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Thermoresponsive polymer-coated magnetic nanoparticles loaded with anti-cancer drugs are of considerable interest for novel multi-modal cancer therapies. Such nanoparticles can be used for magnetic drug targeting followed by simultaneous hyperthermia and drug release. Gamma-Fe(2)O(3) iron oxide magnetic nanoparticles (MNP) with average sizes of 14, 19 and 43 nm were synthesized by high temperature decomposition. Composite magnetic nanoparticles (CNP) of 43 nm MNP coated with the thermoresponsive polymer poly-n-isopropylacrylamide (PNIPAM) were prepared by dispersion polymerization of n-isopropylacrylamide monomer in the presence of the MNP. In vitro drug release of doxorubicin-(dox) loaded dehydrated CNP at temperatures below and above the lower critical solution temperature of PNIPAM (34 degrees C) revealed a weak dependence of drug release on swelling behavior. The particles displayed Fickian diffusion release kinetics; the maximum dox release at 42 degrees C after 101 h was 41%. In vitro simultaneous hyperthermia and drug release of therapeutically relevant quantities of dox was achieved, 14.7% of loaded dox was released in 47 min at hyperthermia temperatures. In vivo magnetic targeting of dox-loaded CNP to hepatocellular carcinoma (HCC) in a buffalo rat model was studied by magnetic resonance imaging (MRI) and histology. In summary, the good in vitro and in vivo performance of the doxorubicin-loaded thermoresponsive polymer-coated magnetic nanoparticles suggests considerable promise for applications in multi-modal treatment of cancer.

Biological materials offer a wide range of multifunctional and structural properties that are currently not achieved in synthetic materials. Herein we report on the synthesis and preparation of bioinspired organic/inorganic composites that mimic the key physicochemical features associated with the mechanical strengthening of both squid beaks and mussel thread coatings using chitosan as an initial template. While chitosan is a well-known biocompatible material, it suffers from key drawbacks that have limited its usage in a wider range of structural biomedical applications. First, its load-bearing capability in hydrated conditions remains poor, and second it completely dissolves at pH < 6, preventing its use in mild acidic microenvironments. In order to overcome these intrinsic limitations, a chitosan-based organic/inorganic biocomposite is prepared that mimics the interfacial chemistry of squid beaks and mussel thread coating. Chitosan was functionalized with catechol moieties in a highly controlled fashion and combined with superparamagnetic iron oxide (γ-Fe2O3) nanoparticles to give composites that represent a significant improvement in functionality of chitosan-based biomaterials. The inorganic/organic (γ-Fe2O3/catechol) interfaces are stabilized and strengthened by coordination bonding, resulting in hybrid composites with improved stability at high temperatures, physiological pH conditions, and acid/base conditions. The inclusion of superparamagnetic particles also makes the composites stimuli-responsive.

Composite magnetic nanoparticles ͑MNPs͒ consisting of an MNP core and drug loaded polymer shell can increase the efficacy of cancer therapy by overcoming several limitations of conventional hyperthermia and chemotherapy. Multimodal therapy consisting of simultaneous hyperthermia and chemotherapy can increase therapeutic efficiency compared to individual applications of these modalities. Factors influencing power output in an alternating magnetic field ͑AMF͒ for superparamagnetic ␥-Fe 2 O 3 and Fe 3 O 4 iron oxide MNP were studied. The optimum MNP properties for in vivo magnetic hyperthermia were identified. For a 375 kHz AMF, 23 nm ␥-Fe 2 O 3 MNP and 12 nm Fe 3 O 4 MNP produce maximum heating, heat generation is dependent primarily on Néel relaxation and is insensitive to polymer shell thickness. The heating of tumors by uniformly distributed magnetic clusters of optimized iron oxide MNP was modeled. The MNP mass required to heat tumors to hyperthermia temperatures was calculated, the Fe 3 O 4 MNP concentration in the tumor required for hyperthermia was in the range of 0.12-2.2 g ml −1 for Fe 3 O 4 and 0.06-1.7 g ml −1 for ␥-Fe 2 O 3 MNP respectively. In vitro drug release from doxorubicin loaded poly-n-isopropylacrylamide coated MNP was also modeled to understand the influence of shell thickness on thermoresponsive drug release. An increase in shell thickness or decrease in temperature resulted in decreased drug release rates. The MNP mass requirements for hyperthermia closely match the requirements for chemotherapy confirming the feasibility of these particles for combined hyperthermia and drug release applications.

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