imaging and therapeutic delivery. With various methods being used to form radio-nanomaterials, they can be used for positron emission tomography (PET), single-photon emission computed tomography (SPECT), and multimodal imaging. Therapeutic isotopes-loading radio-nanomaterials can possess selective killing efficacy of diseased cells (e.g. tumor cells) and can provide promises for certain isotopes which are not able to be used in a conventional manner. The successful and versatile biomedical applications of radio-nanomaterials warrants further investigations of those materials and their optimizations can pave the way to future imaging guidable, personalized treatments in patients.
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Affiliation(s)
- Weifei Lu
- Department of Radiology, University of Michigan - Ann Arbor, MI 48109-2200, USA; and College of Animal Sciences and Veterinary Medicine, Henan Agriculture University, Zhengzhou, Henan 450002, China
| | - Hao Hong
- Department of Radiology, University of Michigan - Ann Arbor, MI 48109-2200, USA, , ,
| | - Weibo Cai
- Department of Radiology and Medical Physics, University of Wisconsin - Madison, WI 53705-2275, USA; and University of Wisconsin Carbone Cancer Center, Madison, WI 53705-2275, USA, , ,
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Chakravarty R, Hong H, Cai W. Image-Guided Drug Delivery with Single-Photon Emission Computed Tomography: A Review of Literature. Curr Drug Targets 2016; 16:592-609. [PMID: 25182469 DOI: 10.2174/1389450115666140902125657] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 08/24/2014] [Accepted: 08/26/2014] [Indexed: 12/18/2022]
Abstract
Tremendous resources are being invested all over the world for prevention, diagnosis, and treatment of various types of cancer. Successful cancer management depends on accurate diagnosis of the disease along with precise therapeutic protocol. The conventional systemic drug delivery approaches generally cannot completely remove the competent cancer cells without surpassing the toxicity limits to normal tissues. Therefore, development of efficient drug delivery systems holds prime importance in medicine and healthcare. Also, molecular imaging can play an increasingly important and revolutionizing role in disease management. Synergistic use of molecular imaging and targeted drug delivery approaches provides unique opportunities in a relatively new area called 'image-guided drug delivery' (IGDD). Single-photon emission computed tomography (SPECT) is the most widely used nuclear imaging modality in clinical context and is increasingly being used to guide targeted therapeutics. The innovations in material science have fueled the development of efficient drug carriers based on, polymers, liposomes, micelles, dendrimers, microparticles, nanoparticles, etc. Efficient utilization of these drug carriers along with SPECT imaging technology have the potential to transform patient care by personalizing therapy to the individual patient, lessening the invasiveness of conventional treatment procedures and rapidly monitoring the therapeutic efficacy. SPECT-IGDD is not only effective for the treatment of cancer but might also find utility in the management of several other diseases. Herein, we provide a concise overview of the latest advances in SPECT-IGDD procedures and discuss the challenges and opportunities for advancement of the field.
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Affiliation(s)
- Rubel Chakravarty
- Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.
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The Tumor Microenvironment as a Barrier to Cancer Nanotherapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 936:165-190. [PMID: 27739048 DOI: 10.1007/978-3-319-42023-3_9] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Although extensive research effort and resources have been dedicated to the development of nanotherapeutics to treat cancer, few formulations have reached clinical application. A major reason is that the large number of parameters available to tune nanotherapy characteristics coupled with the variability in tumor tissue precludes evaluation of complex interactions through experimentation alone. In order to optimize the nanotechnology design and gain further insight into these phenomena, mathematical modeling and computational simulation have been applied to complement empirical work. In this chapter, we discuss modeling work related to nanotherapy and the tumor microenvironment. We first summarize the biology underlying the dysregulated tumor microenvironment, followed by a description of major nano-scale parameters. We then present an overview of the mathematical modeling of cancer nanotherapy, including evaluation of nanotherapy in multi-dimensional tumor tissue, coupling of nanotherapy with vascular flow, modeling of nanotherapy in combination with in vivo imaging, modeling of nanoparticle transport based on in vitro data, modeling of vasculature-bound nanoparticles, evaluation of nanotherapy using pharmacokinetic modeling, and modeling of nano-based hyperthermia. We conclude that an even tighter interdisciplinary effort between biological, material, and physical scientists is needed in order to eventually overcome the tumor microenvironment barrier to successful nanotherapy.
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Rauscher A, Frindel M, Rajerison H, Gouard S, Maurel C, Barbet J, Faivre-Chauvet A, Mougin-Degraef M. Improvement of the Targeting of Radiolabeled and Functionalized Liposomes with a Two-Step System Using a Bispecific Monoclonal Antibody (Anti-CEA × Anti-DTPA-In). Front Med (Lausanne) 2015; 2:83. [PMID: 26636087 PMCID: PMC4658472 DOI: 10.3389/fmed.2015.00083] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 11/06/2015] [Indexed: 01/16/2023] Open
Abstract
This study proposes liposomes as a new tool for pretargeted radioimmunotherapy (RIT) in solid tumors. Tumor pretargeting is obtained by using a bispecific monoclonal antibody [BsmAb, anti-CEA × anti-DTPA-indium complex (DTPA–In)] and pegylated radioactive liposomes containing a lipid-hapten conjugate (DSPE–PEG–DTPA–In). In this work, the immunospecificity of tumor targeting is demonstrated both in vitro by fluorescence microscopy and in vivo by biodistribution studies.
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Affiliation(s)
- Aurore Rauscher
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), 6299 CNRS, UMR 892 - INSERM, Université de Nantes , Nantes , France ; Nuclear Medicine Department, Institut de Cancérologie de l'Ouest , Saint Herblain , France
| | - Mathieu Frindel
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), 6299 CNRS, UMR 892 - INSERM, Université de Nantes , Nantes , France ; Nuclear Medicine Department, University Hospital Nantes , Nantes , France
| | - Holisoa Rajerison
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), 6299 CNRS, UMR 892 - INSERM, Université de Nantes , Nantes , France
| | - Sébastien Gouard
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), 6299 CNRS, UMR 892 - INSERM, Université de Nantes , Nantes , France
| | - Catherine Maurel
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), 6299 CNRS, UMR 892 - INSERM, Université de Nantes , Nantes , France
| | - Jacques Barbet
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), 6299 CNRS, UMR 892 - INSERM, Université de Nantes , Nantes , France ; GIP Arronax , Saint Herblain , France
| | - Alain Faivre-Chauvet
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), 6299 CNRS, UMR 892 - INSERM, Université de Nantes , Nantes , France ; Nuclear Medicine Department, University Hospital Nantes , Nantes , France
| | - Marie Mougin-Degraef
- Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), 6299 CNRS, UMR 892 - INSERM, Université de Nantes , Nantes , France ; Nuclear Medicine Department, University Hospital Nantes , Nantes , France
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Kang CM, Koo HJ, An GI, Choe YS, Choi JY, Lee KH, Kim BT. Hybrid PET/optical imaging of integrin αVβ3 receptor expression using a (64)Cu-labeled streptavidin/biotin-based dimeric RGD peptide. EJNMMI Res 2015; 5:60. [PMID: 26518424 PMCID: PMC4628001 DOI: 10.1186/s13550-015-0140-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 10/19/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hybrid PET/optical imaging provides quantitative and complementary information for diagnosis of tumors. Herein, we developed a (64)Cu-labeled AlexaFluor 680-streptavidin ((AF)SAv)/biotin-based dimeric cyclic RGD peptide (RGD2) for hybrid PET/optical imaging of integrin αVβ3 expression. METHODS (64)Cu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-(AF)SAv/biotin-PEG-RGD2 was prepared by formation of a complex comprising DOTA-(AF)SAv and biotin-PEG-RGD2, followed by radiolabeling with (64)Cu. Receptor binding studies of DOTA-(AF)SAv/biotin-PEG-RGD2 were performed using U87MG cells and (125)I-RGDyK as the radioligand, and cellular uptake studies of (64)Cu-DOTA-(AF)SAv/biotin-PEG-RGD2 were also performed. MicroPET imaging followed by optical imaging of U87MG tumor-bearing mice was acquired after injection of the hybrid probe, and region of interest (ROI) analysis of tumors was performed. Ex vivo PET/optical imaging and biodistribution studies of the major tissues were performed after the in vivo imaging, and immunofluorescence staining of the tumor tissue sections was carried out. RESULTS (64)Cu-DOTA-(AF)SAv/biotin-PEG-RGD2 was prepared in 52.1 ± 5.4 % radiochemical yield and with specific activity of 1.0 ± 0.1 GBq/mg. Receptor binding studies showed that DOTA-(AF)SAv/biotin-PEG-RGD2 had higher binding affinity for integrin αVβ3 than RGD2, reflecting a possible polyvalency effect. Moreover, the hybrid probe revealed time-dependent uptake by U87MG cells. In a microPET/optical imaging study, the hybrid probe demonstrated high accumulation in tumors; ROI analysis revealed 2.7 ± 0.2 % ID/g at 1 h and 4.7 ± 0.2 % ID/g at 21 h after injection, and subsequently acquired optical images showed tumors with strong fluorescence intensity. Ex vivo PET/optical images of the major tissues confirmed the in vivo imaging data, and biodistribution studies demonstrated high and specific uptake in tumors (4.8 ± 0.1 % ID/g). Immunofluorescence staining showed the formation of new blood vessels in tumor tissues, suggesting that the tumor uptake was due to specific binding of the hybrid probe to integrin αVβ3 expressed on tumor cells. CONCLUSIONS These results indicate that a (64)Cu-DOTA-(AF)SAv/biotin-PEG-RGD2 is able to provide quantitative information on hybrid PET/optical imaging of integrin αVβ3 expression.
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Affiliation(s)
- Choong Mo Kang
- Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Korea
| | - Hyun-Jung Koo
- Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
| | - Gwang Il An
- Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea
| | - Yearn Seong Choe
- Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea. .,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Korea.
| | - Joon Young Choi
- Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
| | - Kyung-Han Lee
- Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Korea
| | - Byung-Tae Kim
- Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea
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27
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Seo HJ, Nam SH, Im HJ, Park JY, Lee JY, Yoo B, Lee YS, Jeong JM, Hyeon T, Kim JW, Lee JS, Jang IJ, Cho JY, Hwang DW, Suh YD, Lee DS. Rapid Hepatobiliary Excretion of Micelle-Encapsulated/Radiolabeled Upconverting Nanoparticles as an Integrated Form. Sci Rep 2015; 5:15685. [PMID: 26494465 PMCID: PMC4616227 DOI: 10.1038/srep15685] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 09/28/2015] [Indexed: 02/07/2023] Open
Abstract
In the field of nanomedicine, long term accumulation of nanoparticles (NPs) in the mononuclear phagocyte system (MPS) such as liver is the major hurdle in clinical translation. On the other hand, NPs could be excreted via hepatobiliary excretion pathway without overt tissue toxicity. Therefore, it is critical to develop NPs that show favorable excretion property. Herein, we demonstrated that micelle encapsulated 64Cu-labeled upconverting nanoparticles (micelle encapsulated 64Cu-NOTA-UCNPs) showed substantial hepatobiliary excretion by in vivo positron emission tomography (PET) and also upconversion luminescence imaging (ULI). Ex vivo biodistribution study reinforced the imaging results by showing clearance of 84% of initial hepatic uptake in 72 hours. Hepatobiliary excretion of the UCNPs was also verified by transmission electron microscopy (TEM) examination. Micelle encapsulated 64Cu-NOTA-UCNPs could be an optimal bimodal imaging agent owing to quantifiability of 64Cu, ability of in vivo/ex vivo ULI and good hepatobiliary excretion property.
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Affiliation(s)
- Hyo Jung Seo
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.,Department of Nuclear medicine, Seoul National University College of Medicine,Seoul, Korea
| | - Sang Hwan Nam
- Laboratory for Advanced Molecular Probing (LAMP), Research Center for Convergence Nanotechnology, Korea Research Institute of Chemical Technology, Daejeon, Korea
| | - Hyung-Jun Im
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.,Department of Nuclear medicine, Seoul National University College of Medicine,Seoul, Korea
| | - Ji-yong Park
- Department of Nuclear medicine, Seoul National University College of Medicine,Seoul, Korea
| | - Ji Youn Lee
- Department of Nuclear medicine, Seoul National University College of Medicine,Seoul, Korea
| | - Byeongjun Yoo
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Korea.,School of Chemical and Biological Engineering, Seoul National University, Seoul, Korea
| | - Yun-Sang Lee
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.,Department of Nuclear medicine, Seoul National University College of Medicine,Seoul, Korea
| | - Jae Min Jeong
- Department of Nuclear medicine, Seoul National University College of Medicine,Seoul, Korea
| | - Taeghwan Hyeon
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Korea.,School of Chemical and Biological Engineering, Seoul National University, Seoul, Korea
| | - Ji Who Kim
- Department of Nuclear medicine, Seoul National University College of Medicine,Seoul, Korea
| | - Jae Sung Lee
- Department of Nuclear medicine, Seoul National University College of Medicine,Seoul, Korea
| | - In-Jin Jang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea
| | - Joo-Youn Cho
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea
| | - Do Won Hwang
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.,Department of Nuclear medicine, Seoul National University College of Medicine,Seoul, Korea
| | - Yung Doug Suh
- Laboratory for Advanced Molecular Probing (LAMP), Research Center for Convergence Nanotechnology, Korea Research Institute of Chemical Technology, Daejeon, Korea.,School of Chemical Engineering, Sungkyunkwan University, Suwon, Korea
| | - Dong Soo Lee
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.,Department of Nuclear medicine, Seoul National University College of Medicine,Seoul, Korea
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Dixit S, Miller K, Zhu Y, McKinnon E, Novak T, Kenney ME, Broome AM. Dual Receptor-Targeted Theranostic Nanoparticles for Localized Delivery and Activation of Photodynamic Therapy Drug in Glioblastomas. Mol Pharm 2015; 12:3250-60. [PMID: 26198693 PMCID: PMC4564323 DOI: 10.1021/acs.molpharmaceut.5b00216] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Targeting gold nanoparticles (AuNPs) with two or more receptor binding peptides has been proposed to address intratumoral heterogeneity of glioblastomas that overexpress multiple cell surface receptors to ultimately improve therapeutic efficacy. AuNPs conjugated with peptides against both the epidermal growth factor and transferrin receptors and loaded with the photosensitizer phthalocyanine 4 (Pc 4) have been designed and compared with monotargeted AuNPs for in vitro and in vivo studies. The (EGFpep+Tfpep)-AuNPs-Pc 4 with a particle size of ∼41 nm improved both specificity and worked synergistically to decrease time of maximal accumulation in human glioma cells that overexpressed two cell surface receptors as compared to cells that overexpressed only one. Enhanced cellular association and increased cytotoxicity were achieved. In vivo studies show notable accumulation of these agents in the brain tumor regions.
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Affiliation(s)
- Suraj Dixit
- Department of Radiology and Radiological Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, United States
| | - Kayla Miller
- Department of Radiology and Radiological Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, United States
| | - Yun Zhu
- Department of Radiology and Radiological Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, United States
| | - Emilie McKinnon
- Center of Biomedical Imaging, Medical University of South Carolina, Charleston, South Carolina 29425, United States
| | - Thomas Novak
- Department of Radiology and Radiological Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, United States
| | - Malcolm E. Kenney
- Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States
| | - Ann-Marie Broome
- Department of Radiology and Radiological Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, United States
- Center of Biomedical Imaging, Medical University of South Carolina, Charleston, South Carolina 29425, United States
- Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, United States
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Sabnis N, Bowman WP, Lacko AG. Lipoprotein based drug delivery: Potential for pediatric cancer applications. World J Pharmacol 2015; 4:172-179. [DOI: 10.5497/wjp.v4.i2.172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 12/22/2014] [Accepted: 03/05/2015] [Indexed: 02/06/2023] Open
Abstract
While survival rates for patients with childhood cancers have substantially improved, the quality of life of the survivors is often adversely impacted by the residual effects of chemo and radiation therapy. Because of the existing metabolic and physiological disparities between pediatric and adult patients, the treatment of pediatric cancer patients poses special challenges to oncologists. While numerous clinical trials being conducted, to improve treatment outcomes for pediatric cancer patients, new approaches are required to increase the efficacy and to minimize the drug related toxic side effects. Nanotechnology is a potentially effective tool to overcome barriers to effective cancer therapeutics including poor bioavailability and non-specific targeting. Among the nano-delivery approaches, lipoprotein based formulations have shown particularly strong promise to improve cancer therapeutics. The present article describes the challenges faced in the treatment of pediatric cancers and reviews the potential of lipoprotein-based therapeutics for these malignancies.
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30
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Lee DS, Im HJ, Lee YS. Radionanomedicine: Widened perspectives of molecular theragnosis. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2015; 11:795-810. [DOI: 10.1016/j.nano.2014.12.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 12/17/2014] [Accepted: 12/18/2014] [Indexed: 10/24/2022]
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Haedicke K, Kozlova D, Gräfe S, Teichgräber U, Epple M, Hilger I. Multifunctional calcium phosphate nanoparticles for combining near-infrared fluorescence imaging and photodynamic therapy. Acta Biomater 2015; 14:197-207. [PMID: 25529187 DOI: 10.1016/j.actbio.2014.12.009] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/20/2014] [Accepted: 12/14/2014] [Indexed: 01/29/2023]
Abstract
Photodynamic therapy (PDT) of tumors causes skin photosensitivity as a result of unspecific accumulation behavior of the photosensitizers. PDT of tumors was improved by calcium phosphate nanoparticles conjugated with (i) Temoporfin as a photosensitizer, (ii) the RGDfK peptide for favored tumor targeting and (iii) the fluorescent dye molecule DY682-NHS for enabling near-infrared fluorescence (NIRF) optical imaging in vivo. The nanoparticles were characterized with regard to size, spectroscopic properties and uptake into CAL-27 cells. The nanoparticles had a hydrodynamic diameter of approximately 200 nm and a zeta potential of around +22mV. Their biodistribution at 24h after injection was investigated via NIRF optical imaging. After treating tumor-bearing CAL-27 mice with nanoparticle-PDT, the therapeutic efficacy was assessed by a fluorescent DY-734-annexin V probe at 2 days and 2 weeks after treatment to detect apoptosis. Additionally, the contrast agent IRDye® 800CW RGD was used to assess tumor vascularization (up to 4 weeks after PDT). After nanoparticle-PDT in mice, apoptosis in the tumor was detected after 2 days. Decreases in tumor vascularization and tumor volume were detected in the next few days. Calcium phosphate nanoparticles can be used as multifunctional tools for NIRF optical imaging, PDT and tumor targeting as they exhibited a high therapeutic efficacy, being capable of inducing apoptosis and destroying tumor vascularization.
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Affiliation(s)
- Katja Haedicke
- Department of Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich-Schiller University Jena, 07747 Jena, Germany
| | - Diana Kozlova
- Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, 45117 Essen, Germany
| | - Susanna Gräfe
- Biolitec Research GmbH, Research & Development, 07745 Jena, Germany
| | - Ulf Teichgräber
- Department of Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich-Schiller University Jena, 07747 Jena, Germany
| | - Matthias Epple
- Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, 45117 Essen, Germany.
| | - Ingrid Hilger
- Department of Experimental Radiology, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, Friedrich-Schiller University Jena, 07747 Jena, Germany.
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32
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Smilkov K, Janevik E, Guerrini R, Pasquali M, Boschi A, Uccelli L, Di Domenico G, Duatti A. Preparation and first biological evaluation of novel Re-188/Tc-99m peptide conjugates with substance-P. Appl Radiat Isot 2014; 92:25-31. [PMID: 24973465 DOI: 10.1016/j.apradiso.2014.06.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Revised: 04/13/2014] [Accepted: 06/02/2014] [Indexed: 11/26/2022]
Abstract
INTRODUCTION New (188)Re and (99m)Tc peptide conjugates with substance- P (SP) were prepared and biologically evaluated. The radiopharmaceuticals have been labelled with the [M≡N](2+) (M=(99m)Tc, (188)Re) core using a combination of π-donor tridentate and π-acceptor monodentate ancillary ligands. METHODS The new radiopharmaceuticals have been prepared through a two-step reaction by simultaneous addition of the tridentate and monodentate ligands to a vial containing a preformed [M≡N](2+) core. The tridentate ligand was formed by linking two cysteine residues to the terminal arginine of the undecapeptide SP, whereas the monodentate ligand was a tertiary phosphine. The preparation of the corresponding Re-188 derivative required developing a more complex chemical procedure to obtain the [Re≡N](2+) core in satisfactory yields. Characterization of the resulting products was obtained by chromatographic methods. Biological evaluation was performed for both Tc-99m and Re-188 derivatives by in-vitro studies on isolated cells expressing NK1-receptors. In-vivo imaging in mice was carried out using a small-animal YAP(S)PET tomograph. CONCLUSION New Tc-99m and Re-188 peptide radiopharmaceuticals with SP have been prepared in high-yield and with high-specific activity. Both Tc-99m and Re-188 peptide radioconjugates exhibit high affinity for NK1 receptors, thus giving further evidence to the empirical rule that structurally related Tc-99m and Re-188 radiopharmaceuticals exhibit identical biological properties.
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Affiliation(s)
- Katarina Smilkov
- Faculty of Medical Sciences, University 'Goce Delcev', Stip, Macedonia
| | - Emilija Janevik
- Faculty of Medical Sciences, University 'Goce Delcev', Stip, Macedonia
| | - Remo Guerrini
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Micol Pasquali
- Laboratory of Nuclear Medicine, Department of Experimental Medicine, University of Ferrara, Via L. Borsari, 46, 44121 Ferrara, Italy
| | - Alessandra Boschi
- Laboratory of Nuclear Medicine, Department of Experimental Medicine, University of Ferrara, Via L. Borsari, 46, 44121 Ferrara, Italy
| | - Licia Uccelli
- Laboratory of Nuclear Medicine, Department of Experimental Medicine, University of Ferrara, Via L. Borsari, 46, 44121 Ferrara, Italy
| | - Giovanni Di Domenico
- Faculty of Medical Sciences, University 'Goce Delcev', Stip, Macedonia; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy; Laboratory of Nuclear Medicine, Department of Experimental Medicine, University of Ferrara, Via L. Borsari, 46, 44121 Ferrara, Italy
| | - Adriano Duatti
- Laboratory of Nuclear Medicine, Department of Experimental Medicine, University of Ferrara, Via L. Borsari, 46, 44121 Ferrara, Italy.
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Luo H, Hong H, Yang SP, Cai W. Design and applications of bispecific heterodimers: molecular imaging and beyond. Mol Pharm 2014; 11:1750-61. [PMID: 24738564 PMCID: PMC4051252 DOI: 10.1021/mp500115x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Ligand-based molecular imaging probes have been designed with high affinity and specificity for monitoring biological process and responses. Single-target recognition by traditional probes can limit their applicability for disease detection and therapy because synergistic action between disease mediators and different receptors is often involved in disease progression. Consequently, probes that can recognize multiple targets should demonstrate higher targeting efficacy and specificity than their monospecific peers. This concept has been validated by multiple bispecific heterodimer-based imaging probes that have demonstrated promising results in several animal models. This review summarizes the design strategies for bispecific peptide- and antibody-based heterodimers and their applications in molecular targeting and imaging. The design and application of bispecific heterodimer-conjugated nanomaterials are also discussed.
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Affiliation(s)
- Haiming Luo
- Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 53705-2275, United States
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34
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Lale SV, R G A, Aravind A, Kumar DS, Koul V. AS1411 aptamer and folic acid functionalized pH-responsive ATRP fabricated pPEGMA-PCL-pPEGMA polymeric nanoparticles for targeted drug delivery in cancer therapy. Biomacromolecules 2014; 15:1737-52. [PMID: 24689987 DOI: 10.1021/bm5001263] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Nonspecificity and cardiotoxicity are the primary limitations of current doxorubicin chemotherapy. To minimize side effects and to enhance bioavailability of doxorubicin to cancer cells, a dual-targeted pH-sensitive biocompatible polymeric nanosystem was designed and developed. An ATRP-based biodegradable triblock copolymer, poly(poly(ethylene glycol) methacrylate)-poly(caprolactone)-poly(poly(ethylene glycol) methacrylate) (pPEGMA-PCL-pPEGMA), conjugated with doxorubicin via an acid-labile hydrazone bond was synthesized and characterized. Dual targeting was achieved by attaching folic acid and the AS1411 aptamer through EDC-NHS coupling. Nanoparticles of the functionalized triblock copolymer were prepared using the nanoprecipitation method, resulting in an average particle size of ∼140 nm. The biocompatibility of the nanoparticles was evaluated using MTT cytotoxicity assays, blood compatibility studies, and protein adsorption studies. In vitro drug release studies showed a higher cumulative doxorubicin release at pH 5.0 (∼70%) compared to pH 7.4 (∼25%) owing to the presence of the acid-sensitive hydrazone linkage. Dual targeting with folate and the AS1411 aptamer increased the cancer-targeting efficiency of the nanoparticles, resulting in enhanced cellular uptake (10- and 100-fold increase in uptake compared to single-targeted NPs and non-targeted NPs, respectively) and a higher payload of doxorubicin in epithelial cancer cell lines (MCF-7 and PANC-1), with subsequent higher apoptosis, whereas a normal (noncancerous) cell line (L929) was spared from the adverse effects of doxorubicin. The results indicate that the dual-targeted pH-sensitive biocompatible polymeric nanosystem can act as a potential drug delivery vehicle against various epithelial cancers such as those of the breast, ovary, pancreas, lung, and others.
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Affiliation(s)
- Shantanu V Lale
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi , New Delhi 110016, India
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35
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Yang C, Fu ZX. Liposomal delivery and polyethylene glycol-liposomal oxaliplatin for the treatment of colorectal cancer (Review). Biomed Rep 2014; 2:335-339. [PMID: 24748970 PMCID: PMC3990200 DOI: 10.3892/br.2014.249] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 02/25/2014] [Indexed: 12/17/2022] Open
Abstract
Oxaliplatin is effective for the treatment of advanced colorectal cancer; however, its application is restricted due to its dose-limiting toxicity. Liposomes are sphere-shaped vesicles consisting of one or more phospholipid bilayers. Liposomes as drug carriers are characterized by delayed release, lesion targeting and may be used as a drug-delivery system to decrease the side effects of cytotoxic drugs. Active targeting modification of liposomes may change the biological distribution of the anticancer agents, reduce or reverse multidrug resistance of tumor cells and enhance the effects of anticancer therapy. Based on the characteristics mentioned above, the aim of the present review was to demonstrate that polyethylene glycol-liposomes containing oxaliplatin may offer advantages for the treatment of colorectal cancer in clinical practice.
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Affiliation(s)
- Chuang Yang
- Department of General Surgery, Third People's Hospital of Mianyang, Mianyang, Sichuan 621000, P.R. China ; Department of Gastrointestinal Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, Chongqing 400016, P.R. China
| | - Zhong-Xue Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, Chongqing 400016, P.R. China
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36
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De la Garza-Ramos R, Bydon M, Macki M, Huang J, Tamargo RJ, Bydon A. Fluorescent techniques in spine surgery. Neurol Res 2014; 36:928-38. [DOI: 10.1179/1743132814y.0000000340] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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