Evaluation of the Biodistribution of Magnetoliposomes in a Tumor and Organs of Mice by Electron Paramagnetic Resonance Spectroscopy

Electron paramagnetic resonance spectroscopy has been applied for the first time to study the bio-distribution of magnetoliposomes formed with magnetite nanoparticles (Fe₃O₄) in tumors and organs of Lewis carcinoma-bearing mice in the absence and presence of an external magnetic field. The animals of the experimental group were subjected to an external magnetic field (0.6 T) in the tumor area after intravenous injection of magnetoliposomes at a dose of 7.56 Fe/kg. Analysis of the electron-spin resonance spectra of mouse organs and tissue samples showed that exposure to a magnetic field resulted in a two-fold increase in Fe₃O₄ accumulation within the tumor (p < 0.05) compared to the control; this makes it possible to recommend the obtained magnetoliposomes for use as a magnetically controlled carriers for targeted delivery of antitumor agents. A high concentration of superparamagnetic magnetite nanoparticles was detected in the liver in the absence and presence of an external magnetic field. The differences in the accumulation of Fe₃O₄ in the lungs and liver in the presence of a magnetic field were statistically insignificant.

     

磁性纳米粒子作用于肝癌细胞的生物学效应的研究进展

磁性纳米粒子,是一类智能型的纳米材料,因其特有的性质,被广泛应用于生物医学领域,在肝癌的治疗方面也有大量的实验性研究和成果。研究和探索磁性纳米粒子治疗肝癌的新方法和途径,有着很大的现实意义。本文就磁性纳米粒子作用于肝癌细胞的生物学效应的研究现状和进展进行总结整理,从三个方面进行了综述:磁性纳米粒子直接作用于肝癌细胞,探索磁性纳米粒子的生物相容性、在肝癌细胞的分布方式以及磁性纳米粒子本身对肝癌细胞的生物学效应的影响;磁性纳米粒子协同外加磁场(稳恒磁场、极低频交变磁场和高频交变磁场)作用于肝癌细胞;磁性纳米粒子外加修饰(磁性白蛋白纳米颗粒、纳米磁流体、磁性脂质体等),作为药物载体作用于肝癌细胞。     

Controlled Payload Release by Magnetic Field Triggered Neural Stem Cell Destruction for Malignant Glioma Treatment

Stem cells have recently garnered attention as drug and particle carriers to sites of tumors, due to their natural ability to track to the site of interest. Specifically, neural stem cells (NSCs) have demonstrated to be a promising candidate for delivering therapeutics to malignant glioma, a primary brain tumor that is not curable by current treatments, and inevitably fatal. In this article, we demonstrate that NSCs are able to internalize 2 μm magnetic discs (SD), without affecting the health of the cells. The SD can then be remotely triggered in an applied 1 T rotating magnetic field to deliver a payload. Furthermore, we use this NSC-SD delivery system to deliver the SD themselves as a therapeutic agent to mechanically destroy glioma cells. NSCs were incubated with the SD overnight before treatment with a 1T rotating magnetic field to trigger the SD release. The potential timed release effects of the magnetic particles were tested with migration assays, confocal microscopy and immunohistochemistry for apoptosis. After the magnetic field triggered SD release, glioma cells were added and allowed to internalize the particles. Once internalized, another dose of the magnetic field treatment was administered to trigger mechanically induced apoptotic cell death of the glioma cells by the rotating SD. We are able to determine that NSC-SD and magnetic field treatment can achieve over 50% glioma cell death when loaded at 50 SD/cell, making this a promising therapeutic for the treatment of glioma.     

Efficiency, error and yield in light-directed maskless synthesis of DNA microarrays

Background

Rhodium (II) citrate (Rh₂(H₂cit)₄) has significant antitumor, cytotoxic, and cytostatic activity on Ehrlich ascite tumor. Although toxic to normal cells, its lower toxicity when compared to carboxylate analogues of rhodium (II) indicates Rh₂(H₂cit)₄ as a promising agent for chemotherapy. Nevertheless, few studies have been performed to explore this potential. Superparamagnetic particles of iron oxide (SPIOs) represent an attractive platform as carriers in drug delivery systems (DDS) because they can present greater specificity to tumor cells than normal cells. Thus, the association between Rh₂(H₂cit)₄ and SPIOs can represent a strategy to enhance the former's therapeutic action. In this work, we report the cytotoxicity of free rhodium (II) citrate (Rh₂(H₂cit)₄) and rhodium (II) citrate-loaded maghemite nanoparticles or magnetoliposomes, used as drug delivery systems, on both normal and carcinoma breast cell cultures.

Results

Treatment with free Rh₂(H₂cit)₄ induced cytotoxicity that was dependent on dose, time, and cell line. The IC₅₀ values showed that this effect was more intense on breast normal cells (MCF-10A) than on breast carcinoma cells (MCF-7 and 4T1). However, the treatment with 50 μM Rh₂(H₂cit)₄-loaded maghemite nanoparticles (Magh-Rh₂(H₂cit)₄) and Rh₂(H₂cit)₄-loaded magnetoliposomes (Lip-Magh-Rh₂(H₂cit)₄) induced a higher cytotoxicity on MCF-7 and 4T1 than on MCF-10A (p < 0.05). These treatments enhanced cytotoxicity up to 4.6 times. These cytotoxic effects, induced by free Rh₂(H₂cit)₄, were evidenced by morphological alterations such as nuclear fragmentation, membrane blebbing and phosphatidylserine exposure, reduction of actin filaments, mitochondrial condensation and an increase in number of vacuoles, suggesting that Rh₂(H₂cit)₄ induces cell death by apoptosis.

Conclusions

The treatment with rhodium (II) citrate-loaded maghemite nanoparticles and magnetoliposomes induced more specific cytotoxicity on breast carcinoma cells than on breast normal cells, which is the opposite of the results observed with free Rh₂(H₂cit)₄ treatment. Thus, magnetic nanoparticles represent an attractive platform as carriers in Rh₂(H₂cit)₄ delivery systems, since they can act preferentially in tumor cells. Therefore, these nanopaticulate systems may be explored as a potential tool for chemotherapy drug development.     

Toxicological effects of inorganic nanoparticles on human lung cancer A549 cells

Many researches have shown that anionic clays can be used as delivery carriers for drug or gene molecules due to their efficient cellular uptake in vitro, and enhanced permeability and retention effect in vivo. It is, therefore, highly required to establish a guideline on their potential toxicity for practical applications. The toxicity of anionic clay, layered metal hydroxide nanoparticle, was evaluated in two human lung epithelial cells, carcinoma A549 cells and normal L-132 cells, and compared with that in other human cancer cell lines such as cervical adenocarcinoma cells (HeLa) and osteosarcoma cells (HOS). The present nanoparticles showed little cytotoxic effects on the proliferation and viability of four cell lines tested at the concentrations used (<250 μg/ml) within 48 h. However, exposing cancer cells to high concentrations (250-500 μg/ml) for 72 h resulted in an inflammatory response with oxidative stress and membrane damage, which varied with the cell type (A549 > HOS > HeLa). On the other hand, the toxicity mechanism seems to be different from that of other inorganic nanoparticles frequently studied for biological and medicinal applications such as iron oxide, silica, and single walled carbon nanotubes. Iron oxide caused cell death associated with membrane damage, while single walled carbon nanotube induced oxidative stress followed by apoptosis. Silica triggered an inflammation response without causing considerable cell death for both cancer cells and normal cells, whereas layered metal hydroxide nanoparticle did not show any cytotoxic effects on normal L-132 cells in terms of inflammation response, oxidative stress, and membrane damage at the concentration of less than 250 μg/ml. It is , therefore, highly expected that the present nanoparticle can be used as a efficient vehicle for drug delivery and cancer cell targeting as well.     

Calcium uptake by leukemic and normal T-lymphocytes exposed to low frequency magnetic fields

Calcium-ion uptake by normal and leukemia lymphocytes increased during a 30-min exposure to a 13.6 Hz, sinusoidal magnetic field at 20 microT peak. The time-varying field was horizontal and parallel to a 16.5 microT component of the ambient static magnetic field. The uptake of 45Ca2+ increased 102% in a line of murine, cytotoxic T-lymphocytes (C57B1/6-derived CTLL-1), increased 126% in freshly-isolated spleen lymphocytes (C57B1/6 mice), and increased 75% in a line of lymphoma cells (C57B1/6-derived EL4). In contrast, there was no effect when the same field was applied for 30 min immediately before--as opposed to during--incorporation of calcium ions. When spleen lymphocytes were exposed during incubation with 45Ca2+ to a 60 Hz magnetic field at 20 microT peak, a small but statistically significant increase (37%) in uptake of the labeled ions occurred. These results indicate that weak, alternating magnetic fields might affect calcium-dependent functions of normal and leukemic lymphocytes.     

Germination of soybean seeds exposed to the static/alternating magnetic field and algal extract

In the present study, the effect of the static and alternating magnetic field applied individually and in combination with an algal extract on the germination of soybean seeds (Glycine max (L.) Merrill) and chlorophyll content was examined. The exposure time of seeds to the static magnetic field was 3, 6, and 12 min, whereas to the alternating magnetic field was 1, 2.5, and 5 min. The static magnetic field was obtained by means of a permanent magnets system while the alternating magnetic field by means of magnetic coils. Algal extract was produced from a freshwater macroalga—Cladophora glomerata using ultrasound homogenizer. In the germination tests, 10% extract was applied to the paper substrate before sowing. This is the first study that compares the germination of soybean seeds exposed to the static and alternating magnetic field. The best effect on the germination and chlorophyll content in seedlings had synergistic action of the static magnetic field on seeds for 3 min applied together with the extract and alternating magnetic field used for 2.5 min. It is not possible to clearly state which magnetic field better stimulated the germination of seeds, but the chlorophyll content in seedlings was much higher for alternating magnetic field.     

Magnetic dipole interaction of endogenous magnetic nanoparticles with magnetoliposomes for targeted drug delivery

Dynamics of magnetoliposomes binding to the tumor cells and the efficiency of their recognition for targeted drug delivery is largely determined by physical interaction. In this paper we assess the strength of magnetic dipole interaction that occurs between endogenous magnetic nanoparticles in tumor cells and exogenous magnetic nanoparticles as a component of magnetoliposomes, and compare it with the forces of specific binding of the antigen-antibody complex. To assess the strength of magnetic dipole interaction the model of chains of identical particles was used, and an order of magnitude, 10^?9 N, was obtained. Thus, the indicated force has an order of magnitude close to the forces of specific binding, and even more. The force of magnetic dipole interaction between a magnetically marked dosage form and tumor cells is virtually the additional specific binding force — “passive targeting” for targeted drug delivery in consequence of the fact that tumor cells tend to contain the number of biogenic nanoparticles of magnetite (Fe₃O₄) by an order of magnitude greater than normal.     

Magnetic field direction differentially impacts the growth of different cell types

Magnetic resonance imaging (MRI) machines have horizontal or upright static magnetic field (SMF) of 0.1–3 T (Tesla) at sites of patients and operators, but the biological effects of these SMFs still remain elusive. We examined 12 different cell lines, including 5 human solid tumor cell lines, 2 human leukemia cell lines and 4 human non-cancer cell lines, as well as the Chinese hamster ovary cell line. Permanent magnets were used to provide 0.2–1 T SMFs with different magnetic field directions. We found that an upward magnetic field of 0.2–1 T could effectively reduce the cell numbers of all human solid tumor cell lines we tested, but a downward magnetic field mostly had no statistically significant effect. However, the leukemia cells in suspension, which do not have shape-induced anisotropy, were inhibited by both upward and downward magnetic fields. In contrast, the cell numbers of most non-cancer cells were not affected by magnetic fields of all directions. Moreover, the upward magnetic field inhibited GIST-T1 tumor growth in nude mice by 19.3% (p < 0.05) while the downward magnetic field did not produce significant effect. In conclusion, although still lack of mechanistical insights, our results show that different magnetic field directions produce divergent effects on cancer cell numbers as well as tumor growth in mice. This not only verified the safety of SMF exposure related to current MRI machines but also revealed the possible antitumor potential of magnetic field with an upward direction.     

Pulsed Low-Frequency Magnetic Fields Induce Tumor Membrane Disruption and Altered Cell Viability

Tumor cells express a unique cell surface glycocalyx with upregulation of sulfated glycosaminoglycans and charged glycoproteins. Little is known about how electromagnetic fields interact with this layer, particularly with regard to harnessing unique properties for therapeutic benefit. We applied a pulsed 20-millitesla (mT) magnetic field with rate of rise (dB/dt) in the msec range to cultured tumor cells to assess whether this affects membrane integrity as measured using cytolytic assays. A 10-min exposure of A549 human lung cancer cells to sequential 50- and 385-Hz oscillating magnetic fields was sufficient to induce intracellular protease release, suggesting altered membrane integrity after the field exposure. Heparinase treatment, which digests anionic sulfated glycan polymers, before exposure rendered cells insensitive to this effect. We further examined a non-neoplastic human primary cell line (lung lymphatic endothelial cells) as a typical normal host cell from the lung cancer microenvironment and found no effect of field exposure on membrane integrity. The field exposure was also sufficient to alter proliferation of tumor cells in culture, but not that of normal lymphatic cells. Pulsed magnetic field exposure of human breast cancer cells that express a sialic-acid rich glycocalyx also induced protease release, and this was partially abrogated by sialidase pretreatment, which removes cell surface anionic sialic acid. Scanning electron microscopy showed that field exposure may induce unique membrane “rippling” along with nanoscale pores on A549 cells. These effects were caused by a short exposure to pulsed 20-mT magnetic fields, and future work may examine greater magnitude effects. The proof of concept herein points to a mechanistic basis for possible applications of pulsed magnetic fields in novel anticancer strategies.     

An ex vivo readout for evaluation of dendritic cell-induced autologous cytotoxic T lymphocyte responses against esophageal cancer

Esophageal cancer is a highly malignant disease that despite surgery and adjuvant therapies has an extremely poor outcome. Dendritic cell (DC) immunotherapy as a novel promising strategy could be an alternative for treating this malignancy. Effective DC-mediated immune responses can be achieved by raising cytotoxic T lymphocyte (CTL) response against multiple antigens through loading DCs with total tumor RNA. However, the efficacy of this strategy first needs to be evaluated in a pre-clinical setting. The aim of the study was to set up an ex vivo autologous human readout assay for assessing the effects of DC-mediated cytotoxic responses, using total tumor RNA as an antigen load. Biopsy specimens of seven esophageal cancer patients were used to establish primary cultures of normal and cancer cells and to obtain autologous RNA for loading DCs. Mature DCs loaded with either normal or tumor RNA were obtained and subsequently used to raise various lymphocytes populations. Apoptosis levels of the autologous cultures were measured before and after incubating the cultures with the different lymphocytes populations. The mean apoptosis levels in the tumor cell cultures, induced by lymphocytes instructed by DCs loaded with tumor RNA, significantly increased with 15.6% ±2.9 SEM (range 3.4–24.5%, t-test, P < 0.05). Incubation of the normal cultures with the lymphocytes populations showed a mean non-significant increase in apoptosis of 0.4% ±3.4 SEM (range −13.9 to 9.8%, t-test, P = 0.7). Here, we introduce a practical, patient-specific autologous readout assay for pre-clinical testing of DC-mediated cytotoxic responses. Additionally, we demonstrated that the use of autologous tumor RNA as a strategy for raising cytotoxic responses against multiple tumor antigens could be effective for treating esophageal cancer. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The role of the mitochondria in mediating cytotoxicity of anti-cancer therapies

Optimal cytotoxic anticancer therapy, at the cellular level, requires effective and selective induction of cell death to achieve a net reduction of biomass of malignant tissues. Standard cytotoxic chemotherapeutics have been developed based on the observations that mitotically active cancer cells are more susceptible than quiescent normal cells to chromosomal, microtubular or metabolic poisons. More recent development of molecularly targeted drugs for cancer focuses on exploiting biological differentials between normal and transformed cells for selective eradication of cancers. The common thread of “standard” and “novel” cytotoxic drugs is their ability to activate the apoptosis-inducing machinery mediated by mitochondria, also known as the intrinsic death signaling cascade. The aim of this article is to provide an overview of the role of the mitochondria, an energy-generating organelle essential for life, in mediating death when properly activated by cytotoxic stresses.     

Aptameric GT oligomers need to be complexed to ethoxylated polyethylenimine as pre-paired duplexes to efficiently exert their cytotoxic activity in human lymphoblastic cancer cells

The aptameric oligonucleotides GT were found to exert a selective, specific and dose-dependent cell growth inhibition effect on a variety of human cancer cells by recognising specific nuclear proteins and among these in particular an isoform of the eukaryotic elongation factor 1A1 (EEF1A1). The potential development of these aptameric oligomers needs that they retain serum and intracellular stabilities. Polycations are safe non-viral carriers of the nucleic acids. We demonstrated that a weakly basic polycation, the ethoxylated polyethylenimine (EPEI), can efficiently deliver cytotoxic GT oligomers when they were complexed as partial pre-paired duplex. In this way, nuclease-resistance of the oligomer was markedly improved and the administration of the duplex complexed with EPEI to lymphoblastic cancer cells caused a specific cytotoxic effect at concentrations lower than that of naked GT. However, the cytotoxic activity of the oligomer-EPEI complex resulted strictly related to the GC content and Tm of the duplex region. The single-stranded GT and the duplex with high GC content and Tm, although complexed with EPEI failed to exert cytotoxicity. Overall results indicated that aptameric oligomers complexed with polycations can be efficiently delivered into the cells and display the desired biological effect designing a balanced partial duplex whose stability can allow oligomer release from the polycation under the physiological cellular conditions.     

Magnetic fields with frequency of 217 Hz can reduce cell apoptosis caused by electrochemotherapy

Nowadays, due to the wide use of mobile phones, extensive studies have been carried out on the effects of magnetic field (MF) on public health. In this paper, we study the effect of 217 Hz MF similar to that generated by GSM900 mobile phones on cancer and healthy cells treated with electric pulse and cytotoxic drug. The experiments conducted include exposure to (a) electric pulses alone (4000 square-wave electric pulses with low amplitude of 70 V/cm and frequency of 5 kHz), (b) electric pulses following MF exposure, (c) electrochemotherapy (electric pulses and cytotoxic drug) alone and (d) MF exposure with subsequent electrochemotherapy. The results indicate that the percentage of apoptosis decreases significantly (p < 0.05) in treatment groups using electrochemotherapy after MF exposure compared to that in treatment groups using electrochemotherapy alone. We observed that 217 Hz MF similar to that generated by GSM900 mobile phones can incur resistance of the cells in response to electric pulses. Our findings implied the existence of amplitude window effect in alternations induced by extremely low-frequency MF.     

Activation of tumor-specific T lymphocytes after laser-induced thermotherapy in patients with colorectal liver metastases

Purpose  To asses if laser-induced thermotherapy (LITT) induces a specific cytotoxic T cell response in patients treated with LITT for colorectal cancer liver metastases. Methods  Eleven patients with liver metastases of colorectal cancer underwent LITT. Blood was sampled before and after LITT. Peripheral T cell activation was assessed by an interferon gamma (IFNg) secretion assay and flow cytometry. Test antigens were autologous liver and tumor lysate obtained from each patient by biopsy. T cells were stained for CD3/CD4/CD8 and IFNg to detect activated T cells. The ratio of IFNg positive to IFNg negative T cells was determined as the stimulation index (SI). To assess cytolytic activity, T cells were co-incubated with human colorectal cancer cells (CaCo) and cytosolic adenylate kinase release was measured by a luciferase assay. Results  IFNg secretion assay: before LITT SI was 12.73 (±4.83) for CD3+, 4.36 (±3.32) for CD4+ and 3.64 (±1.77) for CD8+ T cells against autologous tumor tissue. Four weeks after LITT SI had increased to 92.09 (±12.04) for CD3+ (P < 0.001), 42.92 (±16.68) for CD4+ (P < 0.001) and 47.54 (±15.68) for CD8+ T cells (P < 0.001) against autologous tumor tissue. No increased SI was observed with normal liver tissue at any time point. Cytotoxicity assay: before LITT activity against the respective cancer cells was low, with RLU = 1,493 (±1,954.68), whereas after LITT cytolytic activity had increased to RLU = 7,260 [±3,929.76 (P < 0.001)]. Conclusion  Patients with liver metastases of colorectal cancer show a tumor-specific cytotoxic T cell stimulation and a significantly increased cytolytic activity of CD3+, CD4+ and CD8+ T cells after LITT against an allogenic tumor (CaCo cell line).     

Magnetic Nanoparticles for the Delivery of Dapagliflozin to Hypoxic Tumors: Physicochemical Characterization and Cell Studies

In solid tumors, hypoxia (lack of oxygen) is developed, which leads to the development of resistance of tumor cells to chemotherapy and radiotherapy through various mechanisms. Nevertheless, hypoxic cells are particularly vulnerable when glycolysis is inhibited. For this reason, in this study, the development of magnetically targetable nanocarriers of the sodium-glucose transporter protein (SGLT2) inhibitor dapagliflozin (DAPA) was developed for the selective delivery of DAPA in tumors. This nanomedicine in combination with radiotherapy or chemotherapy should be useful for effective treatment of hypoxic tumors. The magnetic nanoparticles consisted of a magnetic iron oxide core and a poly(methacrylic acid)-graft-poly(ethyleneglycol methacrylate) (PMAA-g-PEGMA) polymeric shell. The drug (dapagliflozin) molecules were conjugated on the surface of these nanoparticles via in vivo hydrolysable ester bonds. The nanoparticles had an average size of ~ 70 nm and exhibited a DAPA loading capacity 10.75% (w/w) for a theoretical loading 21.68% (w/w). The magnetic responsiveness of the nanoparticles was confirmed with magnetophoresis experiments. The dapagliflozin-loaded magnetic nanoparticles exhibited excellent colloidal stability in aqueous and biological media. Minimal (less than 15% in 24 h) drug release from the nanoparticles occurred in physiological pH 7.4; however, drug release was significantly accelerated in pH 5.5. Drug release was also accelerated (triggered) under the influence of an alternating magnetic field. The DAPA-loaded nanoparticles exhibited higher in vitro anticancer activity (cytotoxicity) against A549 human lung cancer cells than free DAPA. The application of an external magnetic field gradient increased the uptake of nanoparticles by cells, leading to increased cytotoxicity. The results justify further in vivo studies of the suitability of DAPA-loaded magnetic nanoparticles for the treatment of hypoxic tumors.     

Blockade of sensory neuron action potentials by a static magnetic field in the 10 mT range

To characterize the inhibitory effect of a static magnetic field, action potentials (AP) were elicited by intracellular application of 1 ms depolarizing current pulses of constant amplitude to the somata of adult mouse dorsal root ganglion neurons in monolayer dissociated cell culture. During the control period, <5% of stimuli failed to elicit AP. During exposure to an ?11 mT static magnetic field at the cell position produced by an array of four permanent center-charged neodymium magnets of alternating polarity (MAG-4A), 66% of stimuli failed to elicit AP. The number of failures was maximal after about 200-250 s in the field and returned gradually to baseline over 400–600 s. A direct or indirect effect on the conformation of AP generating sodium channels could account for these results because (I) failure was preceded often by reduction of maximal rate of rise, an indirect measure of sodium current; (2) recovery was significantly prolonged in more than one-half of neurons that were not stimulated during exposure to the MAG-4A field; and (3) resting membrane potential, input resistance, and chronaxie were unaffected by the field. The effect was diminished or prevented by moving the MAG-4A array along the X or Z axis away from the neuron under study and by increasing the distance between magnets in the XY plane. Reduction of AP firing during exposure to the ?0.1 mT field produced by a MAG-4A array of micromagnets was about the same as that produced by a MAG-4A array of the large magnets above. The ?28 mT field produced at cell position by two magnets of alternating polarity and the ?88 mT field produced by a single magnet had no significant effect on AP firing. These findings suggest that field strength alone cannot account for AP blockade. © 1995 Wiley-Liss, Inc.     

Drug releasing nanoplatforms activated by alternating magnetic fields

The use of an alternating magnetic field (AMF) to generate non-invasively and spatially a localized heating from a magnetic nano-mediator has become very popular these last years to develop magnetic hyperthermia (MH) as a promising therapeutic modality already used in the clinics. AMF has become highly attractive this last decade over others radiations, as AMF allows a deeper penetration in the body and a less harmful ionizing effect. In addition to pure MH which induces tumor cell death through local T elevation, this AMF-generated magneto-thermal effect can also be exploited as a relevant external stimulus to trigger a drug release from drug-loaded magnetic nanocarriers, temporally and spatially. This review article is focused especially on this concept of AMF induced drug release, possibly combined with MH. The design of such magnetically responsive drug delivery nanoplatforms requires two key and complementary components: a magnetic mediator which collects and turns the magnetic energy into local heat, and a thermoresponsive carrier ensuring thermo-induced drug release, as a consequence of magnetic stimulus. A wide panel of magnetic nanomaterials/chemistries and processes are currently developed to achieve such nanoplatforms. This review article presents a broad overview about the fundamental concepts of drug releasing nanoplatforms activated by AMF, their formulations, and their efficiency in vitro and in vivo. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader.     

TAT Peptide-Conjugated Magnetic PLA-PEG Nanocapsules for the Targeted Delivery of Paclitaxel: <Emphasis Type="Italic">In Vitro</Emphasis> and Cell Studies

Paclitaxel (PTX) and organophilic iron oxide nanocrystals of 7 nm average size were co-encapsulated in the oily core of poly(lactide)-poly(ethyleneglycol) (PLA-PEG) nanocapsules in order to develop magnetically responsive nanocarriers of PTX. The nanocapsules were prepared by a solvent displacement technique and exhibited satisfactory drug and iron oxide loading efficiency, high colloidal stability, and sustained drug release properties. Drug release also proved responsive to an alternating magnetic field. Magnetophoresis experiments showed that the magnetic responsiveness of the nanocapsules depended on their SPION content. The PTX-loaded nanocapsules exhibited comparable to free PTX cytotoxicity against the A549 lung cancer cell line at 24 h of incubation but higher cytotoxicity than free drug at 48 h of incubation. The conjugation of a cysteine-modified TAT peptide (HCys-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-NH₂) on the surface of the nanocapsules resulted to highly increased uptake of nanocapsules by cancer cells, as well as to profound improvement of their cytotoxicity against the cancer cells. The results obtained justify further investigation of the prospects of these multifunctional PLA-PEG nanocapsules as a targeted delivery system of paclitaxel.