Combining hard matter, like inorganic nanocrystals, and soft materials, like polymers, can generate multipurpose materials with a broader range of applications with respect to the individual building blocks. Given their unique properties at the nanoscale, magnetic nanoparticles (MNPs) have drawn a great deal of interest due to their potential use in the biomedical field, targeting several applications such as heat hubs in magnetic hyperthermia (MHT, a heat-damage based therapy), contrast agents in magnetic resonance imaging (MRI), and nanocarriers for targeted drug delivery. At the same time, polymers, with their versatile macromolecular structure, can serve as flexible platforms with regard to constructing advanced functional materials. Advances in the development of novel polymerization techniques has enabled the preparation of a large portfolio of polymers that have intriguing physicochemical properties; in particular, those polymers that can undergo conformational and structural changes in response to their surrounding environmental stimuli. Therefore, merging the unique features of MNPs with polymer responsive properties, such as pH and thermal stimuli activation, enables smart control of polymer properties operated by the MNPs and vice versa at an unprecedented level of sophistication. These magnetic-stimuli-responsive nanosystems will impact the cancer field by combining magnetic hyperthermia with stimuli-dependent controlled drug delivery toward multimodal therapies. In this approach, a malignant tumor may be destroyed by a combination of the synergic effects of thermal energy generated by MNPs and the controlled release of antitumoral agents, activated by means of either heat or pH changes, finally leading to a much more effective cancer treatment than those available today. Also, taking advantage of such a triggered chemotherapy will overcome the notorious drawbacks of classic chemotherapy. Nevertheless, tracking the changes in the magnetic properties of such pH-responsive magnetic nanoparticles, which are provided by changes in relaxation signals of water molecules surrounding the nanoplatform, is a novel approach to the detection of pathological conditions (such as pH-changes at the ischemic and tumor sites). Despite great efforts by chemists to fabricate different featured materials, there have been few successful preclinical studies to date. A clinical translation of magnetic stimuli-responsive systems would require overcoming the actual nanosystem limitations and the joint efforts of an interdisciplinary scientific community. In this Account, we have framed state of the art magnetic stimuli-responsive systems, focusing on thermo- and pH-responsive behavior, following an organization based on the response mechanisms of polymers. By evaluating the features of the most representative and advanced nanosystems that already exist in literature, we present the challenges to overcome, the future directions to undertake for the development of magnetic stimuli-responsive nanoplatforms that will work under clinical operating conditions and have biodegradable and biocompatible features, and a consideration of the technical aspects.

The use of magnetic nanoparticles in oncothermia has been investigated for decades, but an effective combination of magnetic nanoparticles and localized chemotherapy under clinical magnetic hyperthermia (MH) conditions calls for novel platforms. In this study, we have engineered magnetic thermo-responsive iron oxide nanocubes (TR-cubes) to merge MH treatment with heat-mediated drug delivery having in mind the clinical translation of the nanoplatform. We have chosen iron-oxide based-nanoparticles with a cubic shape because of their outstanding heat performance under MH clinical conditions, which makes them benchmark agents for MH. Accomplishing a surface-initiated polymerization of strongly interactive nanoparticles like our iron-oxide nanocubes, however, remains the main challenge to overcome. Here, we demonstrate that it is possible to accelerate the growth of a polymer shell on each nanocube by simply irradiating a copper-mediated polymerization with a ultraviolet light (UV) light, which both speeds up the polymerization and prevents nanocube aggregation. Moreover, we demonstrate herein that these TR-cubes can carry chemotherapeutic doxorubicin (DOXO-loaded-TR-cubes) without compromising their thermo-responsiveness both in vitro and in vivo. In vivo efficacy studies showed complete tumor suppression and the highest survival rate for animals that had been treated with DOXO-loaded-TR-cubes, only when they were exposed to MH. The bio-distribution of intravenously injected TR-cubes showed signs of renal clearance within one week, and complete clearance after five months. This biomedical platform works under clinical MH conditions and at a low iron dosage, which will enable the translation of dual MH/heat-mediated chemotherapy, thus overcoming the clinical limitation of MH, i.e. being able to monitor tumor progression post-MH-treatment by magnetic resonance imaging (MRI).

In this work, a novel drug delivery system consisting of poly(ε-caprolactone) (PCL) electrospun fibers containing an ad-hoc-synthesized star polymer made up of a poly(amido-amine) (PAMAM) core and PCL branches (PAMAM-PCL) was developed. The latter system which was synthesized via the ring opening polymerization of ε-caprolactone, starting from a hydroxyl-terminated PAMAM dendrimer and characterized by means of 1H NMR, IR and DSC, was found to be compatible with both the polymer matrix and a hydrophilic chemotherapeutic drug, doxorubicin (DOXO), the model drug used in this work. The preparation of the dendritic PCL star product with an average arm length of 2000g/mol was characterized using IR and 1H NMR measurements. The prepared star polymer possessed a higher crystallinity and a lower melting temperature than that of the used linear PCL. Electrospun fibers were prepared starting from solutions containing the neat PCL as well as the PCL/PAMAM-PCL mixture. Electrospinning conditions were optimized in order to obtain defect free fibers, which was proven by the structural FE-SEM study. PAMAM moieties enhanced the hydrophilicity of the fibers, as proved by comparing the water absorption for the PCL/PAMAM-PCL fibers to that neat PCL fibers. The drug-loaded system PCL/PAMAM-PCL was prepared by directly introducing DOXO into the electrospinning solutions. The DOXO-loaded PCL/PAMAM-PCL showed a prolonged release of the drug with respect to the DOXO-loaded PCL fibers and elicited effective controlled toxicity over A431 epidermoid carcinoma, HeLa cervical cancer cells and drug resistant MCF-7 breast cancer cells. On the contrary, the drug-free PCL/PAMAM-PCL scaffold demonstrated no toxic effects on human dermal fibroblasts, suggesting the biocompatibility of the proposed system which can be used in cellular scaffold applications.

We report a novel approach based on non-covalent interactions for the functionalization of carbon nano-onions (CNOs) with fluorophores.

In this study, we describe poly (lactic-co-glycolic) acid (PLGA)-based nanoparticles that combine photothermal therapy (PTT) with epigenetic therapy for melanoma. Specifically, we co-encapsulated indocyanine green (ICG), a PTT agent, and Nexturastat A (NextA), an epigenetic drug within PLGA nanoparticles (ICG-NextA-PLGA; INAPs). We hypothesized that combining PTT with epigenetic therapy elicits favorable cytotoxic and immunomodulatory responses that result in improved survival in melanoma-bearing mice. We utilized a nanoemulsion synthesis scheme to co-encapsulate ICG and NextA within stable and monodispersed INAPs. The INAPs exhibited concentration-dependent and near-infrared (NIR) laser power-dependent photothermal heating characteristics, and functioned as effective single-use agents for PTT of melanoma cells in vitro. The INAPs functioned as effective epigenetic therapy agents by inhibiting the expression of pan-histone deacetylase (HDAC) and HDAC6-specific activity in melanoma cells in vitro. When used for both PTT and epigenetic therapy in vitro, the INAPs increased the expression of co-stimulatory molecules and major histocompatibility complex (MHC) Class I in melanoma cells relative to controls. These advantages persisted in vivo in a syngeneic murine model of melanoma, where the combination therapy slowed tumor progression and improved median survival. These findings demonstrate the potential of INAPs as agents of PTT and epigenetic therapy for melanoma.