A continuous-flow platform enables rapid kinetic profiling and accelerated production of block copolymer nano-objects via RAFT aqueous dispersion polymerization.

Cancer stem cells (CSCs) are the tumor cell subpopulation responsible for resistance to chemotherapy, tumor recurrence, and metastasis. An efficient therapy must act on low proliferating quiescent-CSCs (q-CSCs). We here investigate the effect of magnetic hyperthermia (MHT) in combination with local chemotherapy as a dual therapy to inhibit patient-derived colorectal qCR-CSCs. We apply iron oxide nanocubes as MHT heat mediators, coated with a thermoresponsive polymer (TR-Cubes) and loaded with DOXO (TR-DOXO) as a chemotherapeutic agent. The thermoresponsive polymer releases DOXO only at a temperature above 44 °C. In colony-forming assays, the cells exposed to TR-Cubes with MHT reveal that qCR-CSCs struggle to survive the heat damage and, with a due delay, restart the division of dormant cells. The eradication of qCR-CSCs with a complete stop of the colony formation was achieved only with TR-DOXO when exposed to MHT. The in vivo tumor formation study confirms the combined effects of MHT with heat-mediated drug release: only the group of animals that received the CR-CSCs pretreated, in vitro , with TR-DOXO and MHT lacked the formation of tumor even after several months. For DOXO-resistant CR-CSCs cells, the same results were shown, in vitro, when choosing the drug oxaliplatin rather than DOXO and applying MHT. These findings emphasize the potential of our nanoplatforms as an effective patient-personalized cancer treatment against qCR-CSCs.

Here, the synthesis and proof of exploitation of three‐material inorganic heterostructures made of iron oxide‐gold‐copper sulfide (Fe3O4@Au@Cu2−xS) are reported. Starting with Fe3O4‐Au dumbbell heterostructure as seeds, a third Cu2−xS domain is selectively grown on the Au domain. The as‐synthesized trimers are transferred to water by a two‐step ligand exchange procedure exploiting thiol‐polyethylene glycol to coordinate Au and Cu2−xS surfaces and polycatechol–polyethylene glycol to bind the Fe3O4 surface. The saline stable trimers possess multi‐functional properties: the Fe3O4 domain, of appropriate size and crystallinity, guarantees optimal heating losses in magnetic hyperthermia (MHT) under magnetic field conditions of clinical use. These trimers have indeed record values of specific adsorption rate among the inorganic‐heterostructures so far reported. The presence of Au and Cu2−xS domains ensures a large adsorption which falls in the first near‐infrared (NIR) biological window and is here exploited, under laser excitation at 808 nm, to produce photo‐thermal heat alone or in combination with MHT obtained from the Fe3O4 domain. Finally, an intercalation protocol with radioactive 64Cu ions is developed on the Cu2−xS domain, reaching high radiochemical yield and specific activity making the Fe3O4@Au@Cu2−xS trimers suitable as carriers for 64Cu in internal radiotherapy (iRT) and traceable by positron emission tomography (PET).

Exploiting the local heat on the surface of magnetic nanoparticles (MNPs) upon exposure to an alternating magnetic field (AMF) to cleave thermal labile bonds represents an interesting approach in the context of remotely triggered drug delivery. Here, taking advantages of a simple and scalable two-step ligand exchange reaction, we have prepared iron oxide nanocubes (IONCs) functionalized with a novel multifunctional polymer ligand having multiple catechol moieties, furfuryl pendants, and polyethylene glycol (PEG) side chains. Catechol groups ensure a strong binding of the polymer ligands to the IONCs surface, while the PEG chains provide good colloidal stability to the polymer-coated IONCs. More importantly, furfuryl pendants on the polymer enable to click the molecules of interest (either maleimide−fluorescein or maleimide−doxorubicin) via a thermal labile Diels−Alder adduct. The resulting IONCs functionalized with a fluorescein/doxorubicin-conjugated polymer ligand exhibit good colloidal stability in buffer saline and serum solution along with outstanding heating performance in aqueous solution or even in viscous media (81% glycerol/water) when exposed to the AMF of clinical use. The release of conjugated bioactive molecules such as fluorescein and doxorubicin could be boosted by applying AMF conditions of clinical use (16 kAm −1 and 110 kHz). It is remarkable that the magnetic hyperthermia-mediated release of the dye/drug falls in the concentration range 1.0−5.0 μM at an IONCs dose as low as 0.5 g Fe /L and at no macroscopical temperature change. This local release effect makes this magnetic nanoplatform a potential tool for drug delivery with remote magnetic hyperthermia actuation and with a dose-independent action of MNPs.

CuFeS2 chalcopyrite nanoparticles (NPs) can generate heat under exposure to near-infrared laser irradiation. Here, we develop a protocol to decorate the surface of CuFeS2 NPs (13 nm) with a thermoresponsive (TR) polymer based on poly(ethylene glycol methacrylate) to combine heat-mediated drug delivery and photothermal heat damage. The resulting TR-CuFeS2 NPs feature a small hydrodynamic size (∼75 nm), along with high colloidal stability and a TR transition temperature of 41 °C in physiological conditions. Remarkably, TR-CuFeS2 NPs, when exposed to a laser beam (in the range of 0.5 and 1.5 W/cm2) at NP concentrations as low as 40–50 μg Cu/mL, exhibit a high heating performance with a rise in the solution temperature to hyperthermia therapeutic values (42–45 °C). Furthermore, TR-CuFeS2 NPs worked as nanocarriers, being able to load an appreciable amount of doxorubicin (90 μg DOXO/mg Cu), a chemotherapeutic agent whose release could then be triggered by exposing the NPs to a laser beam (through which a hyperthermia temperature above 42 °C could be reached). In an in vitro study performed on U87 human glioblastoma cells, bare TR-CuFeS2 NPs were proven to be nontoxic at a Cu concentration up to 40 μg/mL, while at the same low dose, the drug-loaded TR-CuFeS2-DOXO NPs displayed synergistic cytotoxic effects due to the combination of direct heat damage and DOXO chemotherapy, under photo-irradiation by a 808 nm laser (1.2 W/cm2). Finally, under a 808 nm laser, the TR-CuFeS2 NPs generated a tunable amount of reactive oxygen species depending on the applied power density and NP concentration.