ABSTRACT
Sonodynamic therapy (SDT) has emerged as a useful approach for tumor treatment. However, its widespread application is impeded by poor pharmacokinetics of existing sonosensitizers. Here we developed a metal-organic nanoplatform, wherein a small-molecule sonosensitizer (hematoporphyrin monomethyl ether, HMME) was ingeniously coordinated with zirconium, resulting in a multifunctional nanosonosensitizer termed Zr-HMME. Through post-synthetic modifications involving PEGylation and tumor-targeting peptide (F3) linkage, a nanoplatform capable of homing on melanoma was produced, which could elicit robust immune responses to suppress tumor lung metastasis in the host organism. Importantly, after seamless incorporation of positron-emitting 89Zr into this nanosonosensitizer, positron emission tomography (PET) could be used to monitor its in vivo pharmacokinetics. PET imaging studies revealed that this nanoplatform exhibited potent tumor accumulation and strong in vivo stability. Using intrinsic fluorescence from HMME, a dual-modal diagnostic capability (fluorescence and PET) was confirmed for this nanosonosensitizer. In addition, the mechanisms of how this nanoplatform interacted with immune system were also investigated. The collective data proved that the coordination structure between small-molecule drug cargos and metals may enhance the functions of each other while mitigating their weaknesses. This straightforward approach can expand the potential applications of suitable drug molecules.
Subject(s)
Hematoporphyrins , Positron-Emission Tomography , Zirconium , Zirconium/chemistry , Zirconium/pharmacokinetics , Animals , Positron-Emission Tomography/methods , Cell Line, Tumor , Hematoporphyrins/administration & dosage , Hematoporphyrins/chemistry , Hematoporphyrins/pharmacokinetics , Melanoma/diagnostic imaging , Melanoma/drug therapy , Mice, Inbred C57BL , Ultrasonic Therapy/methods , Mice , Melanoma, Experimental/therapy , Melanoma, Experimental/diagnostic imaging , Nanoparticles/chemistry , Female , Radioisotopes/administration & dosageABSTRACT
BACKGROUND/AIMS: Recombinant adeno-associated viruses (rAAV) are an important tool for lung targeted gene therapy. Substitution of tyrosine with phenylalanine residues (Y-F) in the capsid have been shown to protect the AAV vector from ubiquitin/proteasome degradation, increasing transduction efficiency. We tested the mutant Y733F-AAV8 vector for mucus diffusion, as well as the safety and efficacy of pigment epithelium-derived factor (PEDF) gene transfer to the lung. METHODS: For this purpose, Y733F-AAV8-PEDF (1010 viral genome) was administered intratracheally to C57BL/6 mice. Lung mechanics, morphometry, and inflammation were evaluated 7, 14, 21, and 28 days after injection. RESULTS: The tyrosine-mutant AAV8 vector was efficient at penetrating mucus in ex vivo assays and at transferring the gene to lung cells after in vivo instillation. Increased levels of transgene mRNA were observed 28 days after vector administration. Overexpression of PEDF did not affect in vivo lung parameters. CONCLUSION: These findings provide a basis for further development of Y733F-AAV8-based gene therapies for safe and effective delivery of PEDF, which has anti-angiogenic, anti-inflammatory and anti-fibrotic activities and might be a promising therapy for lung inflammatory disorders.
Subject(s)
Eye Proteins , Gene Transfer Techniques , Serpins , Animals , Mice , Eye Proteins/genetics , Mice, Inbred C57BL , Nerve Growth Factors/genetics , Serpins/geneticsABSTRACT
Vaccine hesitancy and the occurrence of elusive variants necessitate further treatment options for coronavirus disease 2019 (COVID-19). Accumulated evidence indicates that clinically used hypertensive drugs, angiotensin receptor blockers (ARBs), may benefit patients by mitigating disease severity and/or viral propagation. However, current clinical formulations administered orally pose systemic safety concerns and likely require a very high dose to achieve the desired therapeutic window in the lung. To address these limitations, we have developed a nanosuspension formulation of an ARB, entirely based on clinically approved materials, for inhaled treatment of COVID-19. We confirmed in vitro that our formulation exhibits physiological stability, inherent drug activity, and inhibitory effect against SARV-CoV-2 replication. Our formulation also demonstrates excellent lung pharmacokinetics and acceptable tolerability in rodents and/or nonhuman primates following direct administration into the lung. Thus, we are currently pursuing clinical development of our formulation for its uses in patients with COVID-19 or other respiratory infections.
Subject(s)
COVID-19 , Respiratory Tract Infections , Animals , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Telmisartan , Renin-Angiotensin System/physiology , SARS-CoV-2 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Respiratory Tract Infections/drug therapyABSTRACT
Inhaled gene therapy poses a unique potential of curing chronic lung diseases, which are currently managed primarily by symptomatic treatments. However, it has been challenging to achieve therapeutically relevant gene transfer efficacy in the lung due to the presence of numerous biological delivery barriers. Here, we introduce a simple approach that overcomes both extracellular and cellular barriers to enhance gene transfer efficacy in the lung inâ vivo. We endowed tetra(piperazino)fullerene epoxide (TPFE)-based nanoparticles with non-adhesive surface polyethylene glycol (PEG) coatings, thereby enabling the nanoparticles to cross the airway mucus gel layer and avoid phagocytic uptake by alveolar macrophages. In parallel, we utilized a hypotonic vehicle to facilitate endocytic uptake of the PEGylated nanoparticles by lung parenchymal cells via the osmotically driven regulatory volume decrease (RVD) mechanism. We demonstrate that this two-pronged delivery strategy provides safe, wide-spread and high-level transgene expression in the lungs of both healthy mice and mice with chronic lung diseases characterized by reinforced delivery barriers.
Subject(s)
Epoxy Compounds/chemistry , Fullerenes/chemistry , Gene Transfer Techniques , Lung Diseases/therapy , Nanoparticles/chemistry , Chronic Disease , Humans , Lung Diseases/metabolismABSTRACT
The urokinase plasminogen activator (uPA) and its cofactors are important regulators of tumor initiation and progression (including metastasis), and its overexpression is associated with unfavorable situations in cancer patients. We have previously used positron emission tomography (PET) imaging with a radiolabeled monoclonal antibody against the uPA (named ATN-291) to detect the uPA signaling activity in various cancer types; however, good tumor contrast can only be observed 24 h postinjection. To shorten the antibody circulation time and decrease interactions of ATN-291 with the mononuclear phagocyte system (MPS), our goal in this study is to develop an engineered antibody fragment (F(ab')2) from the parent antibody. By pepsin digestion and chromatography purification, ATN-291 F(ab')2 was obtained and characterized. Subsequently, it was conjugated with NOTA-Bn-NCS or fluorescein isothiocyanate (FITC) for PET imaging and fluorescence-mediated cellular analysis (i.e., flow cytometry or fluorescence microscopy). We confirmed that ATN-291 F(ab')2 still maintained a good targeting efficacy for the uPA in MDA-MB-231 cells (uPA+) and it had a faster blood clearance speed compared with ATN-291, while its interaction with MPS has been significantly decreased. In rodent tumor xenografts, radiolabeled ATN-291 F(ab')2 had a selective and persistent uptake in MDA-MB-231 tumors, with an early tumor-to-blood ratio of 1.3 ± 0.8 (n = 4) at 2 h postinjection from PET imaging. During our observation, radiolabeled ATN-291 F(ab')2 was excreted from both renal and hepatobiliary pathways. Radiolabeled ATN-291 F(ab')2 was also used for detecting uPA fluctuation during the tumor treatment in test animals. We concluded that radiolabeled ATN-291 F(ab')2 could be used as fast as PET cancer diagnostics with versatile applicability.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Immunoglobulin Fab Fragments/administration & dosage , Membrane Proteins/antagonists & inhibitors , Positron-Emission Tomography/methods , Triple Negative Breast Neoplasms/diagnosis , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Female , Fluorescein-5-isothiocyanate/chemistry , Humans , Immunoglobulin Fab Fragments/chemistry , Immunoglobulin Fab Fragments/genetics , Membrane Proteins/metabolism , Mice , Protein Engineering , Triple Negative Breast Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
Introduction: Airway mucus gel layer serves as a key delivery barrier that limits the performance of inhaled drug delivery nanoparticles. Conventional nanoparticles are readily trapped by the airway mucus and rapidly cleared from the lung via mucus clearance mechanisms. These nanoparticles cannot distribute throughout the lung airways, long-reside in the lung and/or reach the airway epithelium. To address this challenge, strategies to enhance particle penetration through the airway mucus have been developed and proof-of-concept has been established using mucus model systems..Areas covered: In this review, we first overview the biochemical and biophysical characteristics that render the airway mucus a challenging delivery barrier. We then introduce strategies to improve particle penetration through the airway mucus. Specifically, we walk through two classes of approaches, including modification of physicochemical properties of nanoparticles and modulation of barrier properties of airway mucus.Expert opinion: State-of-the-art strategies to overcome the airway mucus barrier have been introduced and experimentally validated. However, data should be interpreted in the comprehensive context of therapeutic delivery from the site of administration to the final destination to determine clinically-relevant approaches. Further, safety should be carefully monitored, particularly when it comes to mucus-altering strategies that may perturb physiological functions of airway mucus.
Subject(s)
Nanoparticles , Pharmaceutical Preparations , Drug Delivery Systems , Humans , Lung , MucusABSTRACT
Chronic exposure to crystalline silica causes the development of silicosis, which is one of the most important occupational diseases worldwide. In the early stage of silicosis, inhaled silica crystals initiate oxidative stress, a cycle of persistent inflammation and lung injury. And it is crucial to prevent the deteriorative progression in the onset of the disease. Herein, we present a promising candidate for the treatment of crystalline silica-induced pulmonary inflammation, using a silicosis mouse model caused by intratracheal instillation based on local administration of ß-alanine and hydroxyl functionalized C70 fullerene nanoparticles (FNs). The results demonstrate that FNs could significantly alleviate inflammatory cells infiltration, lower the secretion of pro-inflammatory cytokines, and reduce the destruction of lung architecture stimulated by crystalline silica. Further investigations reveal that FNs could effectively inhibit the activation of NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome, and thus prevent the secretion of mature IL-1ß and neutrophil influx, deriving from the superior ROS scavenging capability. Importantly, FNs could not cause any obvious toxicity after pulmonary administration.
Subject(s)
Fullerenes , Nanoparticles , Pneumonia , Silicosis , Animals , Inflammation/drug therapy , Lung , Mice , Pneumonia/drug therapy , Silicon Dioxide , Silicosis/drug therapyABSTRACT
There has been great progress in ocular gene therapy, but delivery of viral vectors to the retinal pigmented epithelium (RPE) and retina can be challenging. Subretinal injection, the preferred route of delivery for most applications, requires a surgical procedure that has risks. Herein we report a novel gene therapy delivery approach, suprachoroidal injection of AAV8 vectors, which is less invasive and could be done in an outpatient setting. Two weeks after suprachoroidal injection of AAV8.GFP in rats, GFP fluorescence covered 18.9% of RPE flat mounts and extended entirely around sagittal and transverse sections in RPE and photoreceptors. After 2 suprachoroidal injections of AAV8.GFP, GFP fluorescence covered 30.5% of RPE flat mounts. Similarly, widespread expression of GFP occurred in nonhuman primate and pig eyes after suprachoroidal injection of AAV8.GFP. Compared with subretinal injection in rats of RGX-314, an AAV8 vector expressing an anti-VEGF Fab, suprachoroidal injection of the same dose of RGX-314 resulted in similar expression of anti-VEGF Fab and similar suppression of VEGF-induced vascular leakage. Suprachoroidal AAV8 vector injection provides a noninvasive outpatient procedure to obtain widespread transgene expression in retina and RPE.
Subject(s)
Dependovirus , Gene Expression , Genetic Vectors , Green Fluorescent Proteins/biosynthesis , Retinal Pigment Epithelium/metabolism , Transduction, Genetic , Transgenes , Animals , Green Fluorescent Proteins/genetics , Macaca mulatta , Retinal Pigment Epithelium/pathologyABSTRACT
Water-soluble gadofullerene nanomaterials have been extensively investigated as magnetic resonance imaging (MRI) contrast agents, radical scavengers, sensitizers for photodynamic therapy, and inherent antineoplastic agents. Most recently, an alanine-modified gadofullerene nanoparticle (Gd@C82-Ala) with excellent anticancer activity has been reported; however, the absolute tumor uptake of Gd@C82-Ala is still far from being satisfactory, and its dynamic pharmacokinetics and long-term metabolic behaviors remain to be elucidated. Herein, Gd@C82-Ala was chemically modified with eight-arm polyethylene glycol amine to improve its biocompatibility and provide the active sites for the attachment of a tumor-homing ligand (cRGD) and positron emission tomography (PET) isotopes (i.e., 64Cu or 89Zr). The physical and chemical properties (e.g., size, surface functionalization condition, radiochemical stability, etc.) of functionalized Gd@C82-Ala were properly characterized. Also, its glioblastoma cell targeting capacity was evaluated in vitro by flow cytometry, confocal fluorescence microscopy, and dynamic cellular interaction assays. Because of the presence of gadolinium ions, the gadofullerene conjugates can act simultaneously as T1* MRI contrast agents and PET probes. Thus, the pharmacokinetic behavior of functionalized Gd@C82-Ala was investigated by PET/MRI, which combines the merits of high resolution and excellent sensitivity. The functionalized Gd@C82-Ala-PEG-cRGD-NOTA-64Cu (NOTA stands for 1,4,7-triazacyclononane-triacetic acid) demonstrated much higher accumulation in U87-MG tumor than its counterpart without cRGD attachment from in vivo PET observation, consistent with observation at the cellular level. In addition, Gd@C82-Ala-PEG-Df-89Zr (Df stands for desferrioxamine) was employed to investigate the metabolic behavior of gadofullerene conjugates in vivo for up to 30 days. It was estimated that nearly 70% of Gd@C82-Ala-PEG-Df-89Zr was excreted from the test subjects primarily through renal pathways within 24 h. With proper surface engineering, functionalized Gd@C82-Ala nanoparticles can show an improved accumulation in glioblastoma. Pharmacokinetic studies also confirmed the safety of this nanoplatform, which can be used as an image-guidable therapeutic agent for glioblastoma.
Subject(s)
Glioblastoma/diagnostic imaging , Magnetic Resonance Imaging/methods , Nanoparticles/chemistry , Positron-Emission Tomography/methods , Animals , Flow Cytometry , Fullerenes/chemistry , Gadolinium/chemistry , Humans , MCF-7 Cells , Mice , Microscopy, ConfocalABSTRACT
Efficient treatment of primary tumor and preventing cancer metastasis present intriguing alternatives to cancer therapy. Herein, for the first time, we reported the photo-triggered nano-gadofullerene (Gd@C82-Ala, abbreviated Gd-Ala) induced malignant tumor vascular disruption by shortening the light interval between Gd-Ala administration and light illumination, where oxygen in blood vessels was employed efficiently to produce cytotoxic reactive oxygen species (ROS). The produced ROS could not only destroy the tumor cells but also devastate the vascular endothelial cells corresponding to the loss of intercellular junctions and vessels disruption. Notably, the irradiated Gd-Ala could enhance dendritic cells (DCs) maturation, which further secreted tumor necrosis factor-α (TNF-α) and interleukin-12 (IL)-12, and then activated T lymphocytes by up-regulation of cluster of differentiation CD4+ and CD8+ T lymphocytes. Furthermore, the down-regulation of matrix metalloprotein 2 (MMP2) and MMP9 also reduce the rate of tumor metastasis. This work explored a new biomedical application of gadofullerene, thereby providing a smart carbon nanomaterial candidate for tumor ablation and inhibition of cancer metastasis.
Subject(s)
Antineoplastic Agents/pharmacology , Fullerenes/pharmacology , Neoplasms/drug therapy , Neovascularization, Pathologic , Photosensitizing Agents/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Line, Tumor , Dendritic Cells/metabolism , Female , Fullerenes/chemistry , Fullerenes/therapeutic use , Human Umbilical Vein Endothelial Cells , Humans , Immune System , Interleukin-12/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred BALB C , Neoplasm Metastasis , Neoplasms/blood supply , Photosensitizing Agents/chemistry , Photosensitizing Agents/therapeutic use , Reactive Oxygen Species/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Reactive oxygen species (ROS) and glutathione (GSH) dual responsive nanoparticulate drug delivery systems (nano-DDSs) hold great promise to improve the therapeutic efficacy and alleviate the side effects of chemo drugs in cancer theranosis. Herein, hydrogen peroxide (H2O2) and GSH dual responsive thioketal nanoparticle (TKN) was rationally designed for paclitaxel (PTX) delivery. Compared to other stimuli-sensitive nano-DDSs, this dual responsive DDS is not only sensitive to biologically relevant H2O2 and GSH for on-demand drug release but also biodegradable into biocompatible byproducts after fulfilling its delivering task. Considering the heterogeneous redox potential gradient, the PTX loaded TKNs (PTX-TKNs) might first respond to the extracellular ROS and then to the intracellular GSH, achieving a programmable release of PTX at the tumor site. The selective toxicity of PTX-TKNs to tumor cells with high levels of ROS and GSH was verified both in vitro and in vivo.
Subject(s)
Antineoplastic Agents/therapeutic use , Drug Carriers/chemistry , Nanoparticles/chemistry , Paclitaxel/therapeutic use , Prostatic Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biodegradable Plastics/chemical synthesis , Biodegradable Plastics/chemistry , Biodegradable Plastics/toxicity , CHO Cells , Cell Line, Tumor , Cricetulus , Drug Carriers/chemical synthesis , Drug Carriers/toxicity , Drug Liberation , Glutathione/chemistry , Green Chemistry Technology/methods , Humans , Hydrogen Peroxide/chemistry , Male , Mice , Nanoparticles/toxicity , Paclitaxel/chemistry , Paclitaxel/pharmacology , Polymers/chemical synthesis , Polymers/chemistry , Polymers/toxicity , Sulfides/chemical synthesis , Sulfides/chemistry , Sulfides/toxicity , Xenograft Model Antitumor AssaysABSTRACT
Nanoscale metal-organic frameworks (nMOF) materials represent an attractive tool for various biomedical applications. Due to the chemical versatility, enormous porosity, and tunable degradability of nMOFs, they have been adopted as carriers for delivery of imaging and/or therapeutic cargos. However, the relatively low stability of most nMOFs has limited practical in vivo applications. Here we report the production and characterization of an intrinsically radioactive UiO-66 nMOF (89Zr-UiO-66) with incorporation of positron-emitting isotope zirconium-89 (89Zr). 89Zr-UiO-66 was further functionalized with pyrene-derived polyethylene glycol (Py-PGA-PEG) and conjugated with a peptide ligand (F3) to nucleolin for targeting of triple-negative breast tumors. Doxorubicin (DOX) was loaded onto UiO-66 with a relatively high loading capacity (1 mg DOX/mg UiO-66) and served as both a therapeutic cargo and a fluorescence visualizer in this study. Functionalized 89Zr-UiO-66 demonstrated strong radiochemical and material stability in different biological media. Based on the findings from cellular targeting and in vivo positron emission tomography (PET) imaging, we can conclude that 89Zr-UiO-66/Py-PGA-PEG-F3 can serve as an image-guidable, tumor-selective cargo delivery nanoplatform. In addition, toxicity evaluation confirmed that properly PEGylated UiO-66 did not impose acute or chronic toxicity to the test subjects. With selective targeting of nucleolin on both tumor vasculature and tumor cells, this intrinsically radioactive nMOF can find broad application in cancer theranostics.
Subject(s)
Drug Carriers/chemistry , Metal-Organic Frameworks/chemistry , Nanoparticles/chemistry , Neoplasms/diagnostic imaging , Neoplasms/therapy , Radiopharmaceuticals/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Line , Cell Line, Tumor , Contrast Media/chemistry , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Drug Liberation , Female , Humans , Metal-Organic Frameworks/toxicity , Mice, Inbred BALB C , Molecular Targeted Therapy , Peptides/chemistry , Polyethylene Glycols/chemistry , Positron-Emission Tomography , Radioisotopes/chemistry , Tissue Distribution , Zirconium/chemistryABSTRACT
Mounting evidence suggests that the urokinase plasminogen activator (uPA) and its receptor (uPAR) play a central role in tumor progression. The goal of this study was to develop an 89Zr-labeled, antibody-based positron emission tomography (PET) tracer for quantitative imaging of the uPA/uPAR system. An anti-uPA monoclonal antibody (ATN-291) was conjugated with a deferoxamine (Df) derivative and subsequently labeled with 89Zr. Flow cytometry, microscopy studies, and competitive binding assays were conducted to validate the binding specificity of Df-ATN-291 against uPA. PET imaging with 89Zr-Df-ATN-291 was carried out in different tumors with distinct expression levels of uPA. Biodistribution, histology examination, and Western blotting were performed to correlate tumor uptake with uPA or uPAR expression. ATN-291 retained uPA binding affinity and specificity after Df conjugation. 89Zr-labeling of ATN-291 was achieved in good radiochemical yield and high specific activity. Serial PET imaging demonstrated that, in most tumors studied (except uPA- LNCaP), the uptake of 89Zr-Df-ATN-291 was higher compared to major organs at 120 h post-injection, providing excellent tumor contrast. The tumor-to-muscle ratio of 89Zr-Df-ATN-291 in U87MG was as high as 45.2 ± 9.0 at 120 h p.i. In vivo uPA specificity of 89Zr-Df-ATN-291 was confirmed by successful pharmacological blocking of tumor uptake with ATN-291 in U87MG tumors. Although the detailed mechanisms behind in vivo 89Zr-Df-ATN-291 tumor uptake remained to be further elucidated, quantitative PET imaging with 89Zr-Df-ATN-291 in tumors can facilitate oncologists to adopt more relevant cancer treatment planning.
Subject(s)
Antibodies, Monoclonal , Molecular Imaging , Neoplasms/diagnostic imaging , Neoplasms/metabolism , Positron-Emission Tomography , Receptors, Urokinase Plasminogen Activator/metabolism , Urokinase-Type Plasminogen Activator/metabolism , Animals , Biomarkers , Cell Line, Tumor , Disease Models, Animal , Fluorescent Antibody Technique , Heterografts , Humans , Mice , Molecular Imaging/methods , Neoplasms/pathology , Positron-Emission Tomography/methods , Protein Binding , Radiopharmaceuticals , Tissue DistributionABSTRACT
Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of â¼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. (64)Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of (64)Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates ((64)Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers with satisfactory drug loading capacity (e.g. for doxorubicin [DOX], 756 mg/g). Enhanced drug delivery efficiency in cbgLuc-MDA-MB-231 metastatic sites was demonstrated in DOX-loaded GO-FSHR-mAb by fluorescence imaging. This FSHR-targeted, GO-based nanoplatform can serve as a useful tool for early metastasis detection and targeted delivery of therapeutics.
Subject(s)
Breast Neoplasms/pathology , Doxorubicin/administration & dosage , Graphite/chemistry , Lung Neoplasms/secondary , Lung Neoplasms/therapy , Nanocapsules/chemistry , Neovascularization, Pathologic/therapy , Angiogenesis Inhibitors/administration & dosage , Animals , Antibodies, Monoclonal/administration & dosage , Breast Neoplasms/blood supply , Breast Neoplasms/therapy , Cell Line, Tumor , Drug Delivery Systems/methods , Female , Humans , Lung Neoplasms/blood supply , Mice , Mice, Nude , Molecular Targeted Therapy/methods , Nanocapsules/administration & dosage , Nanoconjugates/chemistry , Neovascularization, Pathologic/pathology , Oxides/chemistry , Treatment OutcomeABSTRACT
A novel phototheranostic platform based on tri-malonate derivative of fullerene C70 (TFC70)/photosensitizer (Chlorin e6, Ce6) nanovesicles (FCNVs) has been developed for effective tumor imaging and treatment. The FCNVs were prepared from amphiphilic TFC70-oligo ethylene glycol -Ce6 molecules. The developed FCNVs possessed the following advantages: (i) high loading efficiency of Ce6 (up to â¼57 wt%); (ii) efficient absorption in near-infrared light region; (iii) enhanced cellular uptake efficiency of Ce6 in vitro and in vivo; (iv) good biocompatibility and total clearance out from the body. These unique properties suggest that the as-prepared FCNVs could be applied as an ideal theranostic agent for simultaneous imaging and photodynamic therapy of tumor. This finding may provide a good solution to highly efficient phototheranostic applications based on fullerene derivatives fabricated nanostructures.
Subject(s)
Fullerenes/chemistry , Nanocapsules/chemistry , Neoplasms, Experimental/chemistry , Neoplasms, Experimental/drug therapy , Photochemotherapy/methods , Photosensitizing Agents/administration & dosage , Porphyrins/administration & dosage , A549 Cells , Absorption, Physicochemical , Animals , Apoptosis/drug effects , Apoptosis/radiation effects , Chlorophyllides , Diffusion , Female , Humans , Mice , Mice, Inbred BALB C , Nanocapsules/administration & dosage , Nanocapsules/ultrastructure , Neoplasms, Experimental/pathology , Particle Size , Photosensitizing Agents/chemistry , Porphyrins/chemistry , Tissue Distribution , Treatment OutcomeABSTRACT
Nanocarbons such as carbon nanotubes, graphene derivatives, and carbon nanohorns have illustrated their potential uses as cancer theranostics owing to their intrinsic fluorescence or NIR absorbance as well as superior cargo loading capacity. However, some problems still need to be addressed, such as the fates and long-term toxicology of different nanocarbons in vivo and the improvement of their performance in various biomedical imaging-guided cancer therapy systems. Herein, a versatile and clearable nanocarbon theranostic based on carbon dots (CDs) and gadolinium metallofullerene nanocrystals (GFNCs) is first developed, in which GFNCs enhance the tumor accumulation of CDs, and CDs enhance the relaxivity of GFNCs, leading to an efficient multimodal imaging-guided photodynamic therapy in vivo without obvious long-term toxicity. Furthermore, biochemical analysis reveals that the novel nanotheranostic can harmlessly eliminate from the body in a reasonable period of time after exerting diagnostic and therapeutic function.
Subject(s)
Carbon/chemistry , Fullerenes/chemistry , Nanoparticles/chemistry , Photochemotherapy/methods , Quantum Dots/chemistry , Theranostic Nanomedicine/methods , Cell Line , HumansABSTRACT
Nuclear imaging techniques, including primarily positron emission tomography (PET) and single-photon emission computed tomography (SPECT), can provide quantitative information for a biological event in vivo with ultra-high sensitivity, however, the comparatively low spatial resolution is their major limitation in clinical application. By convergence of nuclear imaging with other imaging modalities like computed tomography (CT), magnetic resonance imaging (MRI) and optical imaging, the hybrid imaging platforms can overcome the limitations from each individual imaging technique. Possessing versatile chemical linking ability and good cargo-loading capacity, radioactive nanomaterials can serve as ideal imaging contrast agents. In this review, we provide a brief overview about current state-of-the-art applications of radioactive nanomaterials in the circumstances of multimodality imaging. We present strategies for incorporation of radioisotope(s) into nanomaterials along with applications of radioactive nanomaterials in multimodal imaging. Advantages and limitations of radioactive nanomaterials for multimodal imaging applications are discussed. Finally, a future perspective of possible radioactive nanomaterial utilization is presented for improving diagnosis and patient management in a variety of diseases.
ABSTRACT
A macromolecular magnetic resonance imaging (MRI) contrast agent was successfully synthesized by conjugating the gadolinium/1,4,7,10-tetraazacyclododecane-1,4,7-tetracetic acid complex (Gd-DO3A) with 6,6-phenyl-C61 butyric acid (PC61BA) and upon further modification with human serum albumin (HSA). The final product, PC61BA-(Gd-DO3A)/HSA, has a high stability and exhibits a much higher relaxivity (r1 = 89.1 mM(-1) s(-1) at 0.5 T, 300 K) than Gd-DO3A (r1 = 4.7 mM(-1) s(-1)) does under the same condition, producing the synergistic positive effect of HSA and C60 on the relaxivity of Gd-DO3A. The in vivo MR images of PC61BA-(Gd-DO3A)/HSA-treated tumor-bearing mice show strong signal enhancement for the tumor area due to the enhanced permeability and retention effect. The maximum accumulation of PC61BA-(Gd-DO3A)/HSA at the tumor site was achieved at 4 h postinjection, which may guide surgery. The results from the hematology and histological observations indicate that PC61BA-(Gd-DO3A)/HSA has no obvious toxicity in vivo. These unique properties of PC61BA-(Gd-DO3A)/HSA enable them to be highly efficient for tumor-targeting MRI in vivo, possibly providing a good solution for tumor diagnosis.
Subject(s)
Neoplasms , Animals , Contrast Media , Fullerenes , Gadolinium , Humans , Magnetic Resonance Imaging , Mice , Organometallic Compounds , Serum AlbuminABSTRACT
Carbon based nanomaterials have attracted significant attention over the past decades due to their unique physical properties, versatile functionalization chemistry, and biological compatibility. In this review, we will summarize the current state-of-the-art applications of carbon nanomaterials in cancer imaging and drug delivery/therapy. The carbon nanomaterials will be categorized into fullerenes, nanotubes, nanohorns, nanodiamonds, nanodots and graphene derivatives based on their morphologies. The chemical conjugation/functionalization strategies of each category will be introduced before focusing on their applications in cancer imaging (fluorescence/bioluminescence, magnetic resonance (MR), positron emission tomography (PET), single-photon emission computed tomography (SPECT), photoacoustic, Raman imaging, etc.) and cargo (chemo/gene/therapy) delivery. The advantages and limitations of each category and the potential clinical utilization of these carbon nanomaterials will be discussed. Multifunctional carbon nanoplatforms have the potential to serve as optimal candidates for image-guided delivery vectors for cancer.
Subject(s)
Carbon/therapeutic use , Nanostructures/therapeutic use , Neoplasms/diagnosis , Neoplasms/drug therapy , Animals , Carbon/chemistry , Diagnostic Imaging , Drug Delivery Systems , Humans , Nanostructures/chemistryABSTRACT
Manganese-porphyrin compounds as MRI contrast agents have drawn particular attention due to high relaxivities and unique biodistribution. It has been reported that the charge density of the metal center and steric decompression of the substituents, rather than rotational correlation time, were the key factors to determine the relaxivities of manganese(III) porphyrins. In this study, [6,6]-phenyl-C61-butyric acid (PC61BA) was introduced into 5-(4-aminophenyl)-10,15,20-tris (4-sulfonatophenyl) porphyrin (APTSPP) to investigate the influence on water proton relaxation. The obtained PC61BA-APTSPP-Mn possesses a relaxivity of 19.2 mM(-1) s(-1), which is greater than that of Mn-APTSPP (11.2 mM(-1) s(-1)) and clinically used Gd-DTPA (4.1 mM(-1) s(-1)) at 0.5 T, and even more effective compared with those binding manganese(III) porphyrins to certain macromolecules. It was reasonably speculated that the high relaxivity of PC61BA-APTSPP-Mn should ascribe to the charge density variation of Mn(III) and steric decompression induced by PC61BA. Both fluorescence emission spectra and cyclic voltammetry results verified the presence of electronic communication between PC61BA and APTSPP-Mn. In addition, the hydrodynamic diameter of PC61BA-APTSPP-Mn aggregates was much smaller than that of APTSPP-Mn aggregates, which may contribute to the higher relaxivity by inhibiting the formation of dimers of APTSPP-Mn. Therefore, the introduction of fullerene derivatives is suggested to be a good strategy for the improvement of the relaxivities of manganese(III) porphyrins.