Bio-Inspired Surface Modification of Magnetite Nanoparticles with Dopamine Conjugates.

Organically-coated nanomaterials are intensively studied and find numerous applications in a wide range of areas from optics to biomedicine. One of the recent trends in material science is the application of bio-mimetic polydopamine coatings that can be produced on a variety of substrates in a cost-efficient way under mild conditions. Such coatings not only modify the biocompatibility of the material but also add functional amino groups to the surface that can be further modified by classic conjugation techniques. Here we show an alternative strategy for substrates modification using dopamine conjugates instead of native dopamine. Compared to the classic scheme, the proposed strategy allows separation of the "organic" and "colloidal" stages, and simplified identification and purification steps. Modification with pre-modified dopamine made it possible to achieve high loading capacities with active components up to 10.5% wt. A series of organo-inorganic hybrids were synthesized and their bioactivity was analyzed.

Structural Rearrangements of Carbonic Anhydrase Entrapped in Sol-Gel Magnetite Determined by ATR-FTIR Spectroscopy.

Enzymatically active nanocomposites are a perspective class of bioactive materials that finds their application in numerous fields of science and technology ranging from biosensors and therapeutic agents to industrial catalysts. Key properties of such systems are their stability and activity under various conditions, the problems that are addressed in any research devoted to this class of materials. Understanding the principles that govern these properties is critical to the development of the field, especially when it comes to a new class of bioactive systems. Recently, a new class of enzymatically doped magnetite-based sol-gel systems emerged and paved the way for a variety of potent bioactive magnetic materials with improved thermal stability. Such systems already showed themself as perspective industrial and therapeutic agents, but are still under intense investigation and many aspects are still unclear. Here we made a first attempt to describe the interaction of biomolecules with magnetite-based sol-gel materials and to investigate facets of protein structure rearrangements occurring within the pores of magnetite sol-gel matrix using ATR Fourier-transform infrared spectroscopy.

Fluorescent Magnetic Nanoparticles for Bioimaging through Biomimetic Surface Modification.

Nanostructured materials and systems find various applications in biomedical fields. Hybrid organo-inorganic nanomaterials are intensively studied in a wide range of areas, from visualization to drug delivery or tissue engineering. One of the recent trends in material science is biomimetic approaches toward the synthesis or modification of functional nanosystems. Here, we describe an approach toward multifunctional nanomaterials through the biomimetic polymerization of dopamine derivatives. Magnetite nanoparticles were modified with a combination of dopamine conjugates to give multifunctional magneto-fluorescent nanocomposites in one synthetic step. The obtained material showed excellent biocompatibility at concentrations up to 200 µg/mL and an in vivo biodistribution profile typical for nanosized formulations. The synthesized systems were conjugated with antibodies against HER2 to improve their selectivity toward HER2-positive cancer cells. The produced material can be used for dual magneto-optical in vivo studies or targeted drug delivery. The applied synthetic strategy can be used for the creation of various multifunctional hybrid nanomaterials in mild conditions.

Systematic Review of Cancer Targeting by Nanoparticles Revealed a Global Association between Accumulation in Tumors and Spleen.

Active targeting of nanoparticles toward tumors is one of the most rapidly developing topics in nanomedicine. Typically, this strategy involves the addition of cancer-targeting biomolecules to nanoparticles, and studies on this topic have mainly focused on the localization of such formulations in tumors. Here, the analysis of the factors determining efficient nanoparticle targeting and therapy, various parameters such as types of targeting molecules, nanoparticle type, size, zeta potential, dose, and the circulation time are given. In addition, the important aspects such as how active targeting of nanoparticles alters biodistribution and how non-specific organ uptake influences tumor accumulation of the targeted nanoformulations are discussed. The analysis reveals that an increase in tumor accumulation of targeted nanoparticles is accompanied by a decrease in their uptake by the spleen. There is no association between targeting-induced changes of nanoparticle concentrations in tumors and other organs. The correlation between uptake in tumors and depletion in the spleen is significant for mice with intact immune systems in contrast to nude mice. Noticeably, modulation of splenic and tumor accumulation depends on the targeting molecules and nanoparticle type. The median survival increases with the targeting-induced nanoparticle accumulation in tumors; moreover, combinatorial targeting of nanoparticle drugs demonstrates higher treatment efficiencies. Results of the comprehensive analysis show optimal strategies to enhance the efficiency of actively targeted nanoparticle-based medicines.

Magnetically Controlled Carbonate Nanocomposite with Ciprofloxacin for Biofilm Eradication.

Biofilms are the reason for a vast majority of chronic inflammation cases and most acute inflammation. The treatment of biofilms still is a complicated task due to the low efficiency of drug delivery and high resistivity of the involved bacteria to harmful factors. Here we describe a magnetically controlled nanocomposite with a stimuli-responsive release profile based on calcium carbonate and magnetite with an encapsulated antibiotic (ciprofloxacin) that can be used to solve this problem. The material magnetic properties allowed targeted delivery, accumulation, and penetration of the composite in the biofilm, as well as the rapid triggered release of the entrapped antibiotic. Under the influence of an RF magnetic field with a frequency of 210 kHz, the composite underwent a phase transition from vaterite into calcite and promoted the release of ciprofloxacin. The effectiveness of the composite was tested against formed biofilms of E. coli and S. aureus and showed a 71% reduction in E. coli biofilm biomass and an 85% reduction in S. aureus biofilms. The efficiency of the composite with entrapped ciprofloxacin was higher than for the free antibiotic in the same concentration, up to 72%. The developed composite is a promising material for the treatment of biofilm-associated inflammations.

Test-System for Bacteria Sensing Based on Peroxidase-Like Activity of Inkjet-Printed Magnetite Nanoparticles.

Rapid detection of bacterial contamination is an essential task in numerous medical and technical processes and one of the most rapidly developing areas of nano-based analytics. Here, we present a simple-to-use and special-equipment-free test-system for bacteria detection based on magnetite nanoparticle arrays. The system is based on peroxide oxidation of chromogenic substrate catalyzed by magnetite nanoparticles, and the process undergoes computer-aided visual analysis. The nanoparticles used had a pristine surface free of adsorbed molecules and demonstrated high catalytic activities up to 6585 U/mg. The catalytic process showed the Michaelis-Menten kinetic with Km valued 1.22 mmol/L and Vmax of 4.39 µmol/s. The nanoparticles synthesized were used for the creation of inkjet printing inks and the design of sensor arrays by soft lithography. The printed sensors require no special equipment for data reading and showed a linear response for the detection of model bacteria in the range of 104-108 colony-forming units (CFU) per milliliter with the detection limit of 3.2 × 103 CFU/mL.

Urokinase-Conjugated Magnetite Nanoparticles as a Promising Drug Delivery System for Targeted Thrombolysis: Synthesis and Preclinical Evaluation.

Mortality and disabilities as outcomes of cardiovascular diseases are primarily related to blood clotting. Optimization of thrombolytic drugs is aimed at the prevention of side effects (in particular, bleeding) associated with a disbalance between coagulation and anticoagulation caused by systemically administered agents. Minimally invasive and efficient approaches to deliver the thrombolytic agent to the site of clot formation are needed. Herein, we report a novel nanocomposite prepared by heparin-mediated cross-linking of urokinase with magnetite nanoparticles (MNPs@uPA). We showed that heparin within the composition evoked no inhibitory effects on urokinase activity. Importantly, the magneto-control further increased the thrombolytic efficacy of the composition. Using our nanocomposition, we demonstrated efficient lysis of experimental clots in vitro and in animal vessels followed by complete restoration of blood flow. No sustained toxicity or hemorrhagic complications were registered in rats and rabbits after single bolus i.v. injection of therapeutic doses of MNPs@uPA. We conclude that MNPs@uPA is a prototype of easy-to-prepare, inexpensive, biocompatible, and noninvasive thrombolytic nanomedicines potentially useful in the treatment of blood clotting.

Magnetite Nanocontainers: Toward Injectable Highly Magnetic Materials for Targeted Drug Delivery.

Nanocontainers based solely on magnetite NPs have been synthesized by indirect gelation of stable magnetite hydrosol at ambient temperature using the microemulsion-assisted sol-gel method. Containers synthesized have adjustable size and consist of ∼10 nm magnetite nanoparticles linked by Fe-O-Fe interparticle bonds. The material demonstrates high magnetization values up to 60 emu/g and low cytotoxicity against both HeLa and postnatal human fibroblast (up to 260 µg/mL). The systems developed are perspective as a drug depot, particularly for magnetically controlled thrombolysis.

α-Amylase@Ferria: Magnetic Nanocomposites with Enhanced Thermal Stability for Starch Hydrolysis.

The present study is devoted to the development of a new class recyclable magnetic catalytic nanocomposites for starch hydrolysis. α-Amylase was entrapped within a magnetite-derived xerogel matrix in a course of a room-temperature sol-gel transition, leading to enzyme immobilization within the pores of a rigid magnetic matrix. For hybrid organo-inorganic composites with enzyme mass fractions less than 10 wt %, no enzyme leaching was observed. At 80 °C, the amylase@ferria composite demonstrates catalytic activity on the level of 10 units/mg and the starch hydrolysis rate comparable to free enzyme, while at 90 °C, the activity of amylase@ferria is at least twice higher than that of free amylase as a result of higher thermal stability of the composite. Entrapped amylase showed excellent stability and lost only 9% of its activity after 21 days of storage in a buffer solution, while free enzyme was totally inactivated after 17 days. The material can be used as either a magnetically separable reusable catalyst or a catalytic ceramic coating with at least 10 cycles of use.

Thrombin@Fe3O4 nanoparticles for use as a hemostatic agent in internal bleeding.

Bleeding remains one of the main causes of premature mortality at present, with internal bleeding being the most dangerous case. In this paper, magnetic hemostatic nanoparticles are shown for the first time to assist in minimally invasive treatment of internal bleeding, implying the introduction directly into the circulatory system followed by localization in the bleeding zone due to the application of an external magnetic field. Nanoparticles were produced by entrapping human thrombin (THR) into a sol-gel derived magnetite matrix followed by grinding to sizes below 200 nm and subsequent colloidization. Prepared colloids show protrombotic activity and cause plasma coagulation in in vitro experiments. We also show here using a model blood vessel that the THR@ferria composite does not cause systematic thrombosis due to low activity, but being concentrated by an external magnetic field with simultaneous fibrinogen injection accelerates local hemostasis and stops the bleeding. For instance, a model vessel system with circulating blood at the puncture of the vessel wall and the application of a permanent magnetic field yielded a hemostasis time by a factor of 6.5 shorter than that observed for the control sample. Biocompatibility of composites was tested on HELF and HeLa cells and revealed no toxic effects.

Composites based on heparin and MIL-101(Fe): the drug releasing depot for anticoagulant therapy and advanced medical nanofabrication.

We describe the synthesis and properties of a new composite material based on heparin and MIL-101(Fe) metal-organic framework. The intrinsic instability of MIL-101(Fe) towards hydrolysis enables binding of heparin molecules to the framework structure as is evidenced by DFT calculations and adsorption experiments. The de novo formed heparin-MOF composites showed good biocompatibility in in vitro and demonstrated pronounced anticoagulant activity. The specific interaction between the bioactive molecule and the carrier is critical for the selective degradation of the complex in the body fluids and for the enhanced activity. Hep_MIL-101(Fe) composite could serve as a drug-releasing depot for nanofabrication and to introduce anticoagulant activity to medical devices and biocoatings. Addition of Hep_MIL-101(Fe) to a sol-gel derived thrombolytic matrix allowed the combination of anticoagulant and thrombolytic activities in a single hybrid nanomaterial that could be applied as a bioactive nanocoating for PTFE vein implants.

Enzymatic Nanocomposites with Radio Frequency Field-Modulated Activity.

The control over enzymatic activity by physical stimuli is of interest to many applications in medicine, biotechnology, synthetic biology, and nanobionics. Although the main focus has been on optically responsive systems, alternative strategies to modulate the enzymatic activity of hybrid systems are needed. Here we describe a radiofrequency (RF) field controlled catalytic activity of an enzymatic sol-gel composite. Specifically, the activity of bovine carbonic anhydrase entrapped in sol-gel-derived magnetite (enzyme@ferria) composite was accelerated by a factor of 460% compared to its initial value, by applying the RF field of 937 A/m, with fast response time. This acceleration is reversible and its magnitude controllable. An acceleration mechanism, based on RF-induced heating of the magnetite by the Néel relaxation effect, is proposed and proven. The entrapment within a sol-gel matrix solves the problem of enhancing activity by heating without denaturing the enzyme. RF-controlled enzymatic composites can be potentially applied as biological RF sensors or to control biochemical reactions within living organisms.

A pure magnetite hydrogel: synthesis, properties and possible applications.

A magnetite-only hydrogel was prepared for the first time by weak base mediated gelation of stable magnetite hydrosols at room temperature. The hydrogel consists of 10 nm magnetite nanoparticles linked by interparticle Fe-O-Fe bonds and has the appearance of a dark-brown viscous thixotropic material. The water content in the hydrogel could be up to 93.6% by mass while volume fraction reaches 99%. The material shows excellent biocompatibility and minor cytotoxic effects at concentrations up to 207 µg mL-1. The gel shows excellent sorption capacity for heavy metal adsorption such as chrome and lead ions, which is 225% more than the adsorption capacity of magnetite nanoparticles. Due to thixotropic nature, the gel demonstrates mechanical stimuli-responsive release behavior with up to 98% release triggered by ultrasound irradiation. The material shows superparamagnetic behavior with a coercivity of 65 emu g-1 at 6000 Oe. The magnetite gels prepared could be used for the production of magnetite aerogels, magnetic drug delivery systems with controlled release and highly efficient sorbents for hydrometallurgy.

The controllable destabilization route for synthesis of low cytotoxic magnetic nanospheres with photonic response.

We present a new approach for obtaining magnetic nanospheres with tunable size and high magnetization. The method is implemented via controllable destabilization of a stable magnetite hydrosol with glycerol, leading to the formation of aggregates followed by their stabilization with the citrate shell. This inexpensive, simple and easily scalable approach required no special equipment. The obtained samples were characterized by high stability and magnetization over 80 emu/g. Effects of synthetic conditions on physicochemical properties of nanospheres were monitored by hydrodynamic size, zeta potential, and polydispersity of magnetite aggregates. The size of the resulting aggregates varied between 650 nm and 40 nm, and the zeta potential from +30 mV to -43 mV by changing the ratio of the reagents. Under optimal conditions the clusters with a diameter of 80 nm were produced with a narrow size distribution ±3 nm. These characteristics allowed for optical response to the external magnetic field, thereby producing a magnetic photon liquid. Due to biocompatibility of the reagents used in the synthesis the nanospheres evoked a negligible cytotoxicity for human non-malignant and tumor cell lines. These results make new materials valuable in photonics and biomedicine.

Leach-proof magnetic thrombolytic nanoparticles and coatings of enhanced activity.

Despite the fact that magnetic thrombolytic composites is an emerging area, all known so far systems are based on the similar mechanism of action: thrombolytic enzyme releases from the magnetic carrier leaving non-active matrix, thus making the whole system active only for a limited period of time. Such systems often have very complex structure organization and composition, consisting of materials not approved for parenteral injection, making them poor candidates for real clinical trials and implementation. Here we report, for the first time, the production of thrombolytic magnetic composite material with non-releasing behavior and prolonged action. Obtained composite shows good thrombolytic activity, consists of fully biocompatible materials and could be applied as infinitely active thrombolytic coatings or magnetically-targetable thrombolytic agents.

A universal magnetic ferrofluid: Nanomagnetite stable hydrosol with no added dispersants and at neutral pH.

A facile method to produce highly stable magnetite magnetic fluid at neutral pH without any stabilizing agents, resulting in pure Fe3O4 nanoparticles dispersed in water is described. The hydrosol which consists of only two components - magnetite and water - behaves as a typical ferrofluid, that is, although it responds to a magnetic field, the magnetic particles cannot be phase-separated from the water by that field. No such pure magnetic fluid have been described before, making it a universal carrier which can be easily modified for any application in materials science and chemistry, and in particular for a range of applications where non-corrosivity, low viscosity, and mild conditions are needed, such as in most bioapplications and in nano electro-mechanical systems. Under optimal conditions the hydrosol is stable for at least three months.

Streptokinase@alumina nanoparticles as a promising thrombolytic colloid with prolonged action.

The present study is devoted to the development of a new class of thrombolytic systems - nanocolloids. A non-direct plasminogen activator, streptokinase, was entrapped in a sol-gel matrix based on boehmite nanoparticles used in medical practice as the most common vaccine adjuvant. It is shown that when the enzyme content in the composite is less than 10%, only minor release is observed, while thrombolytic properties are maintained at a relatively high level, demonstrating the prolonged effect. Based on the obtained composites, thrombolytic nanocolloids containing nanoparticles of less than 500 nm size and suitable for parenteral administration were produced. The thrombolytic properties were studied using the plasminogen activation tests, human plasma clots and a model thrombus made from a whole human blood. Based on the obtained results, the structure of the composites and the mechanism of their action are suggested.

Anomalous adsorption of biomolecules on a Zn-based metal-organic framework obtained via a facile room-temperature route.

Herein, we report a new method for the crystal growth of two Zn-based MOFs at room temperature (known MOF-5 and a new modification of [{Zn2(TBAPy)(H2O)2}·3.5DEF]n (1)) by employing slow diffusion conditions. Employing both Zn-based MOFs with different pore morphology made it possible to discover an anomalous adsorption of L-histidine in of up to 24.3 × 10(15) molecules cm(-2) at 25 °C. This is one of the first reports aimed not only at describing a new method for the targeted formation of crystalline MOFs and coordination polymers, but also at demonstrating the use of Zn-based MOFs as potential drug delivery materials, with highly effective adsorption of l-histidine given herein as an example.