Human induced pluripotent stem cells labeled with fluorescent magnetic nanoparticles for targeted imaging and hyperthermia therapy for gastric cancer

Objective: Human induced pluripotent stem(i PS) cells exhibit great potential for generating functional human cells for medical therapies. In this paper, we report for use of human i PS cells labeled with fluorescent magnetic nanoparticles(FMNPs) for targeted imaging and synergistic therapy of gastric cancer cells in vivo. Methods: Human i PS cells were prepared and cultured for 72 h. The culture medium was collected, and then was coincubated with MGC803 cells. Cell viability was analyzed by the MTT method. FMNP-labeled human i PS cells were prepared and injected into gastric cancer-bearing nude mice. The mouse model was observed using a small-animal imaging system. The nude mice were irradiated under an external alternating magnetic field and evaluated using an infrared thermal mapping instrument. Tumor sizes were measured weekly. Results: iP S cells and the collected culture medium inhibited the growth of MGC803 cells. FMNP-labeled human iP S cells targeted and imaged gastric cancer cells in vivo, as well as inhibited cancer growth in vivo through the external magnetic field. Conclusion: FMNP-labeled human i PS cells exhibit considerable potential in applications such as targeted dual-mode imaging and synergistic therapy for early gastric cancer.

M2 macrophage-targeted iron oxide nanoparticles for magnetic resonance image-guided magnetic hyperthermia therapy

Tumor-associated macrophages(TAMs)play an important role in tumor development and progression.In particular,M2 TAMs can promote tumor growth by facilitating tumor progression and malignant behaviors.Selectively targeted elimination of M2 TAMs to inhibit tumor progression is of great significance for cancer treatment.Iron oxide nanoparticles based magnetic hyperthermia therapy(MHT)is a classical approach to destroy tumor tissue with deep penetration depth.In this study,we developed a typical M2 macrophage-targeted peptide(M2pep)functionalized superparamagnetic iron oxide nanoparticle(SPIO)for magnetic resonance imaging(MRI)-guided MHT in an orthotopic breast cancer mouse model.The obtained multifunctional SPIO-M2pep with a hydrodynamic diameter of 20 nm showed efficient targeting capability,high transverse relaxivity(149 mM^(-1) s^(-1))and satisfactory magnetic hyperthermia performance in vitro.In vivo studies demonstrated that the SPIO-M2pep based MRI can monitor the distribution of nanoparticles in tumor and indicate the suitable timing for MHT.The M2 macrophage-targeted MHT significantly reduced the tumor volume and the population of pro-tumoral M2 TAMs in tumor.In addition,the SPIO-M2pep based MHT can remodel the tumor immune microenvironment(TIME).The multifunctional SPIO-M2pep with M2 macrophage-targeting ability,high magnetic hyperthermia efficiency,MR imaging capability and effective role in remodeling the TIME hold great potential to improve clinical cancer therapy outcomes.

A single magnetic nanoplatform-mediated combination therapy of immune checkpoint silencing and magnetic hyperthermia for enhanced anti-cancer immunity

As a revolutionary cancer treatment strategy,immunotherapy has attracted great attention.However,the effect of immunotherapy such as immune checkpoint blockade(ICB)is usually limited by insufficient immune response in the body.Herein,a polycation-based magnetic nanocluster platform was developed to load therapeutic nucleic acids,which could achieve gene therapy-mediated ICB and efficient magnetic hyperthermia therapy(MHT).The silencing of immune checkpoints together with MHT-induced immunogenic cell death(ICD)effectively alleviated the immune escape of cancer cells and significantly enhanced the visibility of cancer cells to the immune system.This combined treatment strategy activated a strong adaptive anti-cancer immune response in vivo,greatly inhibiting tumor growth,metastasis and recurrence.

Autophagy inhibition mediated via an injectable and NO-releasing hydrogelfor amplifying the antitumor efficacy of mild magnetic hyperthermia

While mild hyperthermia holds great potential in the treatment of solid tumors, the thermal stress-triggered selfrepairingautophagy significantly compromises its efficacy. To circumvent this obstacle, an injectable hydrogel(NO-Gel) composed of thermosensitive poly(ethylene glycol)-polypeptide copolymers modified with abundantNO donors on their side chains is developed. Meanwhile, ferrimagnetic Zn0.5Fe2.5O4 magnetic nanoparticles(MNPs) with high magnetic-heat conversion efficiency are synthesized and loaded into NO-Gel to obtainMNPs@NO-Gel. The MNPs@NO-Gel system exhibits a sol-gel transition upon heating, and has the ability toperform multiple magnetic hyperthermia therapy (MHT) after only one administration due to the even distributionand strong immobilization of MNPs in NO-Gel. NO can be continuously liberated from NO-Gel and thisprocess is markedly accelerated by MHT. Additionally, MNPs@NO-Gel maintains its integrity in vivo for over onemonth and the released MNPs are metabolized by the spleen. After a single administration of MNPs@NO-Gel atthe tumor site, three mild MHT treatments with similar effects are fulfilled, and the sufficient supply of NOeffectively inhibits MHT-induced autophagic flux via blocking the formation of autophagosomes and synchronouslydestroying lysosomes, thereby substantially boosting the efficacy of mild MHT. As a consequence, CT-26colon tumors are completely eliminated without causing severe side-effects.

A highly degradable Mg-Al-Ca alloy with superior anti-tumor efficacy

Molecule hydrogen(H_(2)) has been used to suppress tumor growth. To employ the H_(2) therapy, it is necessary to use a proper agent for continuous generation of H_(2). As a biodegradable metal, magnesium(Mg) generates H_(2) in an aqueous environment, but the H_(2) release rate is still too low. Here, we design a Mg-Al-Ca(AX) alloy that degrades very rapidly due to the presence of a secondary phase Al_(2)Ca. Having a reduction potential much higher than Mg and any other Mg-based secondary phases, Al_(2)Ca accelerates the corrosion of the Mg matrix by a micro-galvanic process. Al_(2)Ca also enhances the strength and ductility of the AX alloy. AX alloy rods show better anti-tumor efficacy than pure Mg rods in vivo. Moreover, implanted AX alloy rods can be heated under an alternating magnetic field to suppress large-size tumors.This work suggests that the H_(2) therapy using highly degradable Mg alloys may provide an effective cancer treatment.

Advanced Treatment Planning in Cancer Thermal Therapies

CEM43 thermal dose is a very common concept in thermal oncology.Thermal dose is the maximum amount of energy that can be transmitted during hyperthermia therapy conducted on temperature-sensitive tissue.Thermal dose is also the maximum value of local energy accumulation in human bodies,which can lead to tissue injury and pain.Thermal dose can also decrease the finishing temperature and reduce the energy to the tolerable range.There are two functions of the individualized hyperthermia treatment plan:it determines the setting and location that can realize the best tumor hyperthermia therapy;at the same time,it can decrease the effect of hyperthermia therapy on healthy tissues.There are four steps in the treatment plan of hyperthermia therapy for tumors:the first step is to establish a three dimensional human body model and its corresponding an atomical structure that can be used in numerical algorithm via medical imaging resources;the second step is to determine the volume of the electromagnetic energy accumulation.Based on the peculiarity of frequency and materials,even full-wave electromagnetic wave or quasi-static technique can be used to determine the tissue distribution.Evaluation of the therapy can be conducted based on thermal dose and the corresponding tissue damage model;the third step is to use Arrhenius model to provide direct evaluation of tissues in the thermal ablation zone,solidification zone,as well as the necrotic area;the last step is the optimization of the treatment plan.

In situ engineered magnesium alloy implant for preventing postsurgical tumor recurrence

Invasive tumors are difficult to be completely resected in clinical surgery due to the lack of clear resection margins,which greatly increases the risk of postoperative recurrence.However,chemotherapy and radiotherapy as the traditional means of postoperative adjuvant therapy,are limited in postoperative applications,such as multi-drug resistance and low sensitivity,etc.Therefore,an engineered magnesium alloy rod is designed as a postoperative implant to completely remove postoperative residual tumor tissue and inhibit tumor recurrence by gas and mild magnetic hyperthermia therapy(MMHT).As a reactive metal,magnesium alloy responds to the acidic tumor microenvironment by continuously generating hydrogen.The in-situ generation of hydrogen not only protects the surrounding normal tissue,but also enables the magnesium alloy to achieve MMHT under lowintensity alternating magnetic field(AMF).Furthermore,the numerous reactive oxygen species(ROS)produced by heat stress will combine with nitric oxide(NO)generated in situ,to produce more toxic reactive nitrogen species(RNS)storm.In summary,engineered magnesium alloy can completely remove residual tumor tissue and inhibit tumor recurrence by MMHT and RNS storm under low-intensity AMF,and the biodegradability of magnesium alloy makes great potential for clinical application.