Human mesenchymal stem cell-derived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia.

Magnetic hyperthermia, or the heating of tissues using magnetic materials, is a promising approach for treating cancer. We found that human mesenchymal stem cells (MSCs) isolated from various tissues and MSCs expressing the yeast cytosine deaminase∷uracil phosphoribosyl transferase suicide fusion gene (yCD∷UPRT) can be labeled with Venofer, an iron oxide carbohydrate nanoparticle. Venofer labeling did not affect cell proliferation or the ability to home to tumors. All Venofer-labeled MSCs released exosomes that contained iron oxide. Furthermore, these exosomes were efficiently endocytosed by tumor cells. Exosomes from Venofer-labeled MSCs expressing the yCD∷UPRT gene in the presence of the prodrug 5-fluorocytosine inhibited tumor growth in a dose-dependent fashion. The treated tumor cells were also effectively ablated following induction of hyperthermia using an external alternating magnetic field. Cumulatively, we found that magnetic nanoparticles packaged into MSC exosomes are efficiently endocytosed by tumor cells, facilitating targeted tumor cell ablation via magnetically induced hyperthermia.

Conceptual design of integrated microfluidic system for magnetic cell separation, electroporation, and transfection.

For the purposes of a successful ex vivo gene therapy we have proposed and analyzed a new concept of an integrated microfluidic system for combined magnetic cell separation, electroporation, and magnetofection. For the analysis of magnetic and electric field distribution (given by Maxwell equations) as well as dynamics of magnetically labeled cell and transfection complex, we have used finite element method directly interfaced to the Matlab routine solving Newton dynamical equations of motion. Microfluidic chamber has been modeled as a channel with height and length 1 mm and 1 cm, respectively. Bottom electrode consisted of 100 parallel ferromagnetic straps and the upper electrode was plate of diamagnetic copper. From the dynamics of magnetic particle motion we have found that the characteristic time-scales for the motion of cells (mean capture time âˆ¼ 4 s) and gene complexes (mean capture time âˆ¼ 3 min), when permanent magnets are used, are in the range suitable for efficient cell separation and gene delivery. The largest electric field intensity (∼10 kV/m) was observed at the edges of the microelectrodes, in the close proximity of magnetically separated cells, which is optimal for subsequent cell electroporation.

In vitro analysis of cisplatin functionalized magnetic nanoparticles in combined cancer chemotherapy and electromagnetic hyperthermia.

A novel platform has been developed for combined cancer chemotherapy and hyperthermia based on iron oxide magnetic nanoparticles functionalized with cis-diamminedichloroplatinum(II) (cisplatin). The capabilities of this system for heating and controlled drug release were investigated, and the system was tested in vitro by the treatment of BP6 rat sarcoma cells, where we demonstrated a synergism between the effects of cisplatin-targetMAG nanoparticles and the application of electromagnetic field.

In vivo heating of magnetic nanoparticles in alternating magnetic field.

We have evaluated heating capabilities of new magnetic nanoparticles. In in vitro experiments they were exposed to an alternating magnetic field with frequency 3.5 MHz and induction 1.5 mT produced in three turn pancake coil. In in vivo experiments rats with injected magnetic nanoparticles were also exposed to an ac field. An optimal increase of temperature of the tumor to 44 degrees C was achieved after 10 minutes of exposure. Obtained results showed that magnetic nanoparticles may be easily heated in vitro as well as in vivo, and may be therefore useful for hyperthermic therapy of cancer.

Principles of magnetodynamic chemotherapy.

Basic principles of a novel method of cancer treatment are explained. Method is based on the thermal activation of an inactive prodrug encapsulated in magnetoliposomes via Neél and Brown effects of inductive heating of subdomain superparamagnetic particles to sufficiently high temperatures. This principle may be combined with targeted drug delivery (using constant magnetic field) and controlled release (using high-frequency magnetic field) of an activated drug entrapped in magnetoliposomes. Using this method drug may be applied very selectively in the particular site of organism and this procedure may be repeated several times using e.g. stealth magnetoliposomes which are circulating in a blood-stream for several days. Moreover the magnetoliposomes concentrated by external constant magnetic field in tumor vasculature may lead to embolic lesions and necrosis of a tumor body and further the heat produced for thermal activation of a drug enhances the effect of chemotherapy by local hyperthermic treatment of neoplastic cells.

Spatial distribution of ion channel activity in biological membranes: the role of noise.

A new approach is proposed to model a collective ion channel dynamics. We have assumed that ion channels create a two-component spatio-temporal interaction field. Every channel at its current spatial location in membrane contributes permanently to this field with its state (open or closed) and coupling strength to other channels. This field is described by a reaction-diffusion equation, the transition of ion channel from closed to open state (and vice versa) is described by a master equation, and migration of channels in membrane is described by a set of Langevin equations coupled by the interaction field. Within this model, we have investigated critical conditions for spatial distribution of ion channel activity.

AC-magnetic field controlled drug release from magnetoliposomes: design of a method for site-specific chemotherapy.

Large unilamellar magnetoliposomes (MLs) with encapsulated doxorubicin (DOX) (anticancer drug) were prepared by reverse-phase evaporation. They were exposed to an alternating magnetic field with a frequency of 3.5 MHz and an induction of 1.5 mT produced in three-turn pancake coil. The results showed that magnetoliposomes could be specifically heated to 42 degrees C (phase transition temperature of a used lipid) in a few minutes and during this, the encapsulated doxorubicin is massively released.

High-gradient magnetic capture of ferrofluids: implications for drug targeting and tumor embolization.

One of the perspective methods of cancer chemotherapy is magnetic targeting of drugs to tumors. This task is usually accomplished using small permanent magnets attached near the desired sites. In this study a new much more effective approach is proposed which is based on a strong magnetic gradient using a ferromagnetic wire placed in a strong magnetic field. Feasibility of this approach has been evaluated by the formation of ferrofluid seals and measurement of maximum pressure the formed seal can resists. Using this method it is possible to capture even superparamagnetic particles with nanosize dimensions, therefore the method may have an interesting applications in biomedical sciences.

Blood-specific whole-body electromagnetic hyperthermia.

On the basis of the physical properties of magnetic fluids a new technique of whole-body hyperthermia is proposed. Subdomain dextran stabilized magnetite particles injected into the blood-stream can be efficiently heated using an external high-frequency magnetic field, which allows rapid and controllable delivery of heat to the patient's blood, which may be useful for the treatment of cancer and AIDS.

Resonant absorption of ultrasound energy as a method of HIV destruction.

A new method for eradicating human immunodeficiency virus (HIV) and other enveloped viruses is proposed. The method is based on the highly symmetric structure (e.g. icosahedral) of many viruses, which leads to a well-defined resonant frequency of ultrasound in the GHz range and which may be specifically absorbed by these structures and may subsequently lead to their irreversible damage.

Selective treatment of neoplastic cells using ferritin-mediated electromagnetic hyperthermia.

A new method of cancer treatment is proposed, based on the unique magnetic properties of ferritin iron core which, in alternating magnetic field of frequency approximately 100 kHz, is easily heated to temperatures sufficiently high to destroy neoplastic cells containing an excess of this protein, without damaging the normal cells.

Gene transfer-mediated intracellular photodynamic therapy.

The main limitation of photodynamic therapy is a very short penetrance length of the light in tissues. To overcome this shortcoming, a new method is proposed, where first a gene encoding protein luciferase is delivered using, e.g. adenovirus vector to the neoplastic cells and, after its expression, the photosensitizer, which should be activated, together with luciferin are injected to the organism. After their accumulation in the cancer cells, the photosensitizer activation is accomplished via light produced by chemiluminiscent reaction of luciferase and luciferin.

Site-specific in vivo targeting of magnetoliposomes using externally applied magnetic field.

Human serum albumin labeled with technetium-99m was encapsulated together with magnetite particles into phosphatidylcholine/cholesterol liposomes. In order to investigate the stability of this complex and its ability to be used for magnetic drug targeting, the in-vivo distribution after intravenous administration in rats was estimated. For in-vivo targeting an SmCo permanent magnet with intensity approximately 0.35 T was attached near the right kidney. Difference between the relative radioactivity in the magnetically targeted right kidney (25.92+/-5.84%) and non-targeted left kidney (0.93+/-0.05%) is sufficiently high for relevant clinical applications.

Activation of hematoporphyrin in alternating magnetic field: possible implications for cancer treatment.

A new mechanism of cell damage by alternating magnetic field with hematoporphyrin is described. C6 glioblastoma cell suspensions were exposed to an alternating magnetic field with frequency 180 kHz up to 60 min in the presence of hematoporphyrin in H2O and in D2O. The results presented suggest that an alternating magnetic field is able to activate hematoporphyrin, and this method may be a basis for cancer treatment.

Collective dynamics of ion channels in biological membranes.

Master equation was used to describe the dynamics of coupled ion channels in biological membranes. From the stationary solution it was found that at a critical value of coupling strength the system undergoes phase transition of the second order, which can be of biological relevance.

Self-organized criticality and dynamic instability of microtubule growth.

We have shown that the distribution of lengths of site nucleated microtubules obey an algebraic power law relationship D(s) = A s(-tau), where D(s) is relative number of microtubules with length s, A and tau are constants. This relationship indicates the possibility of a self-organized criticality in the dynamic instability of microtubule growth.

Stochastic description of protein conformational motion.

Green function analysis of the Fokker-Planck equation was used to describe protein conformational motion for approximate variational derivation of typical rate constant of protein relaxation from excited nonequilibrium state to the equilibrium. This approach was illustrated on a simple one-dimensional conformational potential.

Synergetic mechanisms of chiral symmetry breaking in prebiotic evolution.

It was shown on the Frank autocatalytic reaction-diffusion scheme that strong environmental fluctuations, conditioned by external noise (e.g. sunlight fluctuation) and external macroscopic flows (e.g. ebb and flow), typical for conditions on prebiotic earth, may have been beneficial for chiral symmetry breaking and formation and stabilization of biomolecular homochirality.