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1.
RSC Adv ; 10(40): 23759-23766, 2020.
Article in English | MEDLINE | ID: mdl-32774845

ABSTRACT

Radionuclide-stimulated therapy (RaST), which is enhanced by Cherenkov radiation, has enabled deep tissue stimulation of UV photosensitizers, providing a new path for cancer treatment. Previous reports have shown UV-active titanium dioxide (TiO2) nanoparticles (NPs) modified with transferrin inhibit tumour growth after orthogonal treatment with Cherenkov radiation-emitting radionuclides such as 18F-fluorodeoxyglucose (FDG). However, poor understanding of TiO2 NP parameters on reactive oxygen species (ROS) generation and particle distribution limits effective therapy. Here we sought to delineate the effects of crystal phase and core TiO2 crystal dimension (cTd) on ROS production and particle morphology. We prepared Transferrin (Tf)-TiO2 nanoaggregates (NAGs) using solvothermally synthesized cTd sizes from 5 to 1000 nm diameter and holo- or apo-transferrin. Holo-transferrin was unable to stabilize TiO2 NPs while apo-transferrin stabilized TiO2 into uniform nanoaggregates (NAGs), which were invariant with differing cTd, averaging 116 ± 1.04 nm for cTds below 100 nm. ROS production increased from 5 to 25 nm cTd, attaining a peak at 25 nm before decreasing with larger sizes. The supra-25 nm ROS production decrease was partially driven by a ~1/r 3 surface area decline. Additionally, amorphous TiO2 of equal core size exhibited a 2.6-fold increase in ROS production compared to anatase NAGs, although limited stability halted further use. Although both 5 and 25 nm anatase cTds formed similarly sized NAGs, 5 nm anatase showed a four-fold higher tumour-to-muscle ratio than the 25 nm NPs in tumour-bearing mice, demonstrating the intricate relationships between physical and biological properties of NAGs. The combined in vivo and ROS results demonstrate that anatase crystals and cTd size of 25 nm or less are ideal particle parameters to balance biodistribution with ROS production efficiency.

2.
ACS Nano ; 14(4): 4255-4264, 2020 04 28.
Article in English | MEDLINE | ID: mdl-32223222

ABSTRACT

Rapid liver and spleen opsonization of systemically administered nanoparticles (NPs) for in vivo applications remains the Achilles' heel of nanomedicine, allowing only a small fraction of the materials to reach the intended target tissue. Although focusing on diseases that reside in the natural disposal organs for nanoparticles is a viable option, it limits the plurality of lesions that could benefit from nanomedical interventions. Here we designed a theranostic nanoplatform consisting of reactive oxygen (ROS)-generating titanium dioxide (TiO2) NPs, coated with a tumor-targeting agent, transferrin (Tf), and radiolabeled with a radionuclide (89Zr) for targeting bone marrow, imaging the distribution of the NPs, and stimulating ROS generation for cell killing. Radiolabeling of TiO2 NPs with 89Zr afforded thermodynamically and kinetically stable chelate-free 89Zr-TiO2-Tf NPs without altering the NP morphology. Treatment of multiple myeloma (MM) cells, a disease of plasma cells originating in the bone marrow, with 89Zr-TiO2-Tf generated cytotoxic ROS to induce cancer cell killing via the apoptosis pathway. Positron emission tomography/X-ray computed tomography (PET/CT) imaging and tissue biodistribution studies revealed that in vivo administration of 89Zr-TiO2-Tf in mice leveraged the osteotropic effect of 89Zr to selectively localize about 70% of the injected radioactivity in mouse bone tissue. A combination of small-animal PET/CT imaging of NP distribution and bioluminescence imaging of cancer progression showed that a single-dose 89Zr-TiO2-Tf treatment in a disseminated MM mouse model completely inhibited cancer growth at euthanasia of untreated mice and at least doubled the survival of treated mice. Treatment of the mice with cold Zr-TiO2-Tf, 89Zr-oxalate, or 89Zr-Tf had no therapeutic benefit compared to untreated controls. This study reveals an effective radionuclide sensitizing nanophototherapy paradigm for the treatment of MM and possibly other bone-associated malignancies.


Subject(s)
Multiple Myeloma , Animals , Mice , Multiple Myeloma/diagnostic imaging , Multiple Myeloma/drug therapy , Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Radioisotopes , Tissue Distribution , Zirconium
3.
Angew Chem Int Ed Engl ; 56(36): 10717-10720, 2017 08 28.
Article in English | MEDLINE | ID: mdl-28667692

ABSTRACT

Photodynamic therapy (PDT) is widely used to treat diverse diseases, but its dependence on oxygen to produce cytotoxic reactive oxygen species (ROS) diminishes the therapeutic effect in a hypoxic environment, such as solid tumors. Herein, we developed a ROS-producing hybrid nanoparticle-based photosensitizer capable of maintaining high levels of ROS under both normoxic and hypoxic conditions. Conjugation of a ruthenium complex (N3) to a TiO2 nanoparticle afforded TiO2 -N3. Upon exposure of TiO2 -N3 to light, the N3 injected electrons into TiO2 to produce three- and four-fold more hydroxyl radicals and hydrogen peroxide, respectively, than TiO2 at 160 mmHg. TiO2 -N3 maintained three-fold higher hydroxyl radicals than TiO2 under hypoxic conditions via N3-facilitated electron-hole reduction of adsorbed water molecules. The incorporation of N3 transformed TiO2 from a dual type I and II PDT agent to a predominantly type I photosensitizer, irrespective of the oxygen content.


Subject(s)
Hypoxia/drug therapy , Nanoparticles/chemistry , Photosensitizing Agents/pharmacology , Reactive Oxygen Species/metabolism , Ruthenium/pharmacology , Titanium/pharmacology , Photochemotherapy , Photosensitizing Agents/chemistry , Ruthenium/chemistry , Titanium/chemistry
4.
Biomaterials ; 98: 53-63, 2016 08.
Article in English | MEDLINE | ID: mdl-27179433

ABSTRACT

Nanoparticles (NPs) play expanding roles in biomedical applications including imaging and therapy, however, their long-term fate and clearance profiles have yet to be fully characterized in vivo. NP delivery via the airway is particularly challenging, as the clearance may be inefficient and lung immune responses complex. Thus, specific material design is required for cargo delivery and quantitative, noninvasive methods are needed to characterize NP pharmacokinetics. Here, biocompatible poly(acrylamidoethylamine)-b-poly(dl-lactide) block copolymer-based degradable, cationic, shell-cross-linked knedel-like NPs (Dg-cSCKs) were employed to transfect plasmid DNA. Radioactive and optical beacons were attached to monitor biodistribution and imaging. The preferential release of cargo in acidic conditions provided enhanced transfection efficiency compared to non-degradable counterparts. In vivo gene transfer to the lung was correlated with NP pharmacokinetics by radiolabeling Dg-cSCKs and performing quantitative biodistribution with parallel positron emission tomography and Cerenkov imaging. Quantitation of imaging over 14 days corresponded with the pharmacokinetics of NP movement from the lung to gastrointestinal and renal routes, consistent with predicted degradation and excretion. This ability to noninvasively and accurately track NP fate highlights the advantage of incorporating multifunctionality into particle design.


Subject(s)
Luminescence , Lung/metabolism , Nanoparticles/chemistry , Positron-Emission Tomography , Transfection/methods , Animals , DNA/metabolism , HEK293 Cells , Humans , Hydrogen-Ion Concentration , Iodine Radioisotopes , Mice , Multimodal Imaging , Nanoparticles/ultrastructure , Plasmids/metabolism , Solutions , Tissue Distribution
5.
Nanoscale ; 7(2): 440-4, 2015 Jan 14.
Article in English | MEDLINE | ID: mdl-25418982

ABSTRACT

A gold nanoparticle was radiolabeled with (125)I and (111)In and functionalized with an MMP9-cleavable peptide to form a multispectral SPECT imaging contrast agent. Peptide cleavage from the nanoprobe by MMP9 was observed in vitro, and distinct pharmacokinetic properties of the contrast agent were observed between tumors with high or low MMP9 expression.


Subject(s)
Contrast Media/chemistry , Metal Nanoparticles/chemistry , Tomography, Emission-Computed, Single-Photon , Animals , Cell Line, Tumor , Contrast Media/pharmacokinetics , Gold/chemistry , Humans , Indium Radioisotopes/chemistry , Iodine Radioisotopes/chemistry , Matrix Metalloproteinase 9/metabolism , Mice , Tissue Distribution , Transplantation, Heterologous
6.
ACS Nano ; 8(5): 4385-94, 2014 May 27.
Article in English | MEDLINE | ID: mdl-24766522

ABSTRACT

With Au nanocages as an example, we recently demonstrated that radioactive (198)Au could be incorporated into the crystal lattice of Au nanostructures for simple and reliable quantification of their in vivo biodistribution by measuring the γ radiation from (198)Au decay and for optical imaging by detecting the Cerenkov radiation. Here we extend the capability of this strategy to synthesize radioactive (198)Au nanostructures with a similar size but different shapes and then compare their biodistribution, tumor uptake, and intratumoral distribution using a murine EMT6 breast cancer model. Specifically, we investigated Au nanospheres, nanodisks, nanorods, and cubic nanocages. After PEGylation, an aqueous suspension of the radioactive Au nanostructures was injected into a tumor-bearing mouse intravenously, and their biodistribution was measured from the γ radiation while their tumor uptake was directly imaged using the Cerenkov radiation. Significantly higher tumor uptake was observed for the Au nanospheres and nanodisks relative to the Au nanorods and nanocages at 24 h postinjection. Furthermore, autoradiographic imaging was performed on thin slices of the tumor after excision to resolve the intratumoral distributions of the nanostructures. While both the Au nanospheres and nanodisks were only observed on the surfaces of the tumors, the Au nanorods and nanocages were distributed throughout the tumors.


Subject(s)
Gold Radioisotopes/chemistry , Metal Nanoparticles/chemistry , Nanotechnology/methods , Animals , Cell Line, Tumor , Female , Gold/chemistry , Mammary Neoplasms, Animal/pathology , Mice , Mice, Inbred BALB C , Microscopy, Electron, Transmission , Nanospheres/chemistry , Nanotubes/chemistry , Photoacoustic Techniques , Polyethylene Glycols/chemistry , Positron-Emission Tomography , Tissue Distribution , Tomography, X-Ray Computed
7.
Small ; 10(1): 169-178, 2014 Jan 15.
Article in English | MEDLINE | ID: mdl-23847147

ABSTRACT

Illumination of noble metal nanoparticles at the plasmon resonance causes substantial heat generation, and the transient and highly localized temperature increases that result from this energy conversion can be exploited for photothermal therapy by plasmonically heating gold nanorods (NRs) bound to cell surfaces. Here, plasmonic heating is used for the first time to locally release silver from gold core/silver shell (Au@Ag) NRs targeted to bacterial cell walls. A novel biomimetic method of preparing Au@Ag core-shell NRs is employed, involving deposition of a thin organic polydopamine (PD) primer onto Au NR surfaces, followed by spontaneous electroless silver metallization, and conjugation of antibacterial antibodies and passivating polymers for targeting to gram-negative and gram-positive bacteria. Dramatic cytotoxicity of S. epidermidis and E. coli cells targeted with Au@Ag NRs is observed upon exposure to light as a result of the combined antibacterial effects of plasmonic heating and silver release. The antibacterial effect is much greater than with either plasmonic heating or silver alone, implying a strong therapeutic synergy between cell-targeted plasmonic heating and the associated silver release upon irradiation. The findings suggest a potential antibacterial use of Au@Ag NRs when coupled with light irradiation, which has not been previously described.


Subject(s)
Anti-Bacterial Agents/chemistry , Nanotubes/chemistry , Silver/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Biomimetics
8.
ACS Nano ; 7(3): 2068-77, 2013 Mar 26.
Article in English | MEDLINE | ID: mdl-23383982

ABSTRACT

Gold nanohexapods represent a novel class of optically tunable nanostructures consisting of an octahedral core and six arms grown on its vertices. By controlling the length of the arms, their localized surface plasmon resonance peaks could be tuned from the visible to the near-infrared region for deep penetration of light into soft tissues. Herein we compare the in vitro and in vivo capabilities of Au nanohexapods as photothermal transducers for theranostic applications by benchmarking against those of Au nanorods and nanocages. While all these Au nanostructures could absorb and convert near-infrared light into heat, Au nanohexapods exhibited the highest cellular uptake and the lowest cytotoxicity in vitro for both the as-prepared and PEGylated nanostructures. In vivo pharmacokinetic studies showed that the PEGylated Au nanohexapods had significant blood circulation and tumor accumulation in a mouse breast cancer model. Following photothermal treatment, substantial heat was produced in situ and the tumor metabolism was greatly reduced for all these Au nanostructures, as determined with (18)F-flourodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT). Combined together, we can conclude that Au nanohexapods are promising candidates for cancer theranostics in terms of both photothermal destruction and contrast-enhanced diagnosis.


Subject(s)
Hyperthermia, Induced/methods , Metal Nanoparticles/therapeutic use , Phototherapy/methods , Animals , Cell Line, Tumor , Female , Gold/chemistry , Humans , Mammary Neoplasms, Experimental/therapy , Metal Nanoparticles/chemistry , Metal Nanoparticles/ultrastructure , Mice , Mice, Nude , Nanotechnology , Nanotubes/chemistry , Nanotubes/ultrastructure , Polyethylene Glycols/chemistry
9.
Curr Top Med Chem ; 13(4): 470-8, 2013.
Article in English | MEDLINE | ID: mdl-23432009

ABSTRACT

Labeling nanoparticles with radionuclides has been widely used to form multifunctional and multivalency agents for various biomedical applications. A variety of nanostructures including inorganic, organic and lipid nanoparticles have been labeled with positron or gamma emitting radioisotopes through versatile radiochemistry in a number of disease models to track their in vivo fate, image biomarkers, and monitor treatment response. This review briefly summarizes the recent applications of nanoparticles labeled with radionuclides for oncological, cardiovascular, and pulmonary theranostics.


Subject(s)
Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/therapy , Lung Diseases/diagnosis , Lung Diseases/therapy , Nanocapsules/therapeutic use , Neoplasms/diagnosis , Neoplasms/therapy , Animals , Diagnostic Imaging , Humans , Isotope Labeling , Nanocapsules/chemistry
10.
Nanomedicine (Lond) ; 8(1): 17-28, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22891865

ABSTRACT

AIM: A novel biomimetic strategy was employed for presenting antibodies on gold nanorods (NRs) to target growth factor receptors on cancer cells for use in photothermal therapy. MATERIALS & METHODS: Polydopamine (PD) was polymerized onto gold NRs, and EGF receptor antibodies (anti-EGFR) were immobilized onto the layer. Cell-binding affinity and light-activated cell death of cancer cells incubated with anti-EGFR-PD-NRs were quantified by optical imaging. RESULTS: PD was deposited onto gold NRs, and antibodies were bound to PD-coated NRs. Anti-EGFR-PD-NRs were stable in media, and were specifically bound to EGFR-overexpressing cells. Illumination of cells targeted with anti-EGFR-PD-NRs enhanced cell death compared with nonirradiated controls and cells treated with antibody-free NRs. CONCLUSION: PD facilitates the surface functionalization of gold NRs with biomolecules, allowing cell targeting and photothermal killing of cancer cells. PD can potentially coat a large variety of nanoparticles with targeting ligands as a strategy for biofunctionalization of diagnostic and therapeutic nanoparticles.


Subject(s)
Gold/chemistry , Indoles/chemistry , Nanotubes , Neoplasms/pathology , Polymers/chemistry , Microscopy, Electron, Transmission , Polyethylene Glycols/chemistry , Spectroscopy, Near-Infrared
11.
Biotechnol Bioeng ; 109(12): 2970-7, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22729662

ABSTRACT

Here, we present a novel technique to immobilize magnetic particles onto whole Gluconobacter oxydans in situ via a synthetic adhesive biomimetic material inspired by the protein glues of marine mussels. Our approach involves simple coating of a cell adherent polydopamine film onto magnetic nanoparticles, followed by conjugation of the polydopamine-coated nanoparticles to G. oxydans which resulted in cell aggregation. After optimization, 21.3 mg (wet cell weight) G. oxydans per milligram of nanoparticle was aggregated and separated with a magnet. Importantly, the G. oxydan aggregates showed high specific activity and good reusability. The facile approach offers the potential advantages of low cost, easy cell separation, low diffusion resistance, and high efficiency. Furthermore, the approach is a convenient platform technique for magnetization of cells in situ by direct mixing of nanoparticles with a cell suspension.


Subject(s)
Bacterial Adhesion/drug effects , Cells, Immobilized/cytology , Gluconobacter oxydans/cytology , Gluconobacter oxydans/drug effects , Magnetite Nanoparticles/chemistry , Cells, Immobilized/chemistry , Cells, Immobilized/metabolism , Equipment Reuse , Gluconobacter oxydans/chemistry , Gluconobacter oxydans/metabolism , Hydrogen-Ion Concentration , Indoles/chemistry , Indoles/pharmacology , Osmolar Concentration , Polymers/chemistry , Polymers/pharmacology , Sodium Chloride , Temperature
12.
Chem Mater ; 23(5): 1130-1135, 2011 Mar 08.
Article in English | MEDLINE | ID: mdl-21666825

ABSTRACT

A novel strategy was developed to synthesize polymer-coated metal nanoparticles (NPs) through reduction of metal cations with 3,4-dihydroxyphenylalanine (DOPA)-containing polyethylene glycol (PEG) polymers. Catechol redox chemistry was used to both synthesize metal NPs and simultaneously form a cross-linked shell of PEG polymers on their surfaces. DOPA reduced gold and silver cations into neutral metal atoms, producing reactive quinones that covalently cross-linked the PEG molecules around the surface of the NP. Importantly, these PEG-functionalized metal NPs were stable in physiological ionic strengths and under centrifugation, and hold broad appeal since they absorb and scatter light in aqueous solutions.

13.
Mol Imaging ; 7(1): 50-7, 2008.
Article in English | MEDLINE | ID: mdl-18384724

ABSTRACT

Molecularly targeted gold nanorods were investigated for applications in both diagnostic imaging and disease treatment with cellular resolution. The nanorods were tested in two genetically engineered cell lines derived from the human colon carcinoma HCT-116, a model for studying ligand-receptor interactions. One of these lines was modified to express delta opioid receptor (deltaOR) and green fluorescent protein, whereas the other was receptor free and expressed a red fluorescent protein, to serve as the control. Deltorphin, a high-affinity ligand for deltaOR, was stably attached to the gold nanorods through a thiol-terminated linker. In a mixed population of cells, we demonstrated selective imaging and destruction of receptor-expressing cells while sparing those cells that did not express the receptor. The molecularly targeted nanorods can be used as an in vitro ligand-binding and cytotoxic treatment assay platform and could potentially be applied in vivo for diagnostic and therapeutic purposes with endoscopic technology.


Subject(s)
Contrast Media/metabolism , Gold/metabolism , Nanotubes , Receptors, Opioid, delta/metabolism , Amino Acid Sequence , Coculture Techniques , Green Fluorescent Proteins/metabolism , HCT116 Cells , Humans , Luminescent Measurements , Molecular Sequence Data , Oligopeptides/chemistry , Phantoms, Imaging
14.
Clin Exp Metastasis ; 25(4): 411-25, 2008.
Article in English | MEDLINE | ID: mdl-18301995

ABSTRACT

Solid tumors become acidic due to hypoxia and upregulated glycolysis. We have hypothesized that this acidosis leads to more aggressive invasive behavior during carcinogenesis (Nature Reviews Cancer 4:891-899, 2004). Previous work on this subject has shown mixed results. While some have observed an induction of metastasis and invasion with acid treatments, others have not. To investigate this, human melanoma cells were acclimated to low pH growth conditions. Significant cell mortality occurred during acclimation, suggesting that acidosis selected for resistant phenotypes. Cells maintained under acidic conditions exhibited a greater range of motility, a reduced capacity to form flank tumors in SCID mice and did not invade more rapidly in vitro, compared to non-selected control cells. However, re-acclimation of these selected cells to physiological pH gave rise to stable populations with significantly higher in vitro invasion. These re-acclimated cells maintained higher invasion and higher motility for multiple generations. Transcriptomic analyses of these three phenotypes revealed significant differences, including upregulation of relevant pathways important for tissue remodeling, cell cycle control and proliferation. These results reinforce the hypothesis that acidosis promotes selection of stable, more invasive phenotypes, rather than inductive changes, which would be reversible.


Subject(s)
Melanoma/pathology , Cell Line, Tumor , Cell Movement , Gene Expression Profiling , Humans , Hydrogen-Ion Concentration , Melanoma/secondary , Neoplasm Invasiveness , Phenotype
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