Real‐Time Imaging Tracking of Engineered Macrophages as Ultrasound‐Triggered Cell Bombs for Cancer Treatment

Cell‐based drug delivery systems are a promising platform for tumor‐targeted therapy due to their high drug‐loading capacities and inherent tumor‐homing abilities. However, the real‐time tracking of these carrier cells and controlled release of the encapsulated drugs are still challenging. Here, ultrasound‐activatable cell bombs are developed by encapsulating doxorubicin (DOX) and phase transformable perfluoropentane (PFP) into hollow mesoporous organosilica nanoparticles (HMONs) to prepare DOX/PFP‐loaded HMONs (DPH), followed by internalization into macrophages (RAW 264.7 cells). The resulting cell bombs (DPH‐RAWs) can maintain viability and actively home to the tumor. Especially, their migration can be tracked in real time using ultrasound due to the vaporization of a small portion of PFP during cell incubation at 37 °C. After accumulation at the tumor site, the further vaporization of remaining PFP can be triggered by a short‐pulsed high intensity focused ultrasound (HIFU) sonication, resulting in the generation of several large microbubbles, which destroys DPH‐RAWs and allows drug release out of these cells. The DPH‐RAWs combined with short‐pulsed HIFU sonication significantly inhibit tumor growth and prolong survival of tumor‐bearing mice. In conclusion, this study provides a new approach to cell‐based drug delivery systems for real‐time tracking of their migration and targeted cancer treatment.     

Enhancing Therapeutic Efficacy of Combined Cancer Phototherapy by Ultrasound‐Mediated In Situ Conversion of Near‐Infrared Cyanine/Porphyrin Microbubbles into Nanoparticles

Nanoparticles (NPs)‐based diagnosis and phototherapy are emerging as the cutting‐edge technologies for detection and treatment of cancer but their applications are still limited since insufficient and heterogeneous NPs accumulation in cancer often causes recurrence. To overcome these limitations, multifunctional microbubbles (MBs) were constructed with 1, 1‐dioctadecyl‐3, 3, 3, 3‐tetramethylindotricarbocyanine iodide (DiR) and porphyrin grafted lipid (PGL). Both DiR and PGL self‐assembled as microbubbles, the as‐designed PGL‐DiR MBs possess remarkably high drug loading contents (5.8% PGL and 10.38% DiR) and stable co‐delivery drug combinations. In vivo experiments showed PGL‐DiR MBs could serve as an excellent ultrasound contrast agent to enhance ultrasound imaging greatly for identifying the location and size of the tumors. Upon exposure to ultrasound, in situ conversion of PGL‐DiR MBs into nanoparticles resulted in a remarkable increase in fluorescence intensity (~5 folds) in tumor compared with PGL‐DiR NPs, validating the enhanced tumor accumulation and cellular uptake of therapeutic agents. PGL‐DiR MBs showed complete tumor ablation without recurrence in vivo, while PGL‐DiR NPs showed only 72.6% tumor growth inhibition at the same dose. We believe that PGL‐DiR MBs will soon reach their full potential as an important class of phototherapeutic formulations and will contribute to remarkable advances in cancer treatments.     

Amphiphilic Poly(Amino Acid) Nanoparticles Induce Size‐Dependent Dendritic Cell Maturation

Size‐regulated amphiphilic poly(amino acid) nanoparticles (NPs) composed of poly(γ‐glutamic acid) (γ‐PGA) and the hydrophobic amino acid derivative, L ‐phenylalanine ethyl ester (Phe) are prepared to evaluate the effects of particle size on dendritic cell (DC) uptake of NPs and their immune stimulatory activities as delivery carriers and adjuvants. The size of the Phe‐conjugated γ‐PGA NPs (γ‐PGA–Phe NPs) is easily controlled by regulating the aggregated γ‐PGA–Phe numbers. Each of the differently sized γ‐PGA–Phe NPs could efficiently encapsulate ovalbumin (OVA), and the amount of encapsulated OVA per milligram of NPs is almost the same despite the differences in size. The DC uptake of small NPs is lower than for the larger NPs, but the effect of DC activation by NPs is high in the small sizes. The DC activation is significantly affected by the size of the NPs, which suggests that not only the uptake process of the NPs, but also the surface interactions between the NPs and DCs, is important for the induction of DC maturation. The precisely size‐controllable γ‐PGA–Phe NPs have significant potential as an antigen carrier and vaccine adjuvant. These results should provide guidelines for adjuvant design in the development of an effective vaccine.     

Molecular and Cellular Imaging with Targeted Contrast Ultrasound

Molecular imaging is an expanding field that involves the noninvasive detection of cellular and molecular mediators of disease using a range of imaging modalities. Molecular imaging using contrast-enhanced ultrasound relies on the detection of novel site-targeted ultrasound contrast agents. Gas-filled encapsulated microbubbles provide a sensitive and high-resolution ultrasound contrast agent, and site-targeted imaging is facilitated by the manipulation of the shell surface of these microbubbles. Nonmicrobubble agents such as immunoliposomes and small nanoemulsion agents have also been developed for targeting purposes. These contrast agents are retained within regions of a specific pathophysiological process, thereby allowing noninvasive phenotypic characterization of tissue. Since microbubbles are pure intravascular tracers, they provide an optimal agent to assess molecular processes occurring on the vascular endothelial surface. Accordingly, the pathologic states that have been targeted include inflammation, angiogenesis associated with ischemia and neoplasms, and thrombus formation. This review describes: 1) the potential clinical and research uses for targeted imaging; 2) strategies that have been employed for the creation of site-targeted ultrasound contrast agents; 3) the unique challenges for imaging targeted ultrasound contrast agents; and 4) initial results and experience in the imaging of molecular events in animal models of disease.     

Lipoplex‐Loaded Microbubbles for Gene Delivery: A Trojan Horse Controlled by Ultrasound

Cationic poly(ethylene glycol)ylated (PEGylated) liposomes are one of the most important gene transfer reagents in non‐viral gene therapy. However, the low transfection efficiencies of highly PEGylated lipoplexes currently hamper their clinical use. Recently, ultrasound has been used in combination with microbubbles to enhance the uptake of genes in different cell types. However, the gene transfer efficiency still remains low in these experiments. To overcome the limitations of both techniques, we present the attachment of PEGylated lipoplexes to microbubbles via biotin–avidin–biotin linkages. Exposure of these lipoplex‐loaded microbubbles to ultrasound results in the release of unaltered lipoplexes. Furthermore, these lipoplex‐loaded microbubbles exhibit much higher transfection efficiencies than “free” PEGylated lipoplexes or naked plasmid DNA (pDNA) when combined with microbubbles and ultrasound. Interestingly, the lipoplex‐loaded microbubbles only transfect cells when exposed to ultrasound, which is promising for space‐ and time‐controlled gene transfer. Finally, this novel Trojan‐horse‐like concept can also be exploited to achieve the ultrasound‐triggered release of nanoparticles containing other therapeutic agents such as anticancer drugs.     

Ultrasound-Controlled Electron-Phonon Coupling Augmenting Catalysis of Piezoelectric-Based Sonosensitizer Safely Against Osteomyelitis

The energy transfer way and efficiency of ultrasound (US) to piezoelectric materials in fluid determines the US catalytic performance of materials and the subsequent sono-therapeutic effects for deep infection diseases. Herein, on insonation, the microbubble cavitation occurs near the surface of barium orthotitanate/berberine chloride nanoparticles (BTO/Ber NPs), often forming sonoluminescence and high pressure. The light further activates Ber, and the electron transfer happens between activated Ber and changing energy levels of BTO NPs caused by changing pressure. Meanwhile, ultrasound-driven piezoelectric electron-phonon coupling simultaneously narrows bandgap and prolongates carrier-lifetime, leading to more ROS generation. Hence, BTO/Ber NPs show great antibacterial activity against Staphylococcus aureus (99.80 ± 0.09%) by microbubble-mediated sonoporation and catalysis. Meanwhile, BTO/Ber NPs improve bone regeneration by decreasing the inflammatory response and enhancing osteoblast differentiation. US-mediated microbubbles may offer a safe and efficient treatment to millions of patients suffering from osteomyelitis and pave the way for the highly safe use of ultrasound in deep infections.     

Aqueous Two‐Phase System Patterning of Microbubbles: Localized Induction of Apoptosis in Sonoporated Cells

Ultrasound‐driven microbubbles produce mechanical forces that can disrupt cell membranes (sonoporation). However, it is difficult to control microbubble location with respect to cells. This lack of control leads to low sonoporation efficiencies and variable outcomes. In this study, aqueous two‐phase system (ATPS) droplets are used to localize microbubbles in select micro‐regions at the surface of living cells. This is achieved by stably partitioning microbubbles in dextran (DEX) droplets, deposited on living adherent cells in medium containing polyethylene glycol (PEG). The interfacial energy at the PEG‐DEX interface overcomes microbubble buoyancy and prevents microbubbles from floating away from the cells. Spreading of the small DEX droplets retains microbubbles at the cell surface in defined lateral positions without the need for antibody or cell‐binding ligand conjugation. The patterned microbubbles are activated on a cell monolayer exposed to a broadly applied ultrasound field (center frequency 1.25 MHz, active element diameter 0.6 cm, pulse duration 8 μs or 30 s). This system enables efficient testing of different ultrasound conditions for their effects on sonoporation‐mediated membrane disruption and cell viability. Regions of cells without patterned microbubbles show no injury or membrane disruption. In microbubble patterned regions, 8 μs ultrasound pulses (0.2‐0.6 MPa) produce cell death that is primarily apoptotic. Ultrasound‐induced apoptosis increases with higher extracellular calcium concentrations, with cells displaying all of the hallmarks of apoptosis including annexinV labeling, loss of mitochondrial membrane potential, caspase activation and changes in nuclear morphology.     

A Versatile Nanotheranostic Agent for Efficient Dual‐Mode Imaging Guided Synergistic Chemo‐Thermal Tumor Therapy

The integration of efficient imaging for diagnosis and synergistic tumor therapy into a single‐component nanoplatform is much promising for high efficacy tumor treatment but still in a great challenge. Herein, a smart and versatile nanotheranostic platform based on hollow mesoporous Prussian blue nanoparticles (HMPBs) with perfluoropentane (PFP) and doxorubicin (DOX) inside, has been designed, for the first time, to achieve the distinct in vivo synergistic chemo‐thermal tumor therapy and synchronous diagnosis and monitoring by ultrasound (US)/photoacoustic (PA) dual mode imaging. The prepared HMPBs show excellent photothermal conversion properties with large molar extinction coefficient (≈1.2 × 10¹¹m ^?1 cm^?1) and extremely high photothermal conversion efficiency (41.4%). Such a novel theranostic nanoplatform is expected to overcome the inevitable tumor recurrence and metastasis resulting from the inhomogeneous ablation of single thermal therapy, which will find a promising prospect in the application of noninvasive cancer therapy.     

Polydimethylsiloxane Composites for Optical Ultrasound Generation and Multimodality Imaging

Polydimethylsiloxane (PDMS) is widely used in biomedical science and can form composites that have broad applicability. One promising application where PDMS composites offer several advantages is optical ultrasound generation via the photoacoustic effect. Here, methods to create these PDMS composites are reviewed and classified. It is highlighted how the composites can be applied to a range of substrates, from micrometer‐scale, temperature‐sensitive optical fibers to centimeter‐scale curved and planar surfaces. The resulting composites have enabled all‐optical ultrasound imaging of biological tissues both ex vivo and in vivo, with high spatial resolution and with clinically relevant contrast. In addition, the first 3D all‐optical pulse‐echo ultrasound imaging of ex vivo human tissue, using a PDMS‐multiwalled carbon nanotube composite and a fiber‐optic ultrasound receiver, is presented. Gold nanoparticle‐PDMS and crystal violet‐PDMS composites with prominent absorption at one wavelength range for pulse‐echo ultrasound imaging and transmission at a second wavelength range for photoacoustic imaging are also presented. Using these devices, images of diseased human vascular tissue with both structural and molecular contrast are obtained. With a broader perspective, literature on recent advances in PDMS microfabrication from different fields is highlighted, and methods for incorporating them into new generations of optical ultrasound generators are suggested.     

Polyhedral Oligomeric Silsesquioxanes‐Containing Conjugated Polymer Loaded PLGA Nanoparticles with Trastuzumab (Herceptin) Functionalization for HER2‐Positive Cancer Cell Detection

The synthesis of polyhedral oligomeric silsesquioxanes (POSS)‐containing conjugated polymer (CP) and the polymer loaded poly(lactic‐co‐glycolic‐acid) (PLGA) nanoparticles (NPs) with surface antibody functionalization for human epidermal growth factor receptor 2 (HER2)‐positive cancer cell detection are reported. Due to the steric hindrance of POSS, NPs prepared from POSS‐containing CP show improved photoluminescence quantum yield as compared to that for the corresponding linear CP encapsulated NPs. In addition, the amount of ‐NH₂ groups on NP surface is well‐controlled by changing the molar ratio of poly(lactic‐co‐glycolic‐acid)‐b‐poly(ethylene glycol) (PLGA‐b‐PEG‐NH₂) to PLGA‐OCH₃ during NP formulation. Further conjugation of the NH₂‐functionalized CP NPs with trastuzumab (Herceptin) yields NPs with fine‐tuned protein density. These NPs are able to discriminate SKBR‐3 breast cancer cells from MCF‐7 breast cancer cells and NIH/3T3 fibroblast cells both on substrate and in suspension by taking advantage of the specific binding affinity between trastuzumab and HER2 overexpressed in SKBR‐3 breast cancer cell membrane. The high quantum yield and fine‐tuned surface specific protein functionalization make the POSS‐containing CP loaded NPs a good candidate for targeted biological imaging and detection.     

Cancer Detection: Polyhedral Oligomeric Silsesquioxanes‐Containing Conjugated Polymer Loaded PLGA Nanoparticles with Trastuzumab (Herceptin) Functionalization for HER2‐Positive Cancer Cell Detection (Adv. Funct. Mater. 2/2011)

The synthesis of polyhedral oligomeric silsesquioxanes (POSS)‐containing conjugated polymer (CP) and the polymer loaded poly(lactic‐co‐glycolic‐acid) (PLGA) nanoparticles (NPs) with surface antibody functionalization for human epidermal growth factor receptor 2 (HER2)‐positive cancer cell detection are reported. Due to the steric hindrance of POSS, NPs prepared from POSS‐containing CP show improved photoluminescence quantum yield as compared to that for the corresponding linear CP encapsulated NPs. In addition, the amount of ‐NH₂ groups on NP surface is well‐controlled by changing the molar ratio of poly(lactic‐co‐glycolic‐acid)‐b‐poly(ethylene glycol) (PLGA‐b‐PEG‐NH₂) to PLGA‐OCH₃ during NP formulation. Further conjugation of the NH₂‐functionalized CP NPs with trastuzumab (Herceptin) yields NPs with fine‐tuned protein density. These NPs are able to discriminate SKBR‐3 breast cancer cells from MCF‐7 breast cancer cells and NIH/3T3 fibroblast cells both on substrate and in suspension by taking advantage of the specific binding affinity between trastuzumab and HER2 overexpressed in SKBR‐3 breast cancer cell membrane. The high quantum yield and fine‐tuned surface specific protein functionalization make the POSS‐containing CP loaded NPs a good candidate for targeted biological imaging and detection.     

Mechanically Tunable Hollow Silica Ultrathin Nanoshells for Ultrasound Contrast Agents

Perfluoropentane (PFP) gas‐filled biodegradable iron‐doped silica nanoshells have been demonstrated as long‐lived ultrasound contrast agents. Nanoshells are synthesized by a sol–gel process with tetramethyl orthosilicate (TMOS) and iron ethoxide. Substituting a fraction of the TMOS with R‐substituted‐trialkoxysilanes produces ultrathin nanoshells with varying shell thicknesses and morphologies composed of fused nanoflakes. The ultrathin nanoshells have continuous ultrasound Doppler imaging lifetimes exceeding 3 h, are twice as bright using contrast‐specific imaging, and have decreased pressure thresholds compared to control nanoshells synthesized with just TMOS. Transmission electron microscopy shows that the R‐group‐substituted trialkoxysilanes can reduce the mechanically critical nanoshell layer to 1.4 nm. These ultrathin nanoshells have the mechanical behavior of weakly linked nanoflakes but the chemical stability of silica. The synthesis can be adapted for general fabrication of 3D nanostructures composed of nanoflakes, which have thicknesses from 1.4 to 3.8 nm and diameters from 2 to 23 nm.     

Nanoparticles Surmounting Blood–Brain Tumor Barrier Through Both Transcellular and Paracellular Pathways to Target Brain Metastases

Brain metastases are one of the most difficult malignancies to treat owing to their location and mostly multifocal and infiltrative growth. Chemotherapy, which is often effective against tumors outside the brain, offers some hope for brain metastases. However, the efficacy of systemic drug delivery to brain metastases is extremely limited due largely to the blood–brain tumor barrier (BTB). Herein, it is reported that minoxidil‐loaded hyaluronic acid–tethered nanoparticles (M@H‐NPs) can efficiently and specially surmount the BTB through both transcellular and paracellular pathways and target brain metastases through coordination of hyaluronic acid with CD44 target. The transcellular endocytosis, paracellular claudin‐5 expression, and BTB crossing are evaluated to confirm that the developed M@H‐NPs can be endued with minoxidil's ability to boost transcytosis and downregulate tight junction protein in BTB endothelial cells at brain metastases for promoted BTB penetration. M@H‐NPs selectively deliver doxorubicin (DOX) to brain metastatic lesions, while sparing normal brain cells from harm. Treatment with M@H‐NPs/DOX significantly prolongs median survival of mice bearing brain metastases. Due to the fruitful BTB penetration and brain metastasis homing, and improved therapeutic outcome, the minoxidil‐based systemic drug delivery strategy may serve as a potential approach for clinical management of brain metastases.     

Perfluorooctyl Bromide Polymeric Capsules as Dual Contrast Agents for Ultrasonography and Magnetic Resonance Imaging

Polymeric capsules with a thick shell made of biodegradable and biocompatible polymer and a liquid core of perfluorooctyl bromide (PFOB) were evaluated for stability as well as for ultrasound and magnetic resonance imaging (MRI) contrast enhancement. The method of preparation allows the mean capsule diameter to be regulated between 70 nm and 25 µm and the capsule thickness‐to‐radius ratio from 0.25 to 0.54. Capsule diameter remains stable at 37 °C in phosphate buffer for at least 4 and 6 h for nanocapsules and microcapsules, respectively. The in vitro ultrasound signal‐to‐noise ratio (SNR) was measured from 40 to 60 MHz for 6 µm and 150 nm capsules: the SNR increases with capsule concentration up to 20–25 mg mL⁻¹, and then reaches a plateau that depends on capsule diameter (13.5 ± 1.5 dB for 6 µm and 6 ± 2 dB for the 150 nm capsules). The ultrasound SNR is stable for up to 20 min for microcapsules and for several hours for nanocapsules. For nanocapsules, the thinner the shell, the larger the SNR and the more compressible the capsules. Nanocapsule suspensions imaged in vitro with a commercial ultrasound imaging system (normal and tissue harmonic imaging modes, 7–14 MHz probe) were detected down to concentrations of 12.5 mg mL⁻¹. Injections of nanocapsules (200 µg ml⁻¹) in mice in vivo reveal that the initial bolus passage presents significant ultrasound enhancement of the blood pool during hepatic imaging (7–14 MHz probe, tissue harmonic imaging mode). ¹⁹F‐MRI images were obtained in vitro at 9.4T using spin‐echo and gradient echo sequences and allow detecting nanocapsules in suspension (50 mg mL⁻¹). In conclusion, these results show initial feasibility for development of these capsules toward a dual‐modality contrast agent.     

Multicore Liquid Perfluorocarbon‐Loaded Multimodal Nanoparticles for Stable Ultrasound and 19F MRI Applied to In Vivo Cell Tracking

Ultrasound is the most commonly used clinical imaging modality. However, in applications requiring cell‐labeling, the large size and short active lifetime of ultrasound contrast agents limit their longitudinal use. Here, 100 nm radius, clinically applicable, polymeric nanoparticles containing a liquid perfluorocarbon, which enhance ultrasound contrast during repeated ultrasound imaging over the course of at least 48 h, are described. The perfluorocarbon enables monitoring the nanoparticles with quantitative ¹⁹F magnetic resonance imaging, making these particles effective multimodal imaging agents. Unlike typical core–shell perfluorocarbon‐based ultrasound contrast agents, these nanoparticles have an atypical fractal internal structure. The nonvaporizing highly hydrophobic perfluorocarbon forms multiple cores within the polymeric matrix and is, surprisingly, hydrated with water, as determined from small‐angle neutron scattering and nuclear magnetic resonance spectroscopy. Finally, the nanoparticles are used to image therapeutic dendritic cells with ultrasound in vivo, as well as with ¹⁹F MRI and fluorescence imaging, demonstrating their potential for long‐term in vivo multimodal imaging.     

超声微泡介导野生型P53基因转染鼠视网膜母细胞瘤的实验研究

目的:探讨超声微泡造影剂在一定强度的超声波照射下介导野生型p53(wtp53)基因转染荷瘤小鼠的可行性,为实现外源基因高效,定向的转移目的奠定基础。方法:将12只BAlB/C(nu/nu)裸小鼠双眼玻璃体腔接种HXO-Rb44细胞,造模成功后,将动物随机分为2组,第1组于尾静脉注入含质粒的微泡造影剂;第2组尾静脉注射质粒与微泡的混合液,并立即以0.5W/cm2〔1〕的超声波辐照小鼠眼球60s,工作时间控制为20%。转染7天后,处死动物,摘除眼球,RT-PCR检测wtp53基因的表达情况。结果:超声照射组动物的肿瘤组织中均检测到wtp53的mRNA表达,而未照射组动物肿瘤组织中未检测到mRNA的表达。结论:超声微泡能使外源基因wtp53高效的转染小鼠RB肿瘤组织。     

Sandwich,Vertical‐Channeled Thick Electrodes with High Rate and Cycle Performance

3D thick electrode design is a promising strategy to increase the energy density of lithium‐ion batteries but faces challenges such as poor rate and limited cycle life. Herein, a coassembly method is employed to construct low‐tortuosity, mechanically robust 3D thick electrodes. LiFe_0.7Mn_0.3PO₄ nanoplates (LFMP NPs) and graphene are aligned along the growth direction of ice crystals during freezing and assembled into sandwich frameworks with vertical channels, which prompts fast ion transfer within the entire electrode and reveals a 2.5‐fold increase in ion transfer performance as opposed to that of random structured electrodes. In the sandwich framework, LFMP NPs are entrapped in the graphene wall in a “plate‐on‐sheet” contact mode, which avoids the detachment of NPs during cycling and also constitutes electron transfer highways for the thick electrode. Such vertical‐channel sandwich electrodes with mass loading of 21.2 mg cm^?2 exhibit a superior rate capability (0.2C–20C) and ultralong cycle life (1000 cycles). Even under an ultrahigh mass loading of 72 mg cm^?2, the electrode still delivers an areal capacity up to 9.4 mAh cm^?2, ≈2.4 times higher than that of conventional electrodes. This study provides a novel strategy for designing thick electrodes toward high performance batteries.     

From Hybrid Microgels to Photonic Crystals

We have synthesized semiconductor and metal nanoparticles (NPs) in the constrained geometry of polymer microgels. We used electrostatically driven attraction between the ionic groups of the microgels and the precursor cations in the bulk liquid medium to introduce the cations in the interior of the microgel. In the second step, the cations in the microgel interior reacted with the anion (to obtain semiconductor NPs) or they were treated with a reducing agent (to obtain metal NPs). Good control over the size and the concentration of the NPs in the microgel particles was achieved by changing the composition of the corresponding microgel. The doped microgel spheres were heated at pH 4 above the volume‐transition temperature of the polymer to expel the water from the microsphere interior; then the polymer was encapsulated with a hydrophobic polymeric shell. Hybrid core–shell particles were used as the building blocks of the nanostructured material with properties of a photonic crystal.     

Functionalized Holmium‐Doped Hollow Silica Nanospheres for Combined Sonodynamic and Hypoxia‐Activated Therapy

The oxygen concentration dependence of sonodynamic therapy (SDT) and bioreductive therapy can be utilized to design the strategy of synergistic therapy. Herein, holmium‐doped hollow silica nanospheres are synthesized and then sequentially modified with chlorin e6, carboxyl poly(ethylene glycol) silane, and prostate stem cell antigen (PSCA) monoclonal antibody. The resultant nanocomposite designated as HHSN‐C/P‐mAb has good biocompatibility and can specifically target cancer cells overexpressing PSCA. Due to the inner cavity structure and Ho doping, HHSN‐C/P‐mAb shows high ultrasound (US) imaging contrast capability and excellent high‐field magnetic resonance contrast performance. HHSN‐C/P‐mAb can act as a nanocarrier for loading the bioreductive pro‐drug tirapazamine (TPZ), and the degradation of the hollow nanospheres under the trigger of acidic microenvironment favors the pH responsive release of TPZ from the material. Upon US irradiation, HHSN‐C/P‐mAb produces reactive oxygen species to kill the cancer cells, and importantly, the oxygen consumption during SDT induces an intratumoral hypoxic environment to activate the therapeutic function of codelivered TPZ, resulting in a high‐effective synergistic therapy. The findings of this study highlight that HHSN‐C/P‐mAb is a versatile theranostic nanoplatform for efficient cancer treatment.     

Magnetic and Acoustically Active Lipospheres for Magnetically Targeted Nucleic Acid Delivery

With the aim of obtaining a carrier for combined magnetic‐field‐ and ultrasound‐targeted nucleic acid delivery, acoustically active lipospheres are prepared that comprise magnetic nanoparticles and plasmid DNA or synthetic siRNA. The lipospheres, with average diameters of 5 μm and smaller, are obtained upon shaking a mixture of soybean oil, a cationic lipid, magnetic nanoparticles, a nucleic acid, and aqueous buffer in a perfluoropropane atmosphere in a sealed vial. These lipospheres create contrast in ultrasound imaging and display greatly increased magnetophoretic mobility and in consequence greatly improved magnetic retention in a flow model when compared with free magnetic nanoparticles. In cell culture, the lipospheres are sedimented within minutes to the surface of cells using a gradient magnetic field. This sedimentation results in the association of about 50% of the applied plasmid DNA with the cells and in functional DNA and siRNA delivery in vitro. Under these conditions, ultrasound does not have an enhancing effect on nucleic acid delivery. When magnetic, acoustically active lipospheres carrying 125iodine‐labeled plasmid DNA are injected into the tail veins of mice, the application of a gradient magnetic field to the chests of the mice results in a two‐ to threefold enrichment of both lung lobes with the plasmid. A similar enrichment is obtained when ultrasound alone (1 MHz, 10 min) is applied. The combined application of magnetic field and ultrasound has no synergistic effect in terms of liposphere capture in the lungs. Histological analysis reveals intact lipospheres in lung capillaries. A synergistic effect of magnetic field and ultrasound is observed in site‐specific plasmid deposition in a dorsal skinfold chamber model in mice after injection into the carotis. These conditions also result in functional plasmid delivery to the vasculature after intrajugular injection.