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 18F-flourodeoxyglucose positron emission tomography/computed tomography (18F-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.
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.
Working through the oxygen debt: A dual type I and type II photodynamic therapy agent, titanium dioxide–ruthenium nano‐photosensitizer (TiO2‐N3) synergistically produced hydroxyl radicals under both normoxic and hypoxic conditions.
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.
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.
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.
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.
A novel strategy was developed to synthesize polymer-coated metal nanoparticles (NPs) through reduction of metal cations with 3,4-dihydroxyphenylalanine (DOPA)-containing poly(ethylene 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.
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.
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.
Bimetallic gold core/silver shell nanorods are formed with polydopamine‐based biomimetic synthesis and target bacteria with antibody functionalization. Light irradiation of the nanorods causes plasmonic heating and release of silver, which efficiently kills E. coli and S. epidermidis bacteria with a novel multifunctional therapeutic strategy.
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.
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 (TiO
2
) nanoparticles (NPs) modified with transferrin inhibit tumour growth after orthogonal treatment with Cherenkov radiation-emitting radionuclides such as
18
F-fluorodeoxyglucose (FDG). However, poor understanding of TiO
2
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 TiO
2
crystal dimension (cTd) on ROS production and particle morphology. We prepared Transferrin (Tf)-TiO
2
nanoaggregates (NAGs) using solvothermally synthesized cTd sizes from 5 to 1000 nm diameter and holo- or apo-transferrin. Holo-transferrin was unable to stabilize TiO
2
NPs while apo-transferrin stabilized TiO
2
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 TiO
2
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.
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.
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 Čerenkov 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.
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