J. Zach Hilt

Magnetic hydrogel nanocomposites for remote controlled pulsatile drug release

Hydrogel nanocomposites are novel macromolecular biomaterials that promise to impact various applications in medical and pharmaceutical fields. In this paper, magnetic nanocomposites of temperature responsive hydrogels were used to illustrate remote controlled (RC) drug delivery. A high frequency alternating magnetic field (AMF) was used to trigger the on-demand pulsatile drug release from the nanocomposites. Nanocomposites were synthesized by incorporation of superparamagnetic Fe(3)O(4) particles in negative temperature sensitive poly (N-isopropylacrylamide) hydrogels. Pulses of AMF were applied to the nanocomposites and the kinetics of collapse and recovery were characterized. Application of AMF resulted in uniform heating within the nanocomposites leading to accelerated collapse and squeezing out large amounts of imbibed drug (release at a faster rate). Remote controlled pulsatile drug release was characterized for different drugs as well as for different ON-OFF durations of the AMF.

Magnetic nanoparticles in biomedicine: synthesis, functionalization and applications

Magnetic nanoparticles continue to garner widespread interest in biomedical applications, such as visualization agents in MRI, therapeutic vehicles for drug delivery and heat mediators in hyperthermia. Recent advances in colloidal synthesis and surface-functionalization techniques have greatly contributed to the design of functionalized magnetic nanoparticles with controlled properties and multifunctional capabilities, which are harnessed for dual diagnostic and therapeutic purposes. The surface-functionalization methods in particular have aided in obtaining magnetic nanoparticles coated with molecules, with tailored functionalities that enhance their applications. In this article, the methods of synthesis and functionalization are examined, with emphasis on how these impact their biomedical applications.

Hydrogel nanocomposites: a review of applications as remote controlled biomaterials

In the past few years, there has been increased interest in the development and applications of hydrogel nanocomposites, specifically as a new class of biomaterials. In some cases, the nanoparticles (e.g., gold, magnetic, carbon nanotubes) can absorb specific stimuli (e.g., alternating magnetic fields, near-IR light) and generate heat. This unique ability to remotely heat the nanocomposites allows for their remote controlled (RC) applications, including the ability to remotely drive the polymer through a transition event (e.g., swelling transition, glass transition). This review highlights some of the recent studies in the development of the RC hydrogel nanocomposites. In particular, some of the important applications of RC nanocomposites as RC drug delivery devices, as RC actuators, and in cancer treatment are discussed.

Remote Controlled Multishape Polymer Nanocomposites with Selective Radiofrequency Actuations

Shape memory polymers (SMPs) are a class of polymers that can be deformed to stable temporary shapes and recover their permanent shape only when exposed to an external stimulus. [ 1,2 ] The unique ability to actuate SMPs through the setting of temporary shapes and then actuating to a permanent shape has been utilized for a number of applications in various fi elds. Many prototype systems have been developed, including an intravascular device to remove blood clots, [ 3 ] a self-peeling reversible dry adhesive, [ 4,5 ] a biodegradable self-tightening suture, [ 6 ] an active microfl uidic device, [ 7 ] self-healing surfaces, [ 8 ]

Poly(ethylene glycol)-based magnetic hydrogel nanocomposites for hyperthermia cancer therapy

Hyperthermia, the heating of cancerous tissues to between 41 and 45 degrees Celsius, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. Here a novel method for remotely administering heat is presented, which involves the heating of tumor tissue using hydrogel nanocomposites containing magnetic nanoparticles which can be remotely heated upon exposure to an external alternating magnetic field (AMF). Specifically, this research explores the use of hydrogel nanocomposites based on poly(ethylene glycol) methyl ether methacrylate and dimethacrylate with iron oxide as implantable biomaterials for thermal cancer therapy applications. Swelling analysis of the systems indicated a dependence of ethylene glycol (EG) content and cross-linking density on swelling behavior where greater EG amount and lower cross-linking resulted in higher volume swelling ratios. Both the entrapped iron oxide nanoparticles and hydrogel nanocomposites exhibited high cell viability for murine fibroblasts, indicating potential biocompatibility. The hydrogels were heated in an AMF, and the heating response was shown to be dependent on both iron oxide loading in the gels and the strength of the magnetic field. As proof of concept of these systems as a thermal therapeutic the ability to selectively kill M059K glioblastoma cells in vitro with hydrogel nanocomposites exposed to an AMF was demonstrated.

Poly(n-isopropylacrylamide)-based hydrogel coatings on magnetite nanoparticles via atom transfer radical polymerization

Core magnetite (Fe(3)O(4)) nanoparticles have been functionalized with a model intelligent hydrogel system based on the temperature responsive polymer poly(n-isopropyl acrylamide) (PNIPAAm) to obtain magnetically responsive core-shell nanocomposites. Fe(3)O(4) nanoparticles were obtained from a one-pot co-precipitation method which provided either oleic acid (hydrophobic) or citric acid (hydrophilic) coated nanoparticles. Subsequent ligand exchange of these coatings with various bromine alkyl halides and a bromo silane provided initiating sites for functionalization with NIPAAm using atom transfer radical polymerization (ATRP). The bromine alkyl halides that were used were 2-bromo-2-methyl propionic acid (BMPA) and 2-bromopropionyl bromide (BPB). The bromo silane that was used was 3-bromopropyl trimethoxysilane (BPTS). The intelligent polymeric shell consists of NIPAAm crosslinked with poly(ethylene glycol) 400 dimethacrylate (PEG400DMA). Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), and transmission electron microscopy (TEM) were used to confirm the presence of the polymeric shell. Dynamic light scattering (DLS) was used to characterize the nanocomposites for particle size changes with temperature. Their magnetic and temperature responsiveness show great promise for further biomedical applications. This platform for functionalizing magnetic nanoparticles with intelligent hydrogels promises to impact a wide range of medical and biological applications of magnetic nanoparticles.

Characterization and aerosol dispersion performance of advanced spray-dried chemotherapeutic PEGylated phospholipid particles for dry powder inhalation delivery in lung cancer.

Pulmonary inhalation chemotherapeutic drug delivery offers many advantages for lung cancer patients in comparison to conventional systemic chemotherapy. Inhalable particles are advantageous in their ability to deliver drug deep in the lung by utilizing optimally sized particles and higher local drug dose delivery. In this work, spray-dried and co-spray dried inhalable lung surfactant-mimic PEGylated lipopolymers as microparticulate/nanoparticulate dry powders containing paclitaxel were rationally designed via organic solution advanced spray drying (no water) in closed-mode from dilute concentration feed solution. Dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) with varying PEG chain length were mixed with varying amounts of paclitaxel in methanol to produce co-spray dried microparticles and nanoparticles. Scanning electron microscopy showed the spherical particle morphology of the inhalable particles. Thermal analysis and X-ray powder diffraction confirmed the retention of the phospholipid bilayer structure in the solid-state following spray drying, the degree of solid-state molecular order, and solid-state phase transition behavior. The residual water content of the particles was very low as quantified analytically Karl Fisher titration. The amount of paclitaxel loaded into the particles was quantified which indicated high encapsulation efficiencies (43-99%). Dry powder aerosol dispersion performance was measured in vitro using the Next Generation Impactor (NGI) coupled with the Handihaler dry powder inhaler device and showed mass median aerodynamic diameters in the range of 3.4-7 μm. These results demonstrate that this novel microparticulate/nanoparticulate chemotherapeutic PEGylated phospholipid dry powder inhalation aerosol platform has great potential in lung cancer drug delivery.

Nanocomposite Degradable Hydrogels: Demonstration of Remote Controlled Degradation and Drug Release

PurposeTo demonstrate remote controlled degradation of degradable nanocomposite hydrogels by application of an alternating magnetic field (AMF). Further, it was desired to study the AMF effect on the drug release properties of these systems.MethodsDegradable nanocomposite hydrogels were synthesized by incorporating iron oxide nanoparticles into a degradable hydrogel that exhibited temperature dependent degradation. Heating, degradation, and drug release studies were conducted by application of an AMF to determine if modulation of degradation and drug release could be attained.ResultsHydrogels were successfully prepared, shown to have temperature dependent degradation, and shown to heat when exposed to the AMF. The degradation rate of the exposed samples was demonstrated to be higher than control samples, thus modulation of degradation was obtained. The release of a model drug from the system was modulated by exposure to the AMF.ConclusionsThis is the first demonstration of remote controlled degradation using an AMF stimulus. Here, the proof of the concept has been presented, and there is great potential to enhance this effect through various methods. The ability to remotely control degradation of an implanted device opens a new area of improved medical devices.

Biocompatibility analysis of magnetic hydrogel nanocomposites based on poly(N-isopropylacrylamide) and iron oxide

With the growing interest in nanocomposites and their applications in biology and medicine, studies examining the biocompatibility of those materials are critical. Magnetic hydrogel nanocomposites based on poly(N-isopropylacrylamide) and iron oxide nanoparticles were fabricated via UV-polymerization with tetra(ethylene glycol) dimethacrylate acting as the crosslinking agent. In vitro biocompatibility analysis via NIH 3T3 murine fibroblast cytotoxicity was investigated. The fibroblasts in both direct and indirect contact with the hydrogels exhibited favorable cell viability indicating minimal cytotoxicity of the systems. In addition, swelling studies indicated that hydrogels with lower crosslink densities yield higher swelling ratios and that the presence of magnetic nanoparticle did not affect the swelling response of the hydrogel systems. Upon exposure to an alternating magnetic field, the hydrogel nanocomposites with iron oxide nanoparticles showed the capability for remote heating. This evaluation shows that these hydrogels have the potential to be used in biomedical applications such as drug delivery and hyperthermia for cancer treatment.

Design, Physicochemical Characterization, and Optimization of Organic Solution Advanced Spray-Dried Inhalable Dipalmitoylphosphatidylcholine (DPPC) and Dipalmitoylphosphatidylethanolamine Poly(Ethylene Glycol) (DPPE-PEG) Microparticles and Nanoparticles for Targeted Respiratory Nanomedicine Delivery as Dry Powder Inhalation Aerosols

Novel advanced spray-dried and co-spray-dried inhalable lung surfactant-mimic phospholipid and poly(ethylene glycol) (PEG)ylated lipopolymers as microparticulate/nanoparticulate dry powders of biodegradable biocompatible lipopolymers were rationally formulated via an organic solution advanced spray-drying process in closed mode using various phospholipid formulations and rationally chosen spray-drying pump rates. Ratios of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine PEG (DPPE-PEG) with varying PEG lengths were mixed in a dilute methanol solution. Scanning electron microscopy images showed the smooth, spherical particle morphology of the inhalable particles. The size of the particles was statistically analyzed using the scanning electron micrographs and SigmaScan® software and were determined to be 600 nm to 1.2 μm in diameter, which is optimal for deep-lung alveolar penetration. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were performed to analyze solid-state transitions and long-range molecular order, respectively, and allowed for the confirmation of the presence of phospholipid bilayers in the solid state of the particles. The residual water content of the particles was very low, as quantified analytically via Karl Fischer titration. The composition of the particles was confirmed using attenuated total-reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy and confocal Raman microscopy (CRM), and chemical imaging confirmed the chemical homogeneity of the particles. The dry powder aerosol dispersion properties were evaluated using the Next Generation Impactor™ (NGI™) coupled with the HandiHaler® dry powder inhaler device, where the mass median aerodynamic diameter from 2.6 to 4.3 μm with excellent aerosol dispersion performance, as exemplified by high values of emitted dose, fine particle fraction, and respirable fraction. Overall, it was determined that the pump rates defined in the spray-drying process had a significant effect on the solid-state particle properties and that a higher pump rate produced the most optimal system. Advanced dry powder inhalers of inhalable lipopolymers for targeted dry powder inhalation delivery were successfully achieved.