== To study the effect of photothermal treatment on tumor volumes, mice bearing bilateral MDA-MB-435 human carcinoma tumors were intravenously injected with NRs (10mgAu/kg). (LP). The targeting species D-Melibiose employed in this work is usually a cyclic nine-amino acid peptide LyP-1 (Cys-Gly-Asn-Lys-Arg-Thr-Arg-Gly-Cys) that binds to the stress-related protein, p32, which we find to be upregulated on the surface of tumor-associated cells upon thermal treatment. Mice made up of xenografted MDA-MB-435 tumors that are treated with the combined NR/LyP-1LP therapeutic system display significant reductions in tumor volume compared with individual nanoparticles or untargeted cooperative system. Keywords:cancer therapy, gold nanorods, liposomes, magnetic nanoworms, protein expression In the past few decades, nanomaterials have played a propitious role in delivering therapeutic molecules effectively to diseased sites. In addition to their role as effective carriers of conventional therapeutic drugs, nanoscale materials can be harnessed to damage or destroy malignant tissues by converting external electromagnetic energy into heat (16). Furthermore, most nanomaterial surfaces can be decorated with targeting ligands, enhancing their ability to home to diseased tissues through multivalent interactions with tissue-specific receptors (7). Targeted liposomes (8,9), micelles (10,11) and dendrimers (12,13) incorporated with therapeutic molecules have displayed impressive anticancer effects in animal studies, and these nanomaterials are considered to be close to clinical translation due to their biocompatibility. In spite of these merits, nanotechnology-based cancer therapies have been slow to reach the clinic compared to conventional cancer therapies such as small molecule drugs, whole-body or local hyperthermia, and radiation. Tumorigenesis is usually a multistep process that requires expression of tumor-associated proteins and suppression of proteins controlling normal cell growth (14). Many of the identified tumor-specific proteins have been exploited to develop powerful antibody, aptamer, peptide, and small molecule-based ligands for targeting of diagnostic or therapeutic brokers (15). Ligand-directed targeting of therapeutic nanomaterials has been widely pursued to improve therapeutic efficacy, although limitations imposed by the tumor microenvironment, such as restricted transvascular transport and receptor accessibility, have prevented realization of their full capabilities. Although the porous microstructure of tumor blood vessels is favorable for nonspecific infiltration of circulating nanomaterials into the D-Melibiose extravascular region of the tumor (16), extravasated nanomaterials are generally deposited close to the vessels, resulting in a highly heterogeneous distribution of therapeutic brokers in the tumor. Hyperthermia has been reported to not only improve nanoparticle extravasation in tumors, (17) but it also can selectively damage neoplastic cells to activate immunological processes and induce expression of particular proteins (18). Widely used in the clinical setting in concert with chemotherapy and radiotherapy (19,20), tumor-specific hyperthermia would be a powerful tool to manipulate tumor microenvironments in order to enhance the interactions between cancerous tissues and therapeutic brokers. However, hyperthermia methods in clinical practice lack intrinsic specificity for tumor tissues, requiring complex implementation strategies and frequently resulting in exposure of large volumes of normal tissues to hyperthermic temperatures alongside tumors. We hypothesized that gold nanorods (NRs), passively accumulated in tumors via their fenestrated blood vessels, could be used to precisely heat tumor tissues by amplifying their Eltd1 absorption of otherwise benign near-infrared energy (2,6) and allow the recruitment and more effective penetration of a second, specifically targeted nanoparticle. Thus, in this work, we demonstrate a cooperative nanomaterials system, wherein NRs accumulated in D-Melibiose a tumor photothermally activate the local microenvironment to amplify the targeting efficacy of two types of targeted, circulating nanoparticles: magnetic nanoworms (NWs) and liposomes (LPs) loaded with the anticancer drug doxorubicin (DOX) (Fig. 1A). == Fig. 1. == Characterization of the components of cooperative nanosystems. (A) Schematic showing the components of the two cooperative nanomaterials systems used in this study. The first component consists of gold nanorods (NR), which act as a photothermal sensitizer. The second component consists of either magnetic nanoworms (NW), or doxorubicin-loaded liposomes (LP). Irradiation of the NR with a NIR laser induces localized heating that stimulates changes in the tumor environments. The NW or LP components decorated with LyP-1 tumor targeting peptides bind to the heat-modified tumor environments more efficiently than to the normal tumor environments. Transmission electron microscope images of all three components are shown. Scale bars indicate 50 nm. (B) Heat changes induced by localized.