Urchin-like magnetic microspheres for cancer therapy through synergistic effect of mechanical force, photothermal and photodynamic effects.

BACKGROUND: Magnetic materials mediated by mechanical forces to combat cancer cells are currently attracting attention. Firstly, the magnetic force penetrates deeper into tissues than the NIR laser alone to destroy tumours. Secondly, the synergistic effect of nano-magnetic-material characteristics results in a viable option for the targeted killing of cancer cells. Therefore, mechanical force (MF) produced by magnetic nanomaterials under low frequency dynamic magnetic field combined with laser technology is the most effective, safe and efficient tool for killing cancer cells and tumour growth. RESULTS: In this study, we synthesized novel urchin-like hollow magnetic microspheres (UHMMs) composed of superparamagnetic Fe3O4. We demonstrated the excellent performance of UHMMs for killing laryngocarcinoma cancer cells through mechanical force and photothermal effects under a vibrating magnetic field and near-infrared laser, respectively. The killing efficiency was further improved after loading the synthesised UHMMs with Chlorin e6 relative to unloaded UHMMs. Additionally, in animal experiments, laryngocarcinoma solid tumour growth was effectively inhibited by UHMMs@Ce6 through magneto-mechanic force, photothermal and photodynamic therapy. CONCLUSIONS: The biocompatibility and high efficiency of multimodal integrated therapy with the UHMMs prepared in this work provide new insights for developing novel nano therapy and drug loading platforms for tumour treatment. In vivo experiments further demonstrated that UHMMs/Ce6 are excellent tools for strongly inhibiting tumour growth through the above-mentioned characteristic effects.

Low frequency vibrating magnetic field-triggered magnetic microspheres with a nanoflagellum-like surface for cancer therapy.

BACKGROUND: The magneto-mechanical force killing cancer cells is an interesting and important strategy for cancer therapy. RESULTS: Novel magnetic microspheres composed of a Fe3O4 nanocore, a bovine serum albumin (BSA) matrix, and a rod-like SiO2 nanoshell, which had flagellum-like surface for force-mediated cancer therapy were developed. One such magnetic microsphere (Fe3O4/BSA/rSiO2) at a cancer cell (not leave the cell surface) under a low frequency vibrating magnetic field (VMF) could generate 6.17 pN force. Interestingly, this force could induce cancer cell to generate reactive oxygen species (ROS). The force and force-induced ROS could kill cancer cells. The cell killing efficiency of Fe3O4/BSA/rSiO2 exposed to a VMF was enhanced with increasing silica nanorod length, and the microspheres with straight nanorods exhibited stronger cell killing ability than those with curled nanorods. Fe3O4/BSA/rSiO2 triggered by a VMF could efficiently inhibit mouse tumor growth, while these microspheres without a VMF had no significant effect on the cell cycle distribution, cell viability, tumor growth, and mouse health. CONCLUSIONS: These microspheres with unique morphological characteristics under VMF have great potential that can provide a new platform for treating solid tumors at superficial positions whether with hypoxia regions or multidrug resistance.

Corrigendum: "Incorporating quantum dots into polymer microspheres via a spray-drying and thermal-denaturizing approach". Nanotechnology 17 (2006) 1791-1796".

Corrigendum.

Hedgehog-Like Gold-Coated Magnetic Microspheres that Strongly Inhibit Tumor Growth through Magnetomechanical Force and Photothermal Effects.

Using magnetomechanical force to kill cancer cells has attracted great attention recently. This study presents novel hedgehog-like microspheres composed of needle-like magnetic nanoparticles with carbon and gold double shells. Using a novel low-frequency vibrating magnetic field (VMF), these microspheres with sharp surfaces can seriously damage cancer cells and strongly inhibit mouse tumor growth through mechanical force. The cell killing efficiency depends on VMF exposure time, frequency, strength, and microsphere concentration. The maximum mechanical force generated by one microsphere acting on a cancer cell under a VMF is about 35.79 pN. The microspheres also induce photothermal ablation after being triggered by near-infrared laser irradiation. Mouse tumors could not be detected after treatment with the synergistic stimuli of mechanical force and photothermal ablation. These results reveal a simple and highly efficient strategy using magnetic microspheres for local treatment of solid tumors in a remote and noninvasive manner.

Mito-Specific Nutri-Hijacker Synergizing Mitochondrial Metabolism and Glycolysis Intervention for Enhanced Antitumor Bioenergetic Therapy.

Metabolic rewiring, a dynamic metabolic phenotype switch, confers that tumors exist and proliferate after fitness (or preadaptation) in harsh environmental conditions. Glycolysis deprivation was considered to be a tumor's metabolic Achilles heel. However, metabolic configuration can flexibly retune the mitochondrial metabolic ability when glycolysis is scared, potentially resulting in more aggressive clones. To address the challenge of mitochondrial reprogramming, an antiglycolytic nanoparticle (GRPP NP) containing a novel mitochondrial-targeted reactive oxygen species (ROS) generator (diIR780) was prepared to hijack glucose and regulate mitochondria, thus completely eliminating tumorigenic energy sources. In this process, GRPP NPs@diIR780 can catalyze endogenous glucose, leading to significantly suppressed glycolysis. Moreover, diIR780 can be released and selectively accumulated around mitochondria to generate toxic ROS. These combined effects, in turn, can hamper mitochondrial metabolism pathways, which are crucial for driving tumor progression. This synchronous intervention strategy enables utter devastation of metabolic rewiring, providing a promising regiment to eradicate tumor lesions without recurrence.

Magnetotactic Bacteria-Based Drug-Loaded Micromotors for Highly Efficient Magnetic and Biological Double-Targeted Tumor Therapy.

Bacteria-mediated cancer therapy has attracted much attention in recent years. However, using magnetotactic bacteria as both a drug carrier and a drug for cancer therapy has never been reported. Herein, we incorporated a photosensitizer chlorin e6 (Ce6) into the M. magneticum strain AMB-1 through a chemical bond or physical blending. A chemical reaction was finally selected for fabricating AMB-1/Ce6 micromotors, as such micromotors exhibited high drug payload and normal bacterial activities. An interesting finding is that AMB-1 is not only an excellent drug carrier but also a unique drug that could inhibit mouse tumor growth. We also, for the first time, demonstrated that AMB-1 is a photosensitizer. Under laser irradiation, micromotors killed cancer cells with high efficiency due to the high-level reactive oxygen species generated by the micromotors. Micromotors could target the hypoxic and normoxic regions in vitro via both the active swimming of AMB-1 and external magnetic field guidance. Micromotors showed high tumor-homing ability owing to the above double targeting mechanisms. After injection with the micromotors followed by magnetic field guidance and laser irradiation, the growth of mouse tumors was significantly inhibited owing to the AMB-1-based biotherapy and phototoxicity of AMB-1 and Ce6. This micromotor-mediated tumor-targeted therapy strategy may be a great platform for treating many types of solid tumors.

Macrophage membrane coated nanoparticles: a biomimetic approach for enhanced and targeted delivery.

The enhanced and targeted drug delivery with low systemic toxicity and subsequent release of drugs is a major concern among researchers and pharmaceutics. In spite of greater advancement and discoveries in nanotherapeutics, the application of synthetic nanomaterials in clinics is still a challenging task due to immune barriers, limited blood circulation time, biodistribution and toxicity. In order to overcome these issues, cell membrane coated nanoparticles are widely employed for effective and targeted delivery. The macrophages have the ability to cross the physiological barriers and escape immune recognition and intracellular trafficking and have the ability to release potent pro-inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin 6 (IL-6), and therefore macrophage membrane coated nanoparticles have been exploited in the development of various therapeutics. In the present review, we have summarized the role of macrophage membranes as a coating material for the delivery of drugs to the targeted tissue in order to cure different diseases such as cancers, microbial infections, atherosclerosis and various inflammations. The review has critically analysed the latest approaches, and how to develop the macrophage membrane coated nanocarriers and their role in the improvement of the therapeutic index.

Nanodrug-loaded Bifidobacterium bifidum conjugated with anti-death receptor antibody for tumor-targeted photodynamic and sonodynamic synergistic therapy.

Using bacteria for tumor-targeted therapy has attracted much attention in recent years. However, how to improve the targeted delivery and cancer therapy efficacy is an important but challenging scientific issue. Herein, a drug delivery system using a probiotic as a carrier was developed for tumor-targeted photodynamic and sonodynamic synergistic therapy. In this system, chlorin e6 (Ce6) nanoparticles (NPs) were prepared and incorporated into B. bifidum, followed by the conjugation of anti-death receptor 5 antibody (anti-DR5 Ab). Interestingly, B. bifidum under 671 nm laser or ultrasound (US) irradiation could generate reactive oxygen species (ROS), and Ce6-B. bifidum-anti-DR5 Ab obtained could target hypoxic regions in tumor with high efficiency after intravenous injection. The ROS level generated by Ce6-B. bifidum-anti-DR5 Ab under both laser and US irradiation was much higher than the combined ROS generated separately using a laser and US for the same probiotics. The cytotoxicity and laryngeal tumor growth-inhibiting efficiency of Ce6-B. bifidum-anti-DR5 Ab under both laser and US irradiation were significant higher than the values obtained using laser or US irradiation alone, which demonstrated the synergistic effect on tumor growth. B. bifidum could be eliminated from the body without exerting harmful effects on mouse health. This strategy is a platform that can be extended to treat other solid tumors. STATEMENT OF SIGNIFICANCE: Using bacteria as drug delivery carriers will show unique advantages. However, how to improve the targeted delivery efficiency and tumor inhibiting capacity is a challenging scientific issue. Herein, a delivery system using a probiotic as carrier was developed for tumor-targeted therapy. In this delivery system, chlorin e6 nanoparticles were prepared and then incorporated into living Bifidobacterium bifidum (B.bifidum), followed by the conjugation of anti-death receptor 5 antibody. This delivery system could efficiently target to mouse tumors, accumulate the hypoxic areas and inhibit the tumor growth through the photodynamic and sonodynamic synergistic effect. Our results will provide a platform for B.bifidum-mediated tumor targeted therapy.

Transfer of quantum dots from pregnant mice to pups across the placental barrier.

Fluorescent quantum dots (QDs) have great potential for in vivo biomedical imaging and diagnostic applications. However, these nanoparticles are composed of heavy metals and are very small in diameter, and their possible toxicity must therefore be considered. As yet, no studies have reported the transfer of QDs between mother and fetus. The transfer of CdTe/CdS QDs of different sizes and dosages, and with different outer capping materials, from pregnant mice to fetuses is investigated. It is shown that QDs may be transferred from female mice to their fetuses across the placental barrier. Smaller QDs are more easily transferred than larger QDs and the number of QDs transferred increases with increasing dosage. Capping with an inorganic silica shell or organic polyethylene glycol reduces QD transfer but does not eliminate it. These results suggest that the clinical utility of QDs could be limited in pregnant women.

Fluorescent hollow mesoporous carbon spheres for drug loading and tumor treatment through 980-nm laser and microwave co-irradiation.

Hollow mesoporous particles for drug delivery and cancer therapy have attracted significant attention over recent decades. Here, we develop a simple and highly efficient strategy for preparing fluorescent hollow mesoporous carbon spheres (HMCSs). Compared with typical carbon materials such as fullerene C60, carbon nanotubes, reduced graphene oxide, and carbon nanohorns; HMCSs showed fewer effects on cell cycle distribution and lower toxicity to cells. Ten different drugs were incorporated into the HMCSs, and the maximum loading efficiency reached 42.79 ± 2.7%. Importantly, microwaves were found to improve the photothermal effect generated by HMCSs when combined with 980-nm laser irradiation. The cell killing and tumor growth inhibition efficiencies of HMCSs and drug-loaded HMCSs under co-irradiation with laser and microwaves were significantly improved compared with those under laser irradiation alone. After local administration HMCSs were only distributed in tissue at the injection site. HMCSs showed almost no toxicity in mice after local injection and could be completely removed from the injection site.

Biocompatible chitosan-carbon nanocage hybrids for sustained drug release and highly efficient laser and microwave co-irradiation induced cancer therapy.

Graphitic carbon nanocages (GCNCs) are unique graphene-based nanomaterials that can be used for cancer photothermal therapy (PTT). However, low toxicity GCNC-based organic/inorganic hybrid biomaterials for microwave irradiation assisted PTT have not yet been reported. In the present study, chitosan (CS)-coated GCNCs (CS-GCNCs) loaded with 5-fluorouracil (5Fu) were used for cancer therapy when activated by 808-nm laser and microwave co-irradiation. The cytotoxicity of GCNCs was significantly reduced after coating with CS. For example, fewer cell-cycle defects were caused by CS-GCNCs in comparison with non-coated GCNCs. The release rate of 5Fu from CS-GCNCs was significantly slower than that of 5Fu from GCNCs, providing sustained release. The release rate could be accelerated by 808-nm laser and microwave co-irradiation. The 5Fu in CS-GCNCs retained high cancer cell killing bioactivity by enhancing the caspase-3 expression level. The cancer cell killing and tumor inhibition efficiencies of the 5Fu-loaded nanomaterials increased significantly under 808-nm laser and microwave co-irradiation. The strong cell killing and tumor ablation activities were due to the synergy of the enhanced GCNC thermal effect caused by laser and microwave co-irradiation and the chemotherapy of 5Fu. Our research opens a door for the development of drug-loaded GCNC-based nano-biomaterials for chemo-photothermal synergistic therapy with the assistance of microwave irradiation. STATEMENT OF SIGNIFICANCE: Graphitic carbon nanocages (GCNCs) are graphene-based nanomaterials that can be used for both drug loading and cancer photothermal therapy (PTT). Herein, we showed that chitosan (CS)-GCNCs hybrid biomaterials had very low cytotoxicity, high ability for loading drug, and exhibited sustained drug release. In particular, although low-power microwaves alone are unable to trigger cancer cell damage by GCNCs, the cell killing and mouse tumor inhibition efficiencies were significantly improved by near-infrared (NIR) laser and microwave co-irradiation compared with laser-triggered PTT alone. This combined use of laser and microwave co-irradiation promises essential therapeutic modality and opens a new avenue for PTT.

Polymeric Drug Delivery System with Actively Targeted Cell Penetration and Nuclear Targeting for Cancer Therapy.

Targeted tumor cell killing using polymeric micelles with active targeting strategies has been demonstrated to be effectively therapeutic for liver cancers. To implement this strategy, enhancing the cellular uptake of the drug delivery system with targeted anticancer drugs, such as doxorubicin toward nuclear targeting, is of vital importance for increasing drug efficiency and reducing the systemic side effects of encapsulated drugs. In this study, a multifunctional polymeric drug delivery system was designed with actively targeted cell penetration and nuclear targeting for efficient cancer therapy. The nanocarriers were self-assembled from poly(ethylene glycol)-block-poly(ε-caprolactone), decorated with folic acid (FA-PECL) for active targeting via amide reaction for selective delivery of drugs to tumors. A cell penetration peptide (CPP) was decorated with doxorubicin (DOX), and the conjugate (CPP-DOX) was encapsulated in the carrier system for efficient cell penetration and nuclear targeting of drugs. An in vitro study showed an enhanced in vitro cytotoxicity and showed that the tumor volume decreased more than 5 times compared with the nontargeted system, by utilizing the drug-loaded system (FA-PECL/CPP-DOX) with active tumor cell targeting and subsequent nuclear targeting. The FA-PECL/CPP-DOX drug-loading system was well-targeted and enriched on tumor sites, resulting in significant suppression of the liver tumor growth.

Systematic evaluation of graphene quantum dot toxicity to male mouse sexual behaviors, reproductive and offspring health.

Graphene quantum dots (GQDs) have attracted considerable attention across multiple fields, particularly biomedical research. However, the effects of GQDs on reproductive and offspring health in mammals are unclear. Here, we show that GQD exposure via oral gavage or intravenous injection had no effect on the frequency and timing of sexual behaviors in male mice. GQD-exposed male mice retained healthy structural and functional reproductive physiology (e.g., production and storage of healthy sperm, maintenance of normal total protein and key enzyme concentrations in testes) of the testes and epididymides, as well as normal testosterone levels. Female mice housed with GQD-exposed males produced first, second, and subsequent litters of healthy pups without obvious differences to females housed with buffer-treated males. These findings may be explained by the low toxicity of GQDs in germ cells and their rapid excretion after exposure in mice, mainly via the urine and/or feces; GQDs, even at high doses, are virtually undetectable in male mouse testis, epididymis, and brain. Our findings reveal the short- and long-term effects of GQD exposure on male mouse sexual behaviors, reproductive activity, and offspring development and indicate the potential mechanisms of action of GQDs to provide further insight into their bio-safety.

[Application of quantum dots fluorescent nanoprobes in following the migration of inflammatory cells from local tissue to draining lymph node].

Quantum dots (QDs) have favorable physical and photochemical properties. In this work, we used QDs fluorescent nanoprobes to follow the migration of inflammatory cells from local tissue to draining lymph node in inflammation resolution. Electric pulse stimulation was used to establish inflammation model in mouse tibialis anterior. QDs injected to inflammatory tissue were found to aggregate and endocytosed by inflammatory cells. While in the draining lymph node, QDs mainly distributed in the T cell area. TEM and confocal observation showed that most of QDs in the draining lymph node were located in the endosomes of monocytes/macrophages. Our work shows that QDs can be used as fluorescent probes to follow migration of cells especially phagocytic cells. Thus QDs may be explored in application in immunology research.

Drug-Loaded Polymer-Coated Graphitic Carbon Nanocages for Highly Efficient in Vivo Near-Infrared Laser-Induced Synergistic Therapy through Enhancing Initial Temperature.

Graphitic carbon nanocages (GCNCs) have unique geometric structures and physical properties, which have been extensively investigated for various applications. However, no reports focusing on using GCNCs and polymer-coated GCNCs for solid tumor ablation induced by near-infrared laser irradiation under enhanced initial body temperature, or on the biosafety of GCNCs in vivo, have been published. Here, we developed chitosan (CS)-coated GCNCs and showed that both GCNCs and GCNCs/CS in mouse tumors can rapidly convert an 808 nm laser light energy into heat, which efficiently kill nasopharyngeal carcinoma cells and inhibit tumor growth. The tumors are further damaged by the phototoxicity of GCNCs/CS after loading with 5-Fluorouracil (5FU). Tumors are no longer detected after 6 days of 5FU-GCNCs/CS treatment under irradiation, which is due to the synergistic effect of the photothermal response of GCNCs and the chemotherapy of 5FU. None of the tumors reappeared during the following 12 days of no irradiation. Interestingly, increasing the initial body temperature of the mice significantly improved the photothermal effect of GCNCs in vivo and the synergistic effect of photothermal therapy and chemotherapy, thus accelerating the shrinking of tumors. To the best of our knowledge, this is the first study to improve the photothermal ablation of GCNCs and synergetic photothermal-chemotherapy of drug-loaded GCNCs through enhancing the initial body temperature. As the results show that GCNCs, GCNCs/CS, and 5FU-GCNCs/CS are safe in mice after intratumoral injection both with and without laser irradiation, our technique may have great potential for future clinical translation.

[Preparation and characterization of quantum dots-peptides bioconjugations and their specificity related to recognizing tumor cells].

Water-soluble CdTe quantum dots synthesized in aqueous solution have been conjugated with peptide LyP-1 using N-Succinimidyl 3-[2-pyridyldithio]-propionate (SPDP) as a cross-linking reagent. Capillary electrophoresis (CE), UV-Vis absorption and photoluminescent (PL) spectra suggested that the peptide had been successfully linked to the QDs. The QDs-peptides conjugates could specifically recognize the lung adenoma cancer cells (SPCA-1), but did not recognize promyelocytic leukemia cells (HL-60).

Synthesis and characterization of iron oxide/polymer composite nanoparticles with pendent functional groups.

We describe in this paper an approach to synthesize superparamagnetic iron oxide nanoparticles in the presence of polymerized lactic acid. The resulted particles consisted of clusters of iron oxide monocrystals, embedded inside the polymer chains. The composite particles synthesized in situ were highly dispersible in aqueous solution with good stability. X-ray diffraction and magnetometer data all confirmed the crystalline structure and super-paramagnetic property of the particles. They exhibited narrow size distribution with hydrodynamic diameters close to 80 nm. In addition, the particles were shown to have abundant surface carboxyl groups, which can be used to conjugate various biomolecules. Such a preparation would be especially useful for developing target specific MRI contrast agents or drug delivery vehicles.

A Multimodal System with Synergistic Effects of Magneto-Mechanical, Photothermal, Photodynamic and Chemo Therapies of Cancer in Graphene-Quantum Dot-Coated Hollow Magnetic Nanospheres.

In this study, a multimodal therapeutic system was shown to be much more lethal in cancer cell killing compared to a single means of nano therapy, be it photothermal or photodynamic. Hollow magnetic nanospheres (HMNSs) were designed and synthesized for the synergistic effects of both magneto-mechanical and photothermal cancer therapy. By these combined stimuli, the cancer cells were structurally and physically destroyed with the morphological characteristics distinctively different from those by other therapeutics. HMNSs were also coated with the silica shells and conjugated with carboxylated graphene quantum dots (GQDs) as a core-shell composite: HMNS/SiO2/GQDs. The composite was further loaded with an anticancer drug doxorubicin (DOX) and stabilized with liposomes. The multimodal system was able to kill cancer cells with four different therapeutic mechanisms in a synergetic and multilateral fashion, namely, the magnetic field-mediated mechanical stimulation, photothermal damage, photodynamic toxicity, and chemotherapy. The unique nanocomposites with combined mechanical, chemo, and physical effects will provide an alternative strategy for highly improved cancer therapy efficiency.

Melanin nanoparticles derived from a homology of medicine and food for sentinel lymph node mapping and photothermal in vivo cancer therapy.

The use of non-toxic or low toxicity materials exhibiting dual functionality for use in sentinel lymph node (SLN) mapping and cancer therapy has attracted considerable attention during the past two decades. Herein, we report that the natural black sesame melanin (BSM) extracted from black sesame seeds (Sesamum indicum L.) shows exciting potential for SLN mapping and cancer photothermal therapy. Aqueous solutions of BSM under neutral and alkaline conditions can assemble into sheet-like nanoparticles ranging from 20 to 200 nm in size. The BSM nanoparticles were encapsulated by liposomes to improve their water solubility and the encapsulated and bare BSM nanoparticles were both non-toxic to cells. Furthermore, the liposome-encapsulated BSM nanoparticles (liposome-BSM) did not exhibit any long-term toxicity in mice. The liposome-BSM nanoparticles were subsequently used to passively target healthy and tumor-bearing mice SLNs, which were identified by the black color of the nanoparticles. BSM also strongly absorbed light in the near-infrared (NIR) range, which was rapidly converted to heat energy. Human esophagus carcinoma cells (Eca-109) were killed efficiently by liposome-BSM nanocomposites upon NIR laser irradiation. Furthermore, mouse tumor tissues grown from Eca-109 cells were seriously damaged by the photothermal effects of the liposome-BSM nanocomposites, with significant tumor growth suppression compared with controls. Given that BSM is a safe and nutritious biomaterial that can be easily obtained from black sesame seed, the results presented herein represent an important development in the use of natural biomaterials for clinical SLN mapping and cancer therapy.

Long-term toxicity of reduced graphene oxide nanosheets: Effects on female mouse reproductive ability and offspring development.

Reduced graphene oxide (rGO) nanosheets have emerged as novel materials for cancer therapeutics. Their toxicity has attracted much attention since these nanomaterials may have great potential for clinical cancer treatment. Here we report the influence of rGO exposure on female mouse reproductive ability and offspring development. Mouse dams were injected with small or large rGO nanosheets at different doses and time points, pre- or post-fertilization. The sex hormone levels of adult female mice did not significantly change compared with the control group after intravenous injection with either small or large rGO, even at a high dose (25 mg/kg). Mouse dams could produce healthy offspring after treatment with rGO nanosheets before pregnancy and at an early gestational stage (∼6 days). Despite the successful delivery of offspring, malformed fetuses were found among rGO-injected dam litters. All mice had abortions when injected with low (6.25 mg/kg) or intermediate (12.5 mg/kg) doses at a late gestational stage (∼20 days); the majority of pregnant mice died when injected with the high dose of rGO at this stage of pregnancy. Interestingly, all surviving rGO-injected mouse mothers gave birth to another litter of healthy pups. The results presented in this work are important for a deeper understanding of the toxicity of rGO nanosheets on female reproductivity and their offspring development.