Type 1 ribotoxin-curcin conjugated biogenic gold nanoparticles for a multimodal therapeutic approach towards brain cancer.

BACKGROUND: Gliomas have been termed recurrent cancers due to their highly aggressive nature. Their tendency to infiltrate and metastasize has posed significant roadblocks to in attaining fool proof treatment solutions. An initiative to curb such a scenario was successfully demonstrated in vitro, utilizing a multi-conceptual gold nanoparticle based photo-thermal and drug combination therapy. METHODS: Gold nanoparticles (Au NPs) were synthesized with a highly environmentally benign process. The Au NPs were PEGylated and conjugated with folate and transferrin antibody to achieve a dual targeted nano-formulation directed towards gliomas. Curcin, a type 1 ribosome inactivating protein, was attached to the Au NPs as the drug candidate, and its multifarious toxic aspects analyzed in vitro. NIR photo-thermal properties of the Au nano-conjugates were studied to selectively ablate the glioma cancer colonies. RESULTS: Highly cyto-compatible, 10-15nm Au NP conjugates were synthesized with pronounced specificity towards gliomas. Curcin was successfully conjugated to the Au NPs with pH responsive drug release. Prominent toxic aspects of curcin, such as ROS generation, mitochondrial and cytoskeletal destabilization were witnessed. Excellent photo-thermal ablation properties of gold nanoparticles were utilized to completely disrupt the cancer colonies with significant precision. CONCLUSION: The multifunctional nanoconjugate projects its competence in imparting complete arrest of the future proliferation or migration of the cancer mass. GENERAL SIGNIFICANCE: With multifunctionality the essence of nanomedicine in recent years, the present nanoconjugate highlights itself as a viable option for a multimodal treatment option for brain cancers and the like.

Quantum dot tailored to single wall carbon nanotubes: a multifunctional hybrid nanoconstruct for cellular imaging and targeted photothermal therapy.

Hybrid nanomaterial based on quantum dots and SWCNTs is used for cellular imaging and photothermal therapy. Furthermore, the ligand conjugated hybrid system (FaQd@CNT) enables selective targeting in cancer cells. The imaging capability of quantum dots and the therapeutic potential of SWCNT are available in a single system with cancer targeting property. Heat generated by the system is found to be high enough to destroy cancer cells.

Multifunctional carboxymethyl cellulose-based magnetic nanovector as a theragnostic system for folate receptor targeted chemotherapy, imaging, and hyperthermia against cancer.

A multifunctional biocompatible nanovector based on magnetic nanoparticle and carboxymethyl cellulose (CMC) was developed. The nanoparticles have been characterized using TEM, SEM, DLS, FT-IR spectra, VSM, and TGA studies. We found that the synthesized carboxymethyl cellulose magnetic nanoparticles (CMC MNPs) were spherical in shape with an average size of 150 nm having low aggregation and superparamagnetic properties. We found that the folate-tagged CMC MNPs were delivered to cancer cells by a folate-receptor-mediated endocytosis mechanism. 5-FU was encapsulated as a model drug for delivering cytotoxicity, and we could demonstrate the sustained release of 5-FU. It was also observed that the FITC-labeled CMC MNPs could effectively enter cells, and the fate of nanoparticles was tracked with Lysotracker. The CMC MNPs could induce significant cell death when an alternating magnetic field was applied. These results indicate that the multifunctional CMC MNPs possess a high drug loading efficiency and high biocompatibility and with low cell cytotoxicity and can be considered to be promising candidates for CMC-based targeted drug delivery, cellular imaging, and magnetic hyperthermia (MHT).

Synergistic targeting of cancer and associated angiogenesis using triple-targeted dual-drug silica nanoformulations for theragnostics.

The targeting and therapeutic efficacy of dye- and dual-drug-loaded silica nanoparticles, functionalized with triple targeting ligands specific towards cancer and neoangiogenesis simultaneously, are discussed. This synergized, high-precision, multitarget concept culminates in an elevated uptake of nanoparticles by cancer and angiogenic cells with amplified proficiency, thereby imparting superior therapeutic efficacy against breast cancer cells and completely disabling the migration and angiogenic sprouting ability of activated endothelial cells. The exceptional multimodal efficiency achieved by this single therapeutic nanoformulation holds promise for the synergistic targeting and treatment of the yet elusive cancer and its related angiogenesis in a single, lethal shot.

AS1411 aptamer tagged PLGA-lecithin-PEG nanoparticles for tumor cell targeting and drug delivery.

Liposomes and polymers are widely used drug carriers for controlled release since they offer many advantages like increased treatment effectiveness, reduced toxicity and are of biodegradable nature. In this work, anticancer drug-loaded PLGA-lecithin-PEG nanoparticles (NPs) were synthesized and were functionalized with AS1411 anti-nucleolin aptamers for site-specific targeting against tumor cells which over expresses nucleolin receptors. The particles were characterized by transmission electron microscope (TEM) and X-ray photoelectron spectroscopy (XPS). The drug-loading efficiency, encapsulation efficiency and in vitro drug release studies were conducted using UV spectroscopy. Cytotoxicity studies were carried out in two different cancer cell lines, MCF-7 and GI-1 cells and two different normal cells, L929 cells and HMEC cells. Confocal microscopy and flowcytometry confirmed the cellular uptake of particles and targeted drug delivery. The morphology analysis of the NPs proved that the particles were smooth and spherical in shape with a size ranging from 60 to 110 nm. Drug-loading studies indicated that under the same drug loading, the aptamer-targeted NPs show enhanced cancer killing effect compared to the corresponding non-targeted NPs. In addition, the PLGA-lecithin-PEG NPs exhibited high encapsulation efficiency and superior sustained drug release than the drug loaded in plain PLGA NPs. The results confirmed that AS1411 aptamer-PLGA-lecithin-PEG NPs are potential carrier candidates for differential targeted drug delivery.

FITC labeled silica nanoparticles as efficient cell tags: uptake and photostability study in endothelial cells.

The use of fluorescent nanomaterials has gained great importance in the field of medical imaging. Many traditional imaging technologies have been reported utilizing dyes in the past. These methods face drawbacks due to non-specific accumulation and photobleaching of dyes. We studied the uptake and internalization of two different sized (30 nm and 100 nm) FITC labeled silica nanoparticles in Human umbilical vein endothelial cell line. These nanomaterials show high biocompatability and are highly photostable inside live cells for increased period of time in comparison to the dye alone. To our knowledge, we report for the first time the use of 30 nm fluorescent silica nanoparticles as efficient endothelial tags along with the well studied 100 nm particles. We also have emphasized the good photostability of these materials in live cells.

PEG coated biocompatible cadmium chalcogenide quantum dots for targeted imaging of cancer cells.

Cancer stands as a leading cause of mortality worldwide and diagnostics of cancer still faces drawbacks. Optical imaging of cancer would allow early diagnosis, evaluation of disease progression and therapy efficiency. To that aim, we have developed highly biocompatible PEG functionalized cadmium chalcogenide based three differently luminescent quantum dots (QDs) (CdS, CdSe and CdTe). Folate targeting scheme was utilized for targeting cancer cell line, MCF-7. We demonstrate the biocompatibility, specificity and efficiency of our nanotool in detection of cancer cells sparing normal cell lines with retained fluorescence of functionalized QDs as parental counterpart. This is the first time report of utilizing three differently fluorescent QDs and we have detailed about the internalization of these materials and time dependent saturation of targeting schemes. We present here the success of utilizing our biocompatible imaging tool for early diagnosis of cancer.

Ordered complex structures formed by paramagnetic particles via self-assembly under an ac/dc combined magnetic field.

We apply ac and dc magnetic fields simultaneously in orthogonal directions to each other to a solution, in which paramagnetic microparticles are dispersed, and show that complex secondary structures composed of oscillating chain clusters, that is, long linear clusters interconnected by T-, L-, and criss-cross-junctions, are self-assembled. Disklike clusters are formed at some junctions and the number of disklike clusters increases as the frequency of the ac magnetic field increases. We finally show that the angle between long linear clusters can be altered by changing the ratio of the intensities of the ac and dc magnetic fields.

Uptake of FITC labeled silica nanoparticles and quantum dots by rice seedlings: effects on seed germination and their potential as biolabels for plants.

The use of fluorescent nanomaterials with good photostability and biocompatibility in live imaging of cells has gained increased attention. Even though several imaging techniques have been reported for mammalian cells, very limited literatures are available for nanomaterial based live imaging in plant system. We studied the uptake ability of two different nanomaterials, the highly photostable CdSe quantum dots and highly biocompatible FITC-labeled silica nanoparticles by rice seedlings which could provide greater opportunities for developing novel in vivo imaging techniques in plants. The effects of these nanomaterials on rice seed germination have also been studied for analyzing their phytotoxic effects on plants. We observed good germination of seeds in the presence of FITC-labeled silica nanoparticles whereas germination was arrested with quantum dots. The uptake of both the nanomaterials has been observed with rice seedlings, which calls for more research for recommending their safe use as biolabels in plants.

Activity of an enzyme immobilized on superparamagnetic particles in a rotational magnetic field.

We immobilize alpha-amylase extracted from Bacillus Iicheniformis on the surfaces of superparamagnetic particles and investigate the effect of a rotational magnetic field on the enzyme's activity. We find that the activity of the enzyme molecules immobilized on superparamagnetic particles increases in the rotational magnetic field and reaches maximum at a certain frequency. We clarify the effect of the cluster structures formed by the superparamagnetic particles on the activity. Enzyme reactions are enhanced even in a tiny volume of solution using the present method, which is very important for the development of efficient micro reactors and micro total analysis systems (mu-TAS).

Aptamer conjugated magnetic nanoparticles as nanosurgeons.

Magnetic nanoparticles have shown promise in the fields of targeted drug delivery, hyperthermia and magnetic resonance imaging (MRI) in cancer therapy. The ability of magnetic nanoparticles to undergo surface modification and the effect of external magnetic field in the dynamics of their movement make them an excellent nanoplatform for cancer destruction. Surgical removal of cancerous or unwanted cells selectively from the interior of an organ or tissue without any collateral damage is a serious problem due to the highly infiltrative nature of cancer. To address this problem in surgery, we have developed a nanosurgeon for the selective removal of target cells using aptamer conjugated magnetic nanoparticles controlled by an externally applied three-dimensional rotational magnetic field. With the help of the nanosurgeon, we were able to perform surgical actions on target cells in in vitro studies. LDH and intracellular calcium release assay confirmed the death of cancer cells due to the action of the nanosurgeon which in turn nullifies the possibility of proliferation by the removed cells. The nanosurgeon will be a useful tool in the medical field for selective surgery and cell manipulation studies. Additionally, this system could be upgraded for the selective removal of complex cancers from diverse tissues by incorporating various target specific ligands on magnetic nanoparticles.

Tumbling motion of magnetic particles on a magnetic substrate induced by a rotational magnetic field.

We analyze the dynamics of paramagnetic particles on a paramagnetic substrate under a rotational magnetic field. When the paramagnetic particles are subjected to a rotational magnetic field, the rotational plane of which is perpendicular to the substrate surface, the particles form chain clusters caused by the dipole-dipole interaction between the particles and these clusters display a tumbling motion under certain conditions. In this case, the angular momentum of the clusters is converted to a translational one through the force of friction acting between the particles and substrate and, as a result, the clusters move along the surface of the substrate. We analyze the conditions under which the tumbling motion occurs and the dependence of the translational velocity of a cluster on the control parameters by the Stokesian dynamics method. Based on the dynamics of magnetic particles, we propose a method of manipulating nano- and microparticles using a rotational magnetic field. We demonstrate the manipulation of magnetic and nonmagnetic particles, a carbon nanotube, and a biological cell.

Formation of Core-Shell Nanoparticles Composed of Magnetite and Samarium Oxide in Magnetospirillum magneticum Strain RSS-1.

Magnetotactic bacteria (MTB) synthesize magnetosomes composed of membrane-enveloped magnetite (Fe3O4) or greigite (Fe3S4) particles in the cells. Recently, several studies have shown some possibilities of controlling the biomineralization process and altering the magnetic properties of magnetosomes by adding some transition metals to the culture media under various environmental conditions. Here, we successfully grow Magnetospirillum magneticum strain RSS-1, which are isolated from a freshwater environment, and find that synthesis of magnetosomes are encouraged in RSS-1 in the presence of samarium and that each core magnetic crystal composed of magnetite is covered with a thin layer of samarium oxide (Sm2O3). The present results show some possibilities of magnetic recovery of transition metals and synthesis of some novel structures composed of magnetic particles and transition metals utilizing MTB.

Highly versatile SPION encapsulated PLGA nanoparticles as photothermal ablators of cancer cells and as multimodal imaging agents.

We have designed versatile polymeric nanoparticles with cancer cell specific targeting capabilities via aptamer conjugation after the successful encapsulation of curcumin and superparamagnetic iron oxide nanoparticles (SPIONs) inside a PLGA nanocapsule. These targeted nanocomposites were selectively taken up by tumor cells, under in vitro conditions, demonstrating the effectiveness of the aptamer targeting mechanism. Moreover, the nanocomposite potentially functioned as efficient multiprobes for optical, magnetic resonance imaging (MRI) and photoacoustic imaging contrast agents in the field of cancer diagnostics. The hyperthermic ability of these nanocomposites was mediated by SPIONs upon NIR-laser irradiation. In vitro cytotoxicity was shown by curcumin-loaded nanoparticles as well as the photothermal ablation of cancer cells mediated by the drug-encapsulated nanocomposite demonstrated the potential therapeutic effect of the nanocomposite. In short, we portray the aptamer-conjugated nanocomposite as a multimodal material capable of serving as a contrast agent for MR, photoacoustic and optical imaging. Furthermore, the nanocomposite functions as a targetable drug nanocarrier and a NIR-laser inducible hyperthermic material that is capable of ablating PANC-1 and MIA PaCa-2 cancer cell lines.

Magnetic carbon nanotubes: synthesis by electrostatic self-assembly approach and application in biomanipulations.

Magnetic multiwalled carbon nanotubes (MWNTs) were facilely prepared by the electrostatic self-assembly approach. Poly(2-diethylaminoethyl methacrylate) (PDEAEMA) was covalently grafted onto the surfaces of MWNTs by MWNT-initiated in situ atom transfer radical polymerization (ATRP) of 2-diethylaminoethyl methacrylate (DEAEMA). The PDEAEMA-grafted MWNTs were quaternized with methyl iodide (CH(3)I), resulting in cationic polyelectrolyte-grafted MWNTs (MWNT-PAmI). Magnetic iron oxide (Fe(3)O(4)) nanoparticles were loaded onto the MWNT surfaces by electrostatic self-assembling between MWNT-PAmI and Fe(3)O(4), affording magnetic nanotubes. The assembled capability of the nanoparticles can be adjusted to some extent by changing the feed ratio of Fe(3)O(4) to MWNT-PAmI. The obtained magnetic nanotubes were characterized with TEM, EDS, STEM, and element mapping analyses. TEM and EDS measurements confirmed the nanostructures and the components of the resulting nanoobjects. The magnetic nanotubes were assembled onto sheep red blood cells in a phosphate buffer solution, forming magnetic cells. The blood cells attached with or without magnetic nanotubes can be selectively manipulated in a magnetic field. These results promise a general and efficient strategy to magnetic nanotubes and the fascinating potential of such magnetic nanoobjects in applications of bionanoscience and technology.

Synthesis of magnetic alloy-filling carbon nanoparticles in super-critical benzene irradiated with an ultraviolet laser.

Magnetic nanoparticles are of great importance particularly in the field of biomedicine as well as nanotechnology and nano materials science and technology. Here, we synthesise magnetic alloy-filling carbon nanoparticles (MA@C NPs) via the following two-step procedure; (1) Irradiation of a laser beam of 266 nm wavelength into super-critical benzene, in which both ferrocene and cobaltocene are dissolved, at 290 °C; and (2) annealing of the particles at 600 and 800 °C. We find that the core particles are composed of cobalt (Co), iron (Fe) and oxygen (O) and covered with carbon layers. The structure of the core particles as-synthesised, and annealed at 600 and 800 °C, is, respectively, amorphous, CoFe2O4 and FeCo. We also investigate the viability of L929 cells in the presence of MA@C NPs and find that there is no serious advert effect of the MA@C NPs on the cell viability thanks to the carbon layers covering the core particles. The magnetic properties are well characterised. The saturation and remnant magnetisation and coercivity increase and as a result, the hyperthermic efficiency becomes higher with an increase in the annealing temperature. The further modification of the surface of the present particles with several functional molecules becomes easier due to the carbon layers, which makes the present particles more valuable. It is therefore supposed that the presently synthesised MA@C NPs may well be utilised for nanotechnology-based biomedical engineering; e.g., nano bioimaging, nano hyperthermia and nano surgery.

Dual mode of cancer cell destruction for pancreatic cancer therapy using Hsp90 inhibitor loaded polymeric nano magnetic formulation.

Heat Shock Protein 90 (Hsp90) has been extensively explored as a potential drug target for cancer therapies. 17- N-allylamino- 17-demethoxygeldanamycin (17AAG) was the first Hsp90 inhibitor to enter clinical trials for cancer therapy. However, native drug is being shown to have considerable anticancer efficacy against pancreatic cancer when used in combination therapy regime. Further, magnetic hyperthermia has shown to have promising effects against pancreatic cancer in combination with known cyto-toxic drugs under both target and non-targeted scenarios. Hence, in order to enhance the efficacy of 17AAG against pancreatic cancer, we developed poly (lactic-co-glycolic acid) (PLGA) coated, 17AAG and Fe3O4 loaded magnetic nanoparticle formulations by varying the relative concentration of polymer. We found that polymer concentration affects the magnetic strength and physicochemical properties of formulation. We were also able to see that our aqueous dispensable formulations were able to provide anti-pancreatic cancer activity for MIA PaCa-2 cell line in dose and time dependent manner in comparison to mice fibroblast cell lines (L929). Moreover, the in-vitro magnetic hyperthermia against MIA PaCa-2 provided proof principle that our 2-in-1 particles may work against cancer cell lines effectively.

Dynamics of disklike clusters formed in a magnetorheological fluid under a rotational magnetic field.

We investigate the cluster formations and dynamics in a magnetorheological fluid under a rotational magnetic field focusing on the case of a relatively high volume fraction. We find that isotropic disklike clusters, which rotate more slowly than the field rotation, are formed at low Mason numbers (the ratio of viscous to magnetic forces) and, what is more, we show short rod clusters, which rotate stably thanks to the low Mason numbers and circulate along the surface of the disklike clusters. The circulation velocity of the surface particles is much higher than the rotational surface velocity of the rigid disklike clusters.

Effect of Polyethylene Glycol on the Formation of Magnetic Nanoparticles Synthesized by Magnetospirillum magnetotacticum MS-1.

Magnetotactic bacteria (MTB) synthesize intracellular magnetic nanocrystals called magnetosomes, which are composed of either magnetite (Fe3O4) or greigite (Fe3S4) and covered with lipid membranes. The production of magnetosomes is achieved by the biomineralization process with strict control over the formation of magnetosome membrane vesicles, uptake and transport of iron ions, and synthesis of mature crystals. These magnetosomes have high potential for both biotechnological and nanotechnological applications, but it is still extremely difficult to grow MTB and produce a large amount of magnetosomes under the conventional cultural conditions. Here, we investigate as a first attempt the effect of polyethylene glycol (PEG) added to the culture medium on the increase in the yield of magnetosomes formed in Magnetospirillum magnetotacticum MS-1. We find that the yield of the formation of magnetosomes can be increased up to approximately 130 % by adding PEG200 to the culture medium. We also measure the magnetization of the magnetosomes and find that the magnetosomes possess soft ferromagnetic characteristics and the saturation mass magnetization is increased by 7 %.

FITC/suramin harboring silica nanoformulations for cellular and embryonic imaging/anti-angiogenic theranostics.

The in vitro and in vivo uptake, toxicological analysis and anti-angiogenic theranostic prospect of FITC loaded (FITC-Si) and suramin loaded (Sur-Si) silica nanoparticles are presented. FITC/suramin encapsulated silica nanoparticles (NPs) with an average size of <30 nm were synthesized. The uptake of FITC-Si by human umbilical vein endothelial cells (HuVECs) (in vitro) and by early stage medaka embryos (in vivo) was monitored by fluorescence microscopy. The nanoformulation was found to be biocompatible with both cells and embryos. The cytotoxicity analysis, tubulogenesis and migration assay confirmed the anti-angiogenic potential of Sur-Si NPs in HuVECs. The imaging of medaka embryos exposed to FITC-Si, their survival and hatching rate and biocompatibility post FITC-Si exposure were documented. The in vivo drug delivery mediated anti-angiogenic potential of Sur-Si NPs was assessed by survival and hatching rate analysis along with morphological indicators. At higher concentrations, Sur-Si proved lethal to embryos, whereas at lower concentrations it was rather an efficient anti-angiogenic formulation leading to malformed vasculogenesis and inhibited intersegmental vessel formation in an efficient dose dependent mode. The results indicate the potential application of such nanoformulation in future anti-angiogenic theranostics.