Yushen Jin

Gold‐Nanoshelled Microcapsules: A Theranostic Agent for Ultrasound Contrast Imaging and Photothermal Therapy

The term theranostics, which is derived from “diagnostics” and “therapy”, refers to a treatment strategy that combines a diagnostic test and a specific therapy based on the test results. This integration of diagnostic imaging capability with therapy is critical in addressing the challenges of cancer heterogeneity and adaptation. Therefore, theranostic agents have received a great deal of recent research interest in cancer diagnosis and treatment. Among all the diagnostic imaging techniques, ultrasound imaging has a unique advantage because of its features of real-time, low-cost, high safety, and ease of incorporation into portable devices. With the use of ultrasound contrast agents (UCAs), the resolution and sensitivity of clinical ultrasound imaging have been greatly improved. Microcapsules composed of poly(lactic acid) (PLA), which has outstanding biocompatibility and biodegradability, show good ultrasound contrast-enhancing capabilities and other advantages: they have good mechanical strength and are thus stable, they can load either hydrophilic or hydrophobic species or both, and they are surface-charged and have functional groups on the surface so that they could be easily modified to introduce further practical features. Gold nanostructures exhibit good biocompatibility as well as excellent optical and electronic properties, thus allowing use in biological and medical applications. Gold nanoshells have a spherical dielectric core particle surrounded by a thin nanoscale gold shell. By controlling the thickness of the gold shell and the diameter of the core, the plasmon resonance and the resulting optical absorption of gold nanoshells can be tuned to the near-infrared (NIR) region, where the absorption of human tissues is minimal and penetration is optimal. On the other hand, the strong optical absorption of nanoshells can rapidly increase the local temperature under NIR irradiation. Therefore, the gold nanoshells can be used as photoabsorbers for remote NIR photothermal ablation therapy. Lasers and photoabsorbers such as gold nanostructures are used to carry out cancer treatment in photothermal therapy. However, the location and size of cancers must be identified before therapy, the treatment procedure needs to be monitored in real time during therapy, and the effectiveness has to be assessed after therapy. Contrast-enhanced ultrasound imaging could be the technique of choice to address these tasks. Therefore, the development of goldnanoshell-based UCAs could operate as a multifunctional theranostic agent for imaging-guided photothermal therapy. We have developed a novel multifunctional theranostic agent based on gold-nanoshelled microcapsules (GNS-MCs) by electrostatic adsorption of gold nanoparticles as seeds onto the polymeric microcapsule surfaces, followed by the formation of gold nanoshells by using a surface seeding method (Figure 1). The polymeric microcapsules were generated from PLA and polyvinyl alcohol (PVA) materials by employing the water-in-oil-in-water (W/O/W) double-emulsion method, and were negatively charged with a zeta potential of about 25 mV. Upon exposure to positively charged poly(allyl-

Graphene oxide modified PLA microcapsules containing gold nanoparticles for ultrasonic/CT bimodal imaging guided photothermal tumor therapy.

Theranostic microcapsules were successfully fabricated by introducing gold nanoparticles into poly(lactic acid) microcapsules through a double-microemulsion method, followed by depositing graphene oxide onto the microcapsule surface via electrostatic layer-by-layer self-assembly technique. It was proved that the obtained microcapsules could serve as a contrast agent to simultaneously enhance US imaging and X-ray CT imaging greatly both in vitro and in vivo. In addition, the in vivo therapeutic examinations showed that the microcapsule was an effective agent for photothermal therapy of cancer. The near-infrared laser light ablated the tumor completely within 9 days in the presence of the microcapsules and the tumor growth inhibition was 83.8%. The combination of real-time ultrasound with 3-D computed tomography through a single microcapsule agent is very helpful for accurately interpreting the obtained images, identifying the size and location of the tumor, as well as guiding and monitoring the photothermal therapy. Simultaneously, the effectiveness of photothermal therapy could be evaluated by the combined US and CT imaging enhanced by the microcapsule agent. Such a versatile microcapsule system might bring opportunities to the next generation of multimodal imaging guided cancer therapy.

Gold nanoshelled liquid perfluorocarbon magnetic nanocapsules: a nanotheranostic platform for bimodal ultrasound/magnetic resonance imaging guided photothermal tumor ablation.

Imaging guided ablation therapy has been applied in both biomedical research and clinical trials and turned out to be one of the most promising approaches for cancer treatment. Herein, the multifunctional nanocapsules were fabricated through loading perfluorooctylbromide (PFOB) and superparamagnetic iron oxide nanoparticles (SPIOs) into poly(lactic acid) (PLA) nanocapsules (NCs), followed by the formation of PEGylated gold nanoshell on the surface. The resulting multi-component NCs were proved to be able to act as nanotheranostic agent to achieve successful bimodal ultrasound (US)/magnetic resonance imaging (MRI) guided photothermal ablation in human tumor xenograft models non-invasively. Such a single theranostic agent with the combination of real-time US and high-resolution MR imaging would be of great value to offer more comprehensive diagnostic information and dynamics of disease progression for the accurate location of therapeutic focusing spot in the targeted tumor tissue, showing great potential as an effective nanoplatform for contrast imaging guided photothermal therapy.

Magnetic Prussian blue nanoparticles for targeted photothermal therapy under magnetic resonance imaging guidance.

This paper reported a core-shell nanotheranostic agent by growing Prussian blue (PB) nanoshells of 3-6 nm around superparamagnetic Fe3O4 nanocores for targeted photothermal therapy of cancer under magnetic resonance imaging (MRI) guidance. Both in vitro and in vivo experiments proved that the Fe3O4@PB core-shell nanoparticles showed significant contrast enhancement for T2-weighted MRI with the relaxivity value of 58.9 mM(-1)·s(-1). Simultaneously, the composite nanoparticles exhibited a high photothermal effect under irradiation of a near-infrared laser due to the strong absorption of PB nanoshells, which led to more than 80% death of HeLa cells with only 0.016 mg·mL(-1) of the nanoparticles with the aid of the magnetic targeting effect. Using tumor-bearing nude mice as the model, the near-infrared laser light ablated the tumor effectively in the presence of the Fe3O4@PB nanoparticles and the tumor growth inhibition was evaluated to be 87.2%. Capabilities of MRI, magnetic targeting, and photothermal therapy were thus integrated into a single agent to allow efficient MRI-guided targeted photothermal therapy. Most importantly, both PB and Fe3O4 nanoparticles were already clinically approved drugs, so the Fe3O4@PB nanoparticles as a theranostic nanomedicine would be particularly promising for clinical applications in the human body due to the reliable biosafety.

Gold nanoshelled liquid perfluorocarbon nanocapsules for combined dual modal ultrasound/CT imaging and photothermal therapy of cancer.

The integration of multimodal contrast-enhanced diagnostic imaging and therapeutic capabilities could utilize imaging guided therapy to plan the treatment strategy based on the diagnostic results and to guide/monitor the therapeutic procedures. Herein, gold nanoshelled perfluorooctylbromide (PFOB) nanocapsules with PEGylation (PGsP NCs) are constructed by oil-in-water emulsion method to form polymeric PFOB nanocapsules, followed by the formation of PEGylated gold nanoshell on the surface. PGsP NCs could not only provide excellent contrast enhancement for dual modal ultrasound and CT imaging in vitro and in vivo, but also serve as efficient photoabsorbers for photothermal ablation of tumors on xenografted nude mouse model. To our best knowledge, this is the first report of gold nanoshell serving as both CT contrast agents and photoabsorbers for photothermal therapy. The novel multifunctional nanomedicine would be of great value to offer more comprehensive diagnostic information to guide more accurate and effective cancer therapy.

Polypyrrole Hollow Microspheres as Echogenic Photothermal Agent for Ultrasound Imaging Guided Tumor Ablation

Ultrasound (US) imaging provides a valuable opportunity to administer photothermal therapy (PTT) of cancer with real-time guidance to ensure proper targeting, but only a few theranostic agents were developed by physically grafting near infrared (NIR)-absorbing inorganic nanomaterials to ready-made ultrasound contrast agents (UCAs) for US imaging guided PTT. In this paper, NIR absorbing hollow microspheres were generated from polypyrrole merely using a facile one-step microemulsion method. It was found that the obtained polypyrrole hollow microspheres (PPyHMs) can act as an efficient theranostic agent not only to enhance US imaging greatly, but also exhibit excellent photohyperthermic effects. The contrast consistently sustained the echo signals for no less than 5 min and the NIR laser light ablated the tumor completely within two weeks in the presence of PPyHMs. More importantly, no use of additional NIR absorber substantially minimizes an onetime dose of the theranostic agent.

Cerasomal doxorubicin with long-term storage stability and controllable sustained release

Liposomal nanohybrid cerasomes display a remarkable ability to maintain their size and retain encapsulated doxorubicin (DOX) over a period of 90days under storage conditions in solution compared with liposomes and liposils. Cerasomes retained 92.1±2.9% of the drug payload after 90days storage, much more than liposomes (35.2±2.5%) and liposils (53.2±5.5%). Under physiologically relevant conditions cerasomes exhibit a low initial burst in the first 5h and subsequent sustained release of DOX over the next 150h. Moreover, the magnitude of the initial burst and the rate of sustained release of DOX from cerasomes can be modulated by incorporating dipalmitoylphosphatidylglycerol (DPPG) in the cerasome structure and altering the ratios of the cerasome-forming lipid and phospholipids. Consequently, a wide range of release profiles can be achieved by altering the vesicle composition. Finally, human ovarian cancer cells are effectively killed by DOX released from cerasomes. Together these results suggest that cerasomes may be a promising drug delivery system for the long-term storage and controllable sustained release of the anticancer drug DOX.

Multifunctional ultrasound contrast agents for imaging guided photothermal therapy.

Among all the imaging techniques, ultrasound imaging has a unique advantage due to its features of real-time, low cost, high safety, and portability. Ultrasound contrast agents (UCAs) have been widely used to enhance ultrasonic signals. One of the most exciting features of UCAs for use in biomedicine is the possibility of easily putting new combinations of functional molecules into microbubbles (MBs), which are the most routinely used UCAs. Various therapeutic agents and medical nanoparticles (quantum dots, gold, Fe3O4, etc.) can be loaded into ultrasound-responsive MBs. Hence, UCAs can be developed as multifunctional agents that integrate capabilities for early detection and diagnosis and for imaging guided therapy of various diseases. The current review will focus on such state-of-the-art UCA platforms that have been exploited for multimodal imaging and for imaging guided photothermal therapy.

Bifunctional gold nanorod-loaded polymeric microcapsules for both contrast-enhanced ultrasound imaging and photothermal therapy

A novel bifunctional theranostic agent has been fabricated through the combination of acoustic responsive poly(lactic acid) microcapsules and near infrared absorbed gold nanorods that holds the potential of simultaneous ultrasound contrast diagnostic imaging and photothermal therapy.

Modulation of release of paclitaxel from composite cerasomes

Efforts to improve the stability of liposomes have recently led to the development of organic-inorganic liposomal cerasomes. In this study, we explore the potential to modulate the sustained release of paclitaxel from cerasomes by alteration in vesicle composition. Specifically, composite cerasomes have been prepared from mixtures of cerasome-forming lipid (lipid 1) and 1,2-distearoyl-sn-glycero-3-phosphocholine (lipid 2) via one-step construction. The influences of vesicle composition on the physical properties (e.g., particle diameter and surface charge density), physiochemical and long-term storage stability, drug-loading capacity, and release rates of paclitaxel have been investigated. Notably, a wide range of the release profiles of paclitaxel have been achieved by varying the contents of lipid 2, and the composite vesicles display excellent stability when the percentage content of lipid 2 is lower than 50%. Composite vesicles composed of lipids 1 and 2 at a 1:1 molar ratio also exhibited good cytocompatibility and the released paclitaxel effectively inhibit the proliferation of HeLa cancer cells. Together, the development of composite vesicles offers a promising strategy to obtain excellent stability, good drug-loading capacity and cytocompatibility, and enhanced paclitaxel release in single vesicles.