Lipid-coated superparamagnetic nanoparticles for thermoresponsive cancer treatment.

Poor aqueous solubility, chemical instability, and indiscriminate cytotoxicity have limited clinical development of camptothecin (CPT) as potent anticancer therapeutic. This research aimed at fabricating thermoresponsive nanocomposites that enhance solubility and stability of CPT in aqueous milieu and enable stimulus-induced drug release using magnetic hyperthermia. 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and l-α-dipalmitoylphosphatidyl glycerol (DPPG) (1:1, mol/mol) were immobilized on the surface of superparamagnetic Fe3O4 nanoparticles (SPIONs) via high affinity avidin-biotin interactions. Heating behavior was assessed using the MFG-1000 magnetic field generator. Encapsulation efficiency and drug release were quantified by fluorescence spectroscopy. Anticancer efficacy of medicated nanoparticles was measured in vitro using Jurkat cells. The results revealed that drug incorporation did not significantly alter particle size, zeta potential, magnetization, and heating properties of lipid-coated SPIONs. Drug loading efficiency was 93.2 ±â€¯5.1%. Drug release from medicated nanoparticles was significantly faster at temperatures above the lipid transition temperature, reaching 37.8 ±â€¯2.6% of incorporated payload after 12 min under therapeutically relevant hyperthermia (i.e., 42 °C). Medicated SPIONs induced greater cytotoxicity than CPT in solution suggesting synergistic activity of magnetically-induced hyperthermia and drug-induced apoptosis. These results underline the opportunity for thermoresponsive phospholipid-coated SPIONs to enable clinical development of highly lipophilic and chemically unstable drugs such as CPT for stimulus-induced cancer treatment.

Biomarkerless targeting and photothermal cancer cell killing by surface-electrically-charged superparamagnetic Fe3O4 composite nanoparticles.

A major challenge in cancer therapy is localized targeting of cancer cells for maximum therapeutic effectiveness. However, due to cancer heterogeneities, the biomarkers are either not readily available or specific for effective targeting of cancer cells. The key, therefore, is to develop a new targeting strategy that does not rely on biomarkers. A general hallmark of cancer cells is the much increased level of glycolysis. The loss of highly mobile lactate from the cytoplasm inevitably removes labile inorganic cations to form lactate salts and acids as part of the lactate cycle, creating a net of negative surface charges. This net of negative charges on cancer cell surfaces biophysically distinguishes themselves from normal cells. In this study, cancer cells are targeted by using positively-charged, fluorescent, superparamagnetic Fe3O4-composite nanoparticles. The positively-charged Fe3O4 composite nanoparticles bind predominantly to cancer cells due to their negatively-charged surfaces. Upon electrical-charge-mediated Fe3O4 nanoparticle binding onto cancer cells, irradiation by using an 808 nm laser is subsequently applied to induce photothermal hyperthermia that kills the cancer cells directly. The negatively-charged composite nanoparticles are found, however, not to target and bind the cancer cells due to the electrostatic repulsive force between them. This unique strategy paves a new path for effective targeting and direct cancer cell killing without relying on any biomarkers and anticancer drugs.

In-vitro depth-dependent hyperthermia of human mammary gland adenocarcinoma.

Nanoparticle mediated photothermal ablation of cancerous tissue shows promising results and applicability as a highly efficacious treatment method. As a majority of the photothermal work has been conducted with minimal attenuation of the laser before reaching the nanoparticles within surface seeded tumors in-vivo or through buffered media in-vitro, it is important to understand the effects of greater laser attenuation on photothermal efficacy mediated by changes in the scattering and absorption of the laser. Photothermal efficacy using a near infrared (NIR) 785nm laser irradiating polystyrene (PS) stabilized magnetite (Fe3O4) nanoparticles (PS-Fe3O4) is examined on MDA-MB-231 human mammary gland adenocarcinoma in-vitro. Agarose gel columns of various heights were created to simulate soft tissue and subsequently used for NIR laser attenuation. Polystyrene was found to significantly improve magnetite nanoparticle stability in serum containing media and modified Hank's Balanced Salt Solution and was able to induce significant hyperthermic ablation at mass concentrations which also did not elicit significant innate toxicity. Furthermore it was found that the polystyrene coating significantly reduced innate toxicity over 48h compared to uncoated magnetite. Agar gel layers provided similar optical attenuation in the NIR region to skin and prostate.

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.

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.

Photo-fluorescent and magnetic properties of iron oxide nanoparticles for biomedical applications.

Iron oxide exhibits fascinating physical properties especially in the nanometer range, not only from the standpoint of basic science, but also for a variety of engineering, particularly biomedical applications. For instance, Fe3O4 behaves as superparamagnetic as the particle size is reduced to a few nanometers in the single-domain region depending on the type of the material. The superparamagnetism is an important property for biomedical applications such as magnetic hyperthermia therapy of cancer. In this review article, we report on some of the most recent experimental and theoretical studies on magnetic heating mechanisms under an alternating (AC) magnetic field. The heating mechanisms are interpreted based on Néel and Brownian relaxations, and hysteresis loss. We also report on the recently discovered photoluminescence of Fe3O4 and explain the emission mechanisms in terms of the electronic band structures. Both optical and magnetic properties are correlated to the materials parameters of particle size, distribution, and physical confinement. By adjusting these parameters, both optical and magnetic properties are optimized. An important motivation to study iron oxide is due to its high potential in biomedical applications. Iron oxide nanoparticles can be used for MRI/optical multimodal imaging as well as the therapeutic mediator in cancer treatment. Both magnetic hyperthermia and photothermal effect has been utilized to kill cancer cells and inhibit tumor growth. Once the iron oxide nanoparticles are up taken by the tumor with sufficient concentration, greater localization provides enhanced effects over disseminated delivery while simultaneously requiring less therapeutic mass to elicit an equal response. Multi-modality provides highly beneficial co-localization. For magnetite (Fe3O4) nanoparticles the co-localization of diagnostics and therapeutics is achieved through magnetic based imaging and local hyperthermia generation through magnetic field or photon application. Here, Fe3O4 nanoparticles are shown to provide excellent conjugation bases for entrapment of therapeutic molecules, fluorescent agents, and targeting ligands; enhancement of solid tumor treatment is achieved through co-application of local hyperthermia with chemotherapeutic agents.

Photothermal effects and toxicity of Fe3O4 nanoparticles via near infrared laser irradiation for cancer therapy.

The photothermal effect of magnetite (Fe3O4) nanoparticles was characterized by photonic absorption in the near-infrared (NIR) region. Upon laser irradiation at 785 nm, the Fe3O4 nanoparticles generate localized hyperthermia in tumorous lesions, which is an effective strategy for cancer therapy; however, uncoated magnetite possesses an innate toxicity which can lead to drawbacks in the clinical setting. To reduce innate toxicity, a poly(acrylic acid) (PAA) coating on the nanoparticles was investigated in order to determine the alterations to stability and the degree of toxicity in an attempt to create a higher utility vector. It was found that the PAA coating significantly reduced the innate toxicity of the uncoated magnetite. Furthermore, the efficacy of PAA-coated magnetite nanoparticles (PAA-Fe3O4) was investigated for treating MDA-MB-231 (human mammary gland adenocarcinoma) cultures in viable concentration ranges (0.1-0.5mg/ml). An appropriate PAA-Fe3O4 concentration range was then established for inducing significant cell death by hyperthermic ablation, but not through innate toxicity.

Enhanced synergism of thermo-chemotherapy by combining highly efficient magnetic hyperthermia with magnetothermally-facilitated drug release.

A magnetothermally-responsive nanocarrier was developed for efficient thermo-chemotherapy by combining efficient magnetic hyperthermia (MH) and magnetothermally-facilitated drug release. The effective magnetothermal-response contributed to high enhancement of tumor cell killing by an operating mechanism involving MH-facilitated cellular uptake and Heat Shock Protein over-expression.

Enhanced magnetic fluid hyperthermia by micellar magnetic nanoclusters composed of Mn(x)Zn(1-x)Fe(2)O(4) nanoparticles for induced tumor cell apoptosis.

Monodispersed MnxZn1-xFe2O4 magnetic nanoparticles of 8 nm are synthesized and encapsulated in amphiphilic block copolymer for development of the hydrophilic magnetic nanoclusters (MNCs). These MNCs exhibit superparamagnetic characteristics, high specific absorption rate (SAR), large saturation magnetization (Ms), excellent stability, and good biocompatibility. MnFe2O4 and Mn0.6Zn0.4Fe2O4 are selected as optimum compositions for the MNCs (MnFe2O4/MNC and Mn0.6Zn0.4Fe2O4/MNC) and employed for magnetic fluid hyperthermia (MFH) in vitro. To ensure biosafety of MFH, the parameters of alternating magnetic field (AMF) and exposure time are optimized with low frequency, f, and strength of applied magnetic field, Happlied. Under optimized conditions, MFH of MnFe2O4/MNC and Mn0.6Zn0.4Fe2O4/MNC result in cancer cell death rate up to 90% within 15 min. The pathway of cancer cell death is identified as apoptosis, which occurs in mild hyperthermia near 43 °C. Both MnFe2O4/MNC and Mn0.6Zn0.4Fe2O4/MNC show similar efficiencies on drug-sensitive and drug-resistant cancer cells. On the basis of these findings, those MnxZn1-xFe2O4 nanoclusters can serve as a promising candidate for effective targeting, diagnosis, and therapy of cancers. The multimodal cancer treatment is also possible as amphiphilic block copolymer can encapsulate, in a similar fashion, different nanoparticles, hydrophobic drugs, and other functional molecules.

Pluronic-encapsulated natural chlorophyll nanocomposites for in vivo cancer imaging and photothermal/photodynamic therapies.

A great challenge in developing nanotechnologies for cancer diagnosis and therapy has been the combined functionalities required for complicated clinical procedures. Among all requirements, toxicity has been the major hurdle that has prevented most of the nano-carriers from clinical use. Here, we extracted chlorophyll (Chl) from vegetable and encapsulated it into polymer (pluronic F68, Plu) micelles for cancer imaging and therapy. The results showed that the Chl-containing nanocomposites were capable of mouse tumor targeting, and the nanocomposite fluorescence within the tumor sites remained at high intensity more than two days after tail-vein injection. It is interesting that oral administration with the nanocomposites was also successful for tumor target imaging. Furthermore, the dietary Chl was found to be able to efficiently convert near-infrared laser irradiation to heat. The growths of melanoma cells and mouse tumors were effectively inhibited after being treated with the nanocomposites and irradiation. The suppression of the tumors was achieved by laser-triggered photothermal and photodynamic synergistic effects of Chl. As a natural substance from vegetable, Chl is non-toxic, making it an ideal nano-carrier for cancer diagnosis and treatment. Based on the results of this research, the Plu-Chl nanocomposites have shown promise for future clinical applications.

Near-infrared laser light mediated cancer therapy by photothermal effect of Fe3O4 magnetic nanoparticles.

The photothermal effect of Fe3O4 magnetic nanoparticles is investigated for cancer therapy both in vitro and in vivo experiments. Heat is found to be rapidly generated by red and near-infrared (NIR) range laser irradiation of Fe3O4 nanoparticles with spherical, hexagonal and wire-like shapes. These Fe3O4 nanoparticles are coated with carboxyl-terminated poly (ethylene glycol)-phospholipid for enhanced dispersion in water. The surface-functionalized Fe3O4 nanoparticles can be taken up by esophageal cancer cells and do not obviously affect the cell structure and viability. Upon irradiation at 808 nm however, the esophageal cancer cell viability is effectively suppressed, and the cellular organelles are obviously damaged when incubated with the NIR laser activated Fe3O4 nanoparticles. Mouse esophageal tumor growth was found to be significantly inhibited by the photothermal effect of Fe3O4 nanoparticles, resulting in effective tumor reduction. A morphological examination revealed that after a photothermal therapy, the tumor tissue structure exhibited discontinuation, the cells were significantly shriveled and some cells have finally disintegrated.

The effect of structural characteristics on the in vitro bioactivity of hydroxyapatite.

In previous studies a film of hydroxylapatite (HA) was coated onto the inner pore surfaces of reticulated alumina for bone substitutes with the use of a so-called thermal deposition method. In this process, the HA films must be sintered at high temperatures for a strong adhesion to the alumina substrate. It has been found that high-temperature sintering inevitably changes the crystallinity of the coated HA, and in turn affects its bioactivity. Therefore, in this study, in vitro experiments were carried out to investigate the effects of structural changes on the in vitro bioactivity. The factors dominating in vitro bioactivity of HA, including surface area, degree of crystallinity, and temperature, were identified. The activation energy for volume diffusion was calculated for different in vitro solution temperatures. Also discussed is the underlying mechanism of growth and dissolution processes during the in vitro test.