Development of Aerosol Dry Powder Chemotherapeutic-Loaded Microparticles for the Treatment of Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide, resulting in the highest mortality rates among both men and women with respect to all other types of cancer. Difficulties in treating lung cancer arise from late-stage diagnoses and tumor heterogeneity and current treatment involves a combination of chemotherapeutics, surgery, and radiation. Chemotherapeutics administered systemically can lead to undesirable side effects and severe off-site toxicity. For example, chronic administration of the chemotherapeutic doxorubicin (DOX) leads to cardiotoxicity, thereby limiting its long-term use. Systemic administration of the highly lipophilic molecule paclitaxel (PTX) is hindered by its water solubility, necessitating the use of solubilizing agents, which can induce side effects. Thus, in this investigation, formulations consisting of spray-dried microparticles (MP) containing DOX and PTX were produced to be administered as dry powder aerosols directly to the lungs. Acetalated dextran (Ac-Dex) was used as the polymer in these formulations, as it is a biocompatible and biodegradable polymer that exhibits pH-responsive degradation. Solid-state characterization revealed that DOX and PTX remained in solubility favoring amorphous states in the MP formulations and that both drugs remained thermally stable throughout the spray drying process. In vitro release studies demonstrated the pH sensitivity of the formulations due to the use of Ac-Dex, as well as the release of both therapeutics over the course of at least 48 h. In vitro aerosol dispersion studies demonstrated that both formulations exhibited suitable aerosol dispersion properties for deep lung delivery.

Lung cell membrane-coated nanoparticles capable of enhanced internalization and translocation in pulmonary epithelial cells.

Cell membrane-coated nanoparticles (CMCNP), which involve coating a core nanoparticle (NP) with cell membranes, have been gaining attention due to their ability to mimic the properties of the cells, allowing for enhanced delivery and efficacy of therapeutics. Two CMCNP systems comprised of an acetalated dextran-based NP core loaded with curcumin (CUR) coated with cell membranes derived from pulmonary epithelial cells were developed. The NP were approximately 200 nm and their surface charges varied based on their coating, where CMCNP systems exhibited negative surface charge like natural cell membranes. The NP were smooth, spherical, and homogeneous with distinct coatings on their cores. Minimal in vitro toxicity was observed for the NP and controlled release of CUR was observed. The CMCNP internalized into and translocated across an in vitro pulmonary epithelial monolayer significantly more than the control NP. Blocking endocytosis pathways reduced the transcytosis of NP, indicating a relationship between endocytosis and transcytosis. These newly developed CMCNP have the potential to be used in pulmonary drug delivery applications to potentially enhance NP internalization and transport into and across the pulmonary epithelium.

Radiofrequency and Near-Infrared Responsive Core-Shell Nanostructures Using Layersome Templates for Cancer Treatment.

We report a multifunctional nanotherapeutic platform based on liposomes loaded with drug and iron oxide nanoparticles (IONs) coated with a gold nanoshell synthesized using a polyelectrolyte (layersome) soft templating technique. IONs and gold nanoshells were used to provide combined hyperthermia and triggered drug release via radio frequency (RF) or near-infrared (NIR) stimulation. IONs and the anticancer drug doxorubicin (DOX) were coencapsulated inside liposomes composed of zwitterionic phosphatidylcholine, anionic phosphatidylglycerol, and cholesterol lipids. Coating the magneto-liposomes with positively charged poly-l-lysine enriched the interface with gold anions to form a dense gold nanoshell and protected the structure against deformation and DOX cargo release during shell formation. After modification with thiol-terminated polyethylene glycol, intracellular delivery and release of DOX from the nanostructures was examined in A549 human lung cancer cells. The nanostructures retained their DOX cargo and remained in the cytosol after cellular uptake. Only when triggered by RF or NIR stimuli did the nanostructures release DOX, which then entered the cell nucleus. Compared to the single photothermal therapy or radio frequency treatment, the carriers with combined DOX and RF or NIR stimulation displayed higher therapeutic effect on A549 cells.

Development and Evaluation of Paclitaxel-Loaded Aerosol Nanocomposite Microparticles and Their Efficacy Against Air-Grown Lung Cancer Tumor Spheroids.

Paclitaxel (as intravenous Taxol) is one of the most applied chemotherapeutics used for the treatment of lung cancer. This project involves the development of a dry powder nanocomposite microparticle (nCmP) aerosol containing PTX-loaded nanoparticles (NP) to be delivered via a dry powder inhaler to the lungs for the treatment of non-small cell lung cancer (NSCLC). Nanoparticles were formulated by a single emulsion and solvent evaporation method, producing smooth, neutral PTX NP of approximately 200 nm in size. PTX nCmP were obtained via spray drying PTX NP with mannitol, producing amorphous wrinkled particles that demonstrated optimal aerosol deposition for in vitro pulmonary delivery. Free PTX, PTX NP, and PTX nCmP were evaluated in vitro in both 2D monolayers and 3D multicellular spheroids (MCS). PTX NP enhanced cytotoxicity when compared to pure drug in the 2D evaluation. However, on a liquid culture 3D tumor spheroid model, PTX NP and pure PTX showed similar efficacy in growth inhibition of MCS. The PTX nCmP formulation had a comparable cytotoxicity impact on MCS compared with free PTX. Finally, PTX nCmP were evaluated in an air-grown 3D MCS platform that mimics the pulmonary environment, representing a new model for the assessment of dry powder formulations.

Coadministration of a tumor-penetrating peptide improves the therapeutic efficacy of paclitaxel in a novel air-grown lung cancer 3D spheroid model.

Three-dimensional (3 D) cell culture platforms are increasingly being used in cancer research and drug development since they mimic avascular tumors in vitro. In this study, we focused on the development of a novel air-grown multicellular spheroid (MCS) model to mimic in vivo tumors for understanding lung cancer biology and improvement in the evaluation of aerosol anticancer therapeutics. 3 D MCS were formed using A549 lung adenocarcinoma cells, comprising cellular heterogeneity with respect to different proliferative and metabolic gradients. The growth kinetics, morphology and 3 D structure of air-grown MCS were characterized by brightfield, fluorescent and scanning electron microscopy. MCS demonstrated a significant decrease in growth when the tumor-penetrating peptide iRGD and paclitaxel (PTX) were coadministered as compared with PTX alone. It was also found that when treated with both iRGD and PTX, A549 MCS exhibited an increase in apoptosis and decrease in clonogenic survival capacity in contrast to PTX treatment alone. This study demonstrated that coadministration of iRGD resulted in the improvement of the tumor penetration ability of PTX in an in vitro A549 3 D MCS model. In addition, this is the first time a high-throughput air-grown lung cancer tumor spheroid model has been developed and evaluated.

Nanocomposite microparticles (nCmP) for the delivery of tacrolimus in the treatment of pulmonary arterial hypertension.

Tacrolimus (TAC) has exhibited promising therapeutic potential in the treatment of pulmonary arterial hypertension (PAH); however, its application is prevented by its poor solubility, instability, poor bioavailability, and negative systemic side effects. To overcome the obstacles of using TAC for the treatment of PAH, we developed nanocomposite microparticles (nCmP) for the pulmonary delivery of tacrolimus in the form of dry powder aerosols. These particles can provide targeted pulmonary delivery, improved solubility of tacrolimus, the potential of penetration through mucus barrier, and controlled drug release. In this system, tacrolimus-loaded polymeric nanoparticles (NP) were prepared via emulsion solvent evaporation and nCmP were prepared by spray drying these NP with mannitol. The NP were approximately 200nm in diameter with narrow size distribution both before loading into and after redispersion from nCmP. The NP exhibited smooth, spherical morphology and the nCmP were raisin-like spheres. High encapsulation efficacy was achieved both in the encapsulation of tacrolimus in NP and that of NP in nCmP. nCmP exhibited desirable aerosol dispersion properties, allowing them to deposit into the deep lung regions for effective drug delivery. A549 cells were used as in vitro models to demonstrate the non-cytotoxicity of TAC nCmP. Overall, the designed nCmP have the potential to aid in the delivery of tacrolimus for the treatment of PAH.

Synthesis and Characterization of Nanocomposite Microparticles (nCmP) for the Treatment of Cystic Fibrosis-Related Infections.

PURPOSE: Pulmonary antibiotic delivery is recommended as maintenance therapy for cystic fibrosis (CF) patients who experience chronic infections. However, abnormally thick and sticky mucus present in the respiratory tract of CF patients impairs mucus penetration and limits the efficacy of inhaled antibiotics. To overcome the obstacles of pulmonary antibiotic delivery, we have developed nanocomposite microparticles (nCmP) for the inhalation application of antibiotics in the form of dry powder aerosols. METHODS: Azithromycin-loaded and rapamycin-loaded polymeric nanoparticles (NP) were prepared via nanoprecipitation and nCmP were prepared by spray drying and the physicochemical characteristics were evaluated. RESULTS: The nanoparticles were 200 nm in diameter both before loading into and after redispersion from nCmP. The NP exhibited smooth, spherical morphology and the nCmP were corrugated spheres about 1 µm in diameter. Both drugs were successfully encapsulated into the NP and were released in a sustained manner. The NP were successfully loaded into nCmP with favorable encapsulation efficacy. All materials were stable at manufacturing and storage conditions and nCmP were in an amorphous state after spray drying. nCmP demonstrated desirable aerosol dispersion characteristics, allowing them to deposit into the deep lung regions for effective drug delivery. CONCLUSIONS: The described nCmP have the potential to overcome mucus-limited pulmonary delivery of antibiotics.

Development of three-dimensional lung multicellular spheroids in air- and liquid-interface culture for the evaluation of anticancer therapeutics.

Three-dimensional (3D) lung multicellular spheroids (MCS) in liquid-covered culture (LCC) and air-interface culture (AIC) conditions have both been developed for the evaluation of aerosol anticancer therapeutics in solution and aerosols, respectively. The MCS were formed by seeding lung cancer cells on top of collagen where they formed spheroids due to the prevalence of cell-to-cell interactions. LCC MCS were exposed to paclitaxel (PTX) in media whereas AIC MCS were exposed to dry powder PEGylated phospholipid aerosol microparticles containing paclitaxel. The difference in viability for 2D versus 3D culture for both LCC and AIC was evaluated along with the effects of the particles on lung epithelium via transepithelial electrical resistance (TEER) measurements. For LCC and AIC conditions, the 3D spheroids were more resistant to treatment with higher IC50 values for A549 and H358 cell lines. TEER results initially indicated a decrease in resistance upon drug or particle exposure, however, these values increased over the course of several days indicating the ability of the cells to recover. Overall, these studies offer a comprehensive in vitro evaluation of aerosol particles used in the treatment of lung cancer while introducing a new method for culturing lung cancer MCS in both LCC and AIC conditions.

High-performing dry powder inhalers of paclitaxel DPPC/DPPG lung surfactant-mimic multifunctional particles in lung cancer: physicochemical characterization, in vitro aerosol dispersion, and cellular studies.

Inhalable lung surfactant-based carriers composed of synthetic phospholipids, dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG), along with paclitaxel (PTX), were designed and optimized as respirable dry powders using organic solution co-spray-drying particle engineering design. These materials can be used to deliver and treat a wide variety of pulmonary diseases with this current work focusing on lung cancer. In particular, this is the first time dry powder lung surfactant-based particles have been developed and characterized for this purpose. Comprehensive physicochemical characterization was carried out to analyze the particle morphology, surface structure, solid-state transitions, amorphous character, residual water content, and phospholipid bilayer structure. The particle chemical composition was confirmed using attenuated total reflectance-Fourier-transform infrared (ATR-FTIR) spectroscopy. PTX loading was high, as quantified using UV-VIS spectroscopy, and sustained PTX release was measured over weeks. In vitro cellular characterization on lung cancer cells demonstrated the enhanced chemotherapeutic cytotoxic activity of paclitaxel from co-spray-dried DPPC/DPPG (co-SD DPPC/DPPG) lung surfactant-based carrier particles and the cytotoxicity of the particles via pulmonary cell viability analysis, fluorescent microscopy imaging, and transepithelial electrical resistance (TEER) testing at air-interface conditions. In vitro aerosol performance using a Next Generation Impactor™ (NGI™) showed measurable powder deposition on all stages of the NGI and was relatively high on the lower stages (nanometer aerodynamic size). Aerosol dispersion analysis of these high-performing DPIs showed mass median diameters (MMADs) that ranged from 1.9 to 2.3 µm with excellent aerosol dispersion performance as exemplified by high values of emitted dose, fine particle fractions, and respirable fractions.

Synthesis and characterization of CREKA-conjugated iron oxide nanoparticles for hyperthermia applications.

One of the current challenges in the systemic delivery of nanoparticles in cancer therapy applications is the lack of effective tumor localization. Iron oxide nanoparticles (IONPs) coated with crosslinked dextran were functionalized with the tumor-homing peptide CREKA, which binds to fibrinogen complexes in the extracellular matrix of tumors. This allows for the homing of these nanoparticles to tumor tissue. The IONP core allows for particle heating upon exposure to an alternating magnetic field (AMF), while the dextran coating stabilizes the particles in suspension and decreases the cytotoxicity of the system. Magnetically mediated hyperthermia (MMH) allows for the heating of tumor tissue to increase the efficacy of traditional cancer treatments using IONPs. While MMH provides the opportunity for localized heating, this method is currently limited by the lack of particle penetration into tumor tissue, even after effective targeted delivery to the tumor site. The CREKA-conjugated nanoparticles presented were characterized for their size, stability, heating capabilities and biocompatibility. The particles had a hydrated diameter of 52nm, were stable in phosphate buffered saline solution and media with 10% v/v fetal bovine serum over at least 12h, and generated enough heat to raise solution temperatures well into the hyperthermia range (41-45°C) when exposed to an AMF, owing to an average specific absorption rate of 83.5Wg(-1). Cytotoxicity studies demonstrated that the particles have low cytotoxicity over long exposure times at low concentrations. A fibrinogen clotting assay was used to determine the binding affinity of CREKA-conjugated particles, which was significantly greater than the binding affinity of dextran, only coated IONPs demonstrating the potential for this particle system to effectively home to a variety of tumor locations. Finally, it was shown that in vitro MMH increased the effects of cisplatin compared with cisplatin or MMH treatments alone.

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.

Characterization of PEG-iron oxide hydrogel nanocomposites for dual hyperthermia and paclitaxel delivery.

Hyperthermia, the heating of tissue from 41 to 45 °C, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. In this work, hydrogel nanocomposites have been developed that can control the delivery of both heat and a chemotherapeutic agent (e.g. paclitaxel). The nanocomposites studied involve a stealth, poly(ethylene glycol) (PEG)-based system comprised of PEG (n = 1000) methyl ether methacrylate and PEG (n = 400) dimethacrylate with iron oxide nanoparticles physically entrapped within the hydrogel matrices. The capability of the hydrogel nanocomposites to be heated in an alternating magnetic field was demonstrated. The heating of the hydrogel systems was dependent on the crosslinking of the hydrogel network where hydrogels with lower swelling ratios were found to heat to a greater extent than those with higher ratios. In addition, paclitaxel was shown to exhibit non-Fickian release from the hydrogel systems, with the amount of drug released dependent on the hydrogel network structure. Three cell lines: M059K (glioblastoma), MDA MB 231 (breast carcinoma), and A549 (lung adenocarcinoma) were exposed to paclitaxel only, hyperthermia only, and both paclitaxel and hyperthermia to determine if a synergistic cytotoxic effect was possible for these cell lines. The efficacy of paclitaxel was greater with hyperthermia for the A549 cells; however, the M059K and MDA MB 231 did not show the same response.

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.

Controlled synergistic delivery of paclitaxel and heat from poly(ß-amino ester)/iron oxide-based hydrogel nanocomposites.

Poly(ß-amino ester) (PBAE) biodegradable hydrogels were investigated for potential combined chemotherapeutic and heat delivery in the synergistic treatment of cancer. Hyperthermia, the heating of cancerous tissue from 41 to 45 °C, increases the efficacy of conventional cancer therapies such as irradiation and chemotherapy. The hydrogel nanocomposites in this work provide a drug delivery vehicle (via the biodegradable PBAE polymer network) and the ability to be heated remotely upon exposure to an alternating magnetic field (via iron oxide nanoparticles incorporated into the hydrogel matrix). PBAE macromers composed of poly(ethylene glycol) (N=400) diacrylate (PEG400DA) or diethylene glycol diacrylate (DEGDA) with isobutylamine (IBA) were synthesized. Hydrogel nanocomposites were fabricated via free-radical polymerization to form a bulk hydrogel matrix entrapping both iron oxide nanoparticles and paclitaxel. The 2EG-IBA hydrogel exhibited complete degradation after approximately 7 weeks whereas the 9EG-IBA hydrogel degraded completely in 11h. The hydrogels heated upon exposure to an alternating magnetic field throughout the degradation process. Additionally, the cytotoxicity of the degradation products was evaluated. Paclitaxel release was controlled via bulk degradation of the hydrogels. The tailorability of these nanocomposites makes them solid candidates for the synergistic treatment of cancer.

Synthesis, optimization, and characterization of camptothecin-loaded acetalated dextran porous microparticles for pulmonary delivery.

We propose the use of a new biopolymer, acetalated dextran (Ac-DEX), to synthesize porous microparticles for pulmonary drug delivery. Ac-DEX is derived from the polysaccharide dextran and, unlike polyesters, has tunable degradation from days to months and pH neutral degradation products. Ac-DEX microparticles fabricated through emulsion techniques were optimized using a variety of postprocessing techniques to enhance the respirable fraction for pulmonary delivery. Tangential flow filtration resulted in a maximum 37% respirable fraction for Ac-DEX porous microparticles, compared to a 10% respirable fraction for poly(lactic-co-glycolic acid) (PLGA) porous microparticles. Ac-DEX microparticles were of an optimum diameter to minimize macrophage clearance but had a low enough theoretical density for deep lung penetration. Transepithelial electrical resistance (TEER) measurements showed that the particles did not impinge on a monolayer of lung epithelial cells in either air or liquid conditions. Also, the release of the chemotherapeutic camptothecin was shown to be tunable depending on Ac-DEX degradation time and molecular weight, and drug release was shown to be bioactive over a range of concentrations. Our results indicate that both release kinetics and fraction of burst release of drug from Ac-DEX porous microparticles can be tuned by simply changing the Ac-DEX polymer properties, affording a large range of formulation options for drug delivery to the pulmonary cavity. Overall, Ac-DEX porous microparticles show promise as an emerging carrier for pulmonary delivery of drugs to the alveolar region of the lung, particularly for the treatment of lung diseases.

Optimization of rapamycin-loaded acetalated dextran microparticles for immunosuppression.

Immunosuppressive drugs can treat autoimmune disorders and limit rejection with organ transplants. However, delivering immunosuppressants like rapamycin systemically can have harmful side-effects. We aim to potentially reduce these toxic side-effects by encapsulating rapamycin in a polymeric microparticle to passively target phagocytes, the cells integral in immunosuppression. Acetalated dextran (Ac-DEX) is a recently described, biocompatible polymer which undergoes tunable burst degradation at the acidic conditions present in the phagosome (pH 5) but slower degradation at extracellular conditions (pH 7.4), thereby making it an ideal candidate for immune applications. Rapamycin-loaded microparticles were fabricated from Ac-DEX through a single emulsion (water/oil) technique. Optimized microparticles were determined by varying the chemical and physical parameters during particle synthesis. Microparticles synthesized from Ac-DEX with a molecular weight of 71 k had higher encapsulation efficiency of rapamycin and slower overall degradation than microparticles synthesized from 10k Ac-DEX. To evaluate the ability of rapamycin-loaded Ac-DEX microparticles to reduce a pro-inflammatory response, they were incubated with lipopolysaccharide-stimulated RAW macrophages. RAW macrophages treated with rapamycin-loaded microparticles exhibited reduced nitric oxide production and favorable cell viability. Overall, we have shown optimization of immunosuppressive rapamycin-loaded microparticles using the novel polymer Ac-DEX. These particles will be advantageous for future applications in immune suppression therapies.

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.

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.