Dai Zhifei

Multifunctional magnetic nanoparticles for magnetic resonance image-guided photothermal therapy for cancer

Key advances in multifunctional magnetic nanoparticles (MNPs) for magnetic resonance (MR) image-guided photothermal therapy of cancer are reviewed. We briefly outline the design and fabrication of such multifunctional MNPs. Bimodal image-guided photothermal therapies (MR/fluorescence and MR/ultrasound) are also discussed.

Progress of nanoparticles inhibiting tumor metastasis

Tumor metastasis has become one of the great challenges of cancer diagnosis and effective treatment. Metastasis, a process is depicted that the primary tumor spread to distant organs or tissues to compose the new “citadel”. The circulating tumor cells which are escaping the immune surveillance can transfer to the host tumor and tissue. Once these adapt to the “host organ” microenvironment, composing the “metastatic tumor” with a strong multi-drug resistance. Therefore, curing the metastatic tumor hardly uses the traditional treatment independently. Nowadays, we focus on how to use the functional nanoparticles (NPs)to inhibit tumor metastasis effectively. One of treating metastasis issues is enriching the NPs in the tumor tissue. The EPR effect is the “navigator” of NPs. They can reach the tumor site effectively and tracing or inhibiting the metastatic tumor in possibility. Some research have found that the permeability factor such as nitric oxide contributed to the role of EPR effect in the tumor site, it improved the vascular permeability of the tumor site selectively, proved that NPs can be effectively delivered to the tumor site. Tumor tissues often show the specificity, which make the NPs target to the specific tumor tissue modifying the specific antibody. The NPs can be encapsulated by the homologous cancer cell membrane and release the anti-tumor drugs in the vicinity effectively, improving the treatment efficiency and the therapeutic effect obviously.. Nowadays, the CRISPR immune system develop a new gene editing technique. To delivery Cas-9 system in high efficiency, we can design a series of functional-nanoparticle delivery system. It is a kind of method which is safer than the virus vector and much more efficiency than the plasmid. In the meanwhile, it can grasp the relationship between the lack of gene function and phenotype of metastasis with controlling the tumor growth. Inhibition of CTCs in vivo circulation is the most indispensable step in preventing tumor metastasis, but it is hardly to capture circulating CTCs in the background of hundreds of millions of cells in the circulatory system effectively. In view of this problem, the researchers make use of NPs which can be modified. They can targeting and enriching the CTCs to inhibit the metastasis. We can predict that using NPs to develop microchips can capture and enrich CTCs in the blood circulation efficiently. Tumor “relapse” has been a clinical cure for cancer problem, especially malignant glioma which forms in the brain. Due to its good tumor tissue infiltration, it is hardly to remove the tumor completely by making surgery merely, and account for the secondary metastatic easily. Depending on the good targeting to tumor tissue, the magnetic nanoparticles(MNPs) can inhibit the expression of epidermal growth factor (EGFR) within the loaded-antibody. Moreover, they combine it with magnetic resonance imaging, locating the tumor accurately. It is improved that the MNPs inhibit the expression of EGFR and tumor recurrence and secondary metastasis potentially, indicating that the NPs have a great value with a long-distanced applying in clinic. In all, the review pays attention to the two aspects of metastases, including the inhibition of primary tumor invasion or metastasis and metastases proliferation or recurrence. Meanwhile, prospecting that the NPs can make great contributes to change the clinical treatment in the predicted future.

Applications, opportunities and challenges of molecular probes in the diagnosis and treatment of major diseases

Minimally invasive treatment of cancer can significantly reduce surgery risks due to many advantages, such as no laparotomy, small wound and early recovery and so on. Especially, it is suitable for patients who cannot be operated on due to tumor distant metastasis, oldness, weakness, and major organ dysfunction. According to clinical statistics, more than 60% of patients with mid-advanced cancer can be cured by employing minimally invasive surgery. Malignant tumors often show invasive growth and unclear boundary, resulting in partial removal of healthy tissue during surgery, hence postoperative sequelae and dysfunction. In order to carry out minimally invasive surgery and targeted elimination of tumor, the size and location of the tumors must be accurately identified before therapy, which requires the imaging guidance. By using optical molecular imaging, we can find a small tumor less than ~1mm. Therefore, the molecular imaging navigation provides a great opportunity for the development of minimally invasive interventional therapy for cancer. Especially, the cancer specific probes are emerging as one of the key technologies of molecular imaging. Compared with small molecular probes, nanoprobes show longer imaging time, remarkable signal multiplication and drug loading capacity. There, specific nanoprobes become the development direction of the molecular imaging navigation technology. Aiming at accuracy, high efficacy and minimal invasiveness of cancer treatments, we need solve two key scientific issues including identification of tumor boundary and predictability of lymph node metastases, and develop three key technologies including: high accumulation of nanoprobes at tumor sites, high sensitivity of nanoprobes to cancer cells, high precision imaging methods based on nanoprobes. This project will design and construct a variety of safe and efficient nanoprobes and related nanomaterials with independent intellectual property rights. For example, ultra pH (or enzyme)-sensitive fluorescent nanoprobes will be fabricated for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. Multifunctional nanoprobes will be developed for simultaneous molecular imaging and interventional therapy of cancer. Fluorescent/ultrasound nanoprobes will be prepared to achieve a bimodal imaging with excellent signal sensitivity and high spatial resolution. Theranostic nanoprobes will be produced for both targeted imaging (diagnosis) and interventional therapy (laser, ultrasound, microwave, radiofrequency or combination etc.). In addition, we will establish a practical and feasible technology platform for large-scale production of nanoprobes, and in vivo and in vitro evaluation systems for the clinical applications of nanoprobes. It is of crucial importance to investigate the biological influence of nanoprobes on cell division, proliferation, apoptosis and signal transduction pathways, assess in vivo transport mechanism across biological barriers, and evaluate biosafety of nanoprobes, such as acute toxicity, long-term toxicity, nervous system toxicity and immunogenicity. Moreover, fluorescence confocal microendoscope and minimally invasive therapeutic devices will be developed based on nanoprobes. Finally, we will assess invasion depth and lymph node metastasis in early gastric cancer, as well as retroperitoneal lymph node metastasis of ovarian cancer by using nanoprobes in combination of fluorescence confocal microendoscope and molecular imaging navigation system. The sensitivity and specificity of molecular imaging nanoprobes are evaluated by using pathology as the gold standard. The precise interventional therapy (photodynamic, photothermal and sonodynamic etc.) will be implemented by irradiating the tumor tissue using laser or ultrasound under the guidance of nanoprobe-enhanced molecular imaging. It is essential to investigate the evaluation methods of therapeutic efficacy. We will explore the synergistic, anti-metastatic and overcoming drug resistance effects of interventional therapy combined with chemotherapy. In conclusion, molecular imaging nanoprobes can be used not only for imaging and diagnosis, but also for the minimally invasive interventional treatments. In particular, the research and application of nanoprobes will promote the development and application of fluorescence confocal microendoscope, molecular imaging navigation systems and minimally invasive interventional therapy systems. This will accelerate the breakthrough in the key technology of major medical equipment. Undoubtedly, the accomplishment of the project would enhance the innovation capability and international competitiveness of China in nanobiomedicine and medical equipment.

Ultrasound induced cancer immunotherapy

Cancer immunotherapy is rapidly becoming one of the pillars of anti-cancer therapy. Unlike previous cancer therapies, immunotherapy aims at activating or enhancing the natural immune response of the patient to kill cancer cells and tissues. It means that the immune system can be activated to attack the cancer cells but leaving the normal, healthy cells intact. Immunotherapy can be realised in several treatment approaches, such as the increase of the non-specific immune system, by cancer vaccines, adoptive cell transfer and monoclonal antibodies. Considering the heterogenicity and genetic instability of tumors, a certain kind of treatment may not achieve ideal therapeutic effect all the time. In recent years, using ultrasound to achieve immune response towards cancer shows great promise. Ultrasound is one of the most commonly used imaging diagnostic techniques for cancer diseases. Besides, ultrasound has attraction for both direct US treatment and activating drug delivery due to its biological effects. Several studies suggest that ultrasound can be used to boost the host anti-tumor immune responses. The recent advances, the potential and existing problems of US induced cancer immunotherapy are reviewed. Focused ultrasound (FUS) can achieve a high US energy with in a small focal volume, which causes local destruction of tumor tissues with minimal damage to surrounding normal tissues. Destruction of tumors caused by FUS may lead to generate tumor debris and tumor-associated antigens (TAAs) in situ , which can facilitate and amplify the anti-tumor immune responses, and protect the body from tumorgenesis when re-challenged. HIFU also has effects on other than the destruction of the tissue. HIFU treatment, which triggers a Th1 type response, leads to significant changes in cell-mediated immunity. HIFU treatment also acts by balancing the cancer-induced immuno-suppression in tumor micro-environment. Microbubbles (MBs), a kind of US contrast agents, can improve the therapeutic efficacy of FUS because of their intensity reflection and scattering of ultrasonic waves, which shows great value in clinical use. The addition of MBs to FUS can help generate more local destruction in the area of focus. Combination FUS with microbubbles has been found to increase the permeability of the blood-brain barrier (BBB) and provide a temporary and targeted opening of the BBB without inflicting brain damage or inflammation, thus is an attractive means to deliver immune cells and drugs. Sonoporation is the use of sound (typically ultrasonic frequencies) for modifying the permeability of the cell plasma membrane. Sonoporation employs the acoustic cavitation of microbubbles to enhance delivery of large molecules. This technique is usually used in gene therapy and drug delivery. Another way to achieve anti-tumor immune responses is using US and MBs to deliver immune-stimulating substances to immune cells or tumor cells. Drug delivery that using a combination of MBs and US has been explored. Non-destructive US with or without MBs can increase the delivery of active substances including antigens and immune-stimulating genes. Combination of microbubbles with cell-targeting ligands and US provides an even more smart delivery system, therefore, the therapy is not only site specific but also cell specific. Overall, the use of US to achieve immune response towards cancer is showing promise. The field is fairly young and many mechanisms are still not fully understood, thus further researches are needed.

Localized delivery of curcumin-loaded nanoparticles to the brain for treatment of Parkinson's disease using focused ultrasound

Focused ultrasound combined with microbubbles has shown to be a promising technique to induce noninvasively the localized BBB opening. The purpose of the present study is to explore the potential application of curcumin-loaded polysorbate 80-coated cerasomes (CPC) for treatment of Parkinsons disease using focused ultrasound. The CPC nanoparticles were fabricated and characterized and the optimal mole ratio of polysorbate 80 was determined at 1 : 9 (polysorbate 80 to cerasome-forming lipids). The in vitro BBB cell model was developed and the protective property of CPC on SH-SY5Y cells were examined, revealing a significant cell protective effect of CPC and focused ultrasound than that of other treatments. The in vivo permeability experiments revealed a significant higher permeability of CPC through the BBB when the mice were received with CPC and ultrasound. The in vivo efficacy on PD also showed the mouse group treated by CPC with focused ultrasound recovered more effectively than those of the other groups. In conclusion, our study provided a localized delivery of curcumin to the brain for treatment of PD disease through PS80-coated cerasomes combined with focused ultrasound.

Multifunctional nanoprobes for minimallyinvasive interventional diagnosis and therapy of cancer based on molecularimaging navigation

Minimally invasive treatment of cancer can significantly reduce surgery risks due to many advantages, such as no laparotomy, small wound and early recovery and so on. Especially, it is suitable for patients who cannot be operated on due to tumor distant metastasis, oldness, weakness, and major organ dysfunction. According to clinical statistics, more than 60% of patients with mid-advanced cancer can be cured by employing minimally invasive surgery.