Nanosized drug delivery systems have offered promising approaches for cancer theranostics. However, few are effective to simultaneously maximize tumor-specific uptake, imaging, and therapy in a single nanoplatform. Here, we report a simple yet stimuli-responsive anethole dithiolethione (ADT)-loaded magnetic nanoliposome (AML) delivery system, which consists of ADT, hydrogen sulfide (H2S) pro-drug, doped in the lipid bilayer, and superparamagnetic nanoparticles encapsulated inside. HepG2 cells could be effectively bombed after 6 h co-incubation with AMLs. For in vivo applications, after preferentially targeting the tumor tissue when spatiotemporally navigated by an external magnetic field, the nanoscaled AMLs can intratumorally convert to microsized H2S bubbles. This dynamic process can be monitored by magnetic resonance and ultrasound dual modal imaging. Importantly, the intratumoral generated H2S bubbles imaged by real-time ultrasound imaging first can bomb to ablate the tumor tissue when exposed to higher acoustic intensity; then as gasotransmitters, intratumoral generated high-concentration H2S molecules can diffuse into the inner tumor regions to further have a synergetic antitumor effect. After 7-day follow-up observation, AMLs with magnetic field treatments have indicated extremely significantly higher inhibitions of tumor growth. Therefore, such elaborately designed intratumoral conversion of nanostructures to microstructures has exhibited an improved anticancer efficacy, which may be promising for multimodal image-guided accurate cancer therapy.Keywords: hydrogen sulfide; in situ microbubbles; magnetic nanoliposomes; multimodal imaging; ultrasound theranostics;

There has been unprecedented progress in the development of biomedical nanotechnology and nanomaterials over the past few decades, and nanoparticle-based drug delivery systems (DDSs) have great potential for clinical applications. Among these, magnetic drug delivery systems (MDDSs) based on magnetic nanoparticles (MNPs) are attracting increasing attention owing to their favorable biocompatibility and excellent multifunctional loading capability. MDDSs primarily have a solid core of superparamagnetic maghemite (γ-Fe2O3) or magnetite (Fe3O4) nanoparticles ranging in size from 10 to 100 nm. Their surface can be functionalized by organic and/or inorganic modification. Further conjugation with targeting ligands, drug loading, and MNP assembly can provide complex magnetic delivery systems with improved targeting efficacy and reduced toxicity. Owing to their sensitive response to external magnetic fields, MNPs and their assemblies have been developed as novel smart delivery systems. In this review, we first summarize the basic physicochemical and magnetic properties of desirable MDDSs that fulfill the requirements for specific clinical applications. Secondly, we discuss the surface modifications and functionalization issues that arise when designing elaborate MDDSs for future clinical uses. Finally, we highlight recent progress in the design and fabrication of MNPs, magnetic assemblies, and magnetic microbubbles and liposomes as MDDSs for cancer diagnosis and therapy. Recently, researchers have focused on enhanced targeting efficacy and theranostics by applying step-by-step sequential treatment, and by magnetically modulating dosing regimens, which are the current challenges for clinical applications.随着过去几十年来生物医学纳米技术和纳米材料领域的持续发展, 基于纳米颗粒的药物输送系统逐渐开始有望应用于临床研究. 其 中, 由于具有良好的生物相容性和优异的多功能负载能力, 基于磁性纳米粒子的磁性药物传递系统受到越来越多的关注. 本综述首先总结 了磁性药物传递系统的基本物理化学性质, 以阐明磁性药物传递系统需要保持适当的性能以满足特定的临床需要; 其次, 讨论了在设计未 来临床应用的磁性药物传递系统时的表面修饰和功能化问题; 最后, 重点综述了磁性纳米颗粒、磁性组装体以及磁性微泡、磁性脂质体和 生物膜修饰的磁性载体系统的设计和制备最新进展. 最后, 本综述对目前研究的磁性载体系统的设计、制备和安全性进行了总结, 并对未 来进一步解决磁性药物传递系统的临床应用瓶颈和前景进行了展望.

Stimuli-responsive devices that deliver drugs or imaging contrast agents in spatial-, temporal- and dosage-controlled fashions have emerged as the most promising and valuable platform for targeted and controlled drug delivery. However, implementing high performance of these functions in one single delivery carrier remains extremely challenging. Herein, we have developed a sequential strategy for developing glucose and magnetic-responsive microvesicle delivery system, which regulates the glucose levels and spatiotemporally controls the generation of nitric oxide gas free bubbles. It is observed that such injectable microvesicles loaded with enzyme and magnetic nanoparticles can firstly regulate hyperglycemic level based on the enzymatic reactions between glucose oxidase and glucose. In a sequential manner, concomitant magnetic field stimuli enhance the shell permeability while prompts the reaction between H2O2 and l-arginine to generate the gasotransmitters nitric oxide, which can be imaged by ultrasound and further delivered for diabetic nephropathy therapy. Therefore, magnetic microvesicles with glucose oxidase may be designed as a novel theranostic approach for restoring glucose homeostasis and spatiotemporally control NO release for maintaining good overall diabetic health.Magnetic microvesicles loaded with glucose oxidase and magnetic nanoparticles are designed as a novel theranostic system to spatiotemporally control the generation of nitric oxide for restoring glucose homeostasis.

Nanobubbles with a size less than 1 μm could make a promising application in ultrasound molecular imaging and drug delivery. However, the fabrication of stable gas encapsulation nanobubbles is still challenging. In this study, a novel method for preparation of lipid- encapsulated nanobubbles was reported. The dispersed phospholipid molecules in the prefabricated free nanobubbles solution can be assembled to form controllable stable lipid encapsulation gas-filled ultrasound-sensitive liposome (GU-Liposome). The optimized preparation parameters and formation mechanism of GU-Liposome were investigated in detail. Results showed that this type of GU-Liposome had mean diameter of 194.4 ± 6.6 nm and zeta potential of −25.2 ± 1.9 mV with layer by layer self-assembled lipid structure. The acoustic imaging analysis in vitro indicated that ultrasound imaging enhancement could be acquired by both perfusion imaging and accumulation imaging. The imaging enhancement level and duration time was related with the ratios of lipid to gas in the GU-Liposome structure. All in all, by this novel and controllable nanobubble construction technique, it will broaden the future theranostic applications of nanobubbles.Keywords: assembly; liposome; nanobubbles; theranostic; ultrasound imaging

Engineered iron oxide magnetic nanoparticles (MNPs) are one of the most promising tools in nanomedicine-based diagnostics and therapy. However, increasing evidence suggests that their specific delivery efficiency and potential long-term cytotoxicity remain a great concern. In this study, using 12 nm γ-Fe2O3 MNPs, we investigated three types of uptake pathways for MNPs into HepG2 cells: (1) a conventional incubation endocytic pathway; (2) MNPs co-administrated with microbubbles under ultrasound exposure; and (3) ultrasound delivery of MNPs covalently coated on the surface of microbubbles. The delivery efficiency and intracellular distribution of MNPs were evaluated, and the cytotoxicity induced by reactive oxygen species (ROS) was studied in detail. The results show that MNPs can be delivered into the lysosomes via classical incubation endocytic internalization; however, microbubbles and ultrasound allow the MNPs to pass through the cell membrane and enter the cytosol via a non-internalizing uptake route much more evenly and efficiently. Further, these different delivery routes result in different ROS levels and antioxidant capacities, as well as intracellular glutathione peroxidase activity for HepG2 cells. Our data indicate that the microbubble–ultrasound treatment method can serve as an efficient cytosolic delivery strategy to minimize long-term cytotoxicity of MNPs.磁性纳米颗粒在纳米生物医学诊断和治疗研究领域是极具潜力的一种纳米材料. 如何实现纳米颗粒在特定细胞或靶器官的高效率传输以及如何降低细胞毒性是目前纳米材料研究的重点内容. 本文首先研究了12 nm的γ-Fe2O3磁性纳米颗粒进入细胞的三种不同途径: (1) 纳米颗粒与肿瘤细胞共孵育后的内吞途径; (2) 纳米颗粒与微气泡共混合后超声辐照传输途径; (3) 纳米颗粒化学偶联到微气泡膜壳表面后超声辐照传输途径. 其次, 基于上述三种不同的纳米颗粒传输途径, 对纳米颗粒引起的细胞氧化应激毒性进行了深入研究. 结果表明, 纳米颗粒与肿瘤细胞共孵育后的内吞途径使纳米颗粒通过溶酶体包裹进入细胞; 通过超声微气泡辐照, 纳米颗粒能够以更高效率通过非内吞途径直接传输进入细胞质而不被溶酶体包裹. 不同传输途径导致纳米颗粒分别进入溶酶体和细胞质, 造成对细胞内氧化应激水平、总抗氧化能力以及谷胱甘肽过氧化物酶活性的响应不同. 综上研究表明, 超声微气泡介导的磁性纳米颗粒传输能够成为一种高效无损的细胞纳米颗粒输运新方法, 同时通过控制纳米颗粒进入细胞质降低了纳米颗粒的毒性, 从而能够更广泛应用于纳米生物医学的应用研究.

•The DOX-MMS, in which DOX was encapsulated in the core and γ-Fe2O3 were coated on the surface of microsphere, were prepared.•The cumulative drug release from DOX-MMS was significantly enhanced under an external magnetic field.•The magnetic responsive DOX-MMS were designed for chemo-thermal therapy.Controlled drug delivery systems have been extensively investigated for cancer therapy in order to obtain better specific targeting and therapeutic efficiency. Herein, we developed doxorubicin-loaded magnetic PLGA microspheres (DOX-MMS), in which DOX was encapsulated in the core and high contents (28.3 wt%) of γ-Fe2O3 nanoparticles (IOs) were electrostatically assembled on the surface of microsphere to ensure the high sensitivity to response of an external alternating current magnetic field (ACMF). The IOs in PLGA shell can both induce the heat effect and trigger shell permeability enhancement to release drugs when DOX-MMs was activated by ACMF. Results show that the cumulative drug release from DOX-MMs exposed to ACMF for 30 min (21.6%) was significantly higher (approximately 7 times higher) than that not exposed to ACMF (2.8%). The combination of hyperthermia and enhanced DOX release from DOX-MMS is beneficial for in vitro 4T1 breast cancer cell apoptosis as well as effective inhibition of tumor growth in 4T1 tumor xenografts. Therefore, the DOX-MMS can be optimized as powerful delivery system for efficient magnetic responsive drug release and chemo-thermal therapy.

Microbubbles (MBs) coupled with nanoparticles represent a new class of multifunctional probe for multiscale biomedical imaging and drug delivery. In this study, we describe the development of multifunctional, microscale microbubble probes that are composed of a nitrogen gas core and a biocompatible polymer shell harboring silver nanoparticles (AgNPs). Ultrasound imaging studies show that the presence of AgNPs in the MB significantly improves the contrast of ultrasound images. The AgNPs within individual MB can be also imaged by using dark-field microscopy (DFM), which suggests that AgNPs in the polymer shell adopt multiple structural forms. AgNPs are released from the polymer shell following a brief exposure to an ultrasonic field and are subsequently taken up by living cells. AgNPs within labeled cells are imaged by DFM, while surface-enhanced Raman scattering is used to identify specific cytoplasmic biomolecules that bind to the surface of the AgNP. Collectively, these studies demonstrate the application of multifunctional MBs for micrometer scale contrast-enhanced ultrasound imaging, as vehicles for the ultrasound-based delivery of optical probes and drugs to cells, and for imaging of chemical sensing of individual nanopartiles within cells and tissue.Keywords: diagnostics; microstructure surface; nanoparticles; optical imaging; ultrasound imaging;