Recently, questions have emerged regarding whether anticancer drug development is headed in the right direction and whether opportunities that are off the accepted path are being overlooked . Largely due to the increasing insight into the series of mutations associated with the development of cancer, drug development has moved into the "molecular target" area. There have been initial successes (e.g. imatinib mesylate for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors); however, the genetic complexity and diversity of tumor cells, including the occurrence of cancer stem cells, have prevented molecular targeting from becoming universally successful. Because the progression of a normal cell to a cancer cell involves numerous genetic mutations, targeting one or even several gene products may be ineffective. Furthermore, many biological processes feature alternate pathways which can be upregulated, if needed, thus thwarting molecularly targeted therapies . To overcome these obstacles, a successful cancer therapy has to combine several approaches. Molecular targeting can be a viable component of this methodology. However, other approaches, such as stem cell delivery, hyperthermia, photodynamic therapy, and the design of multifunctional platforms that combine cancer diagnostics and treatment (theranostics) have not received full attention during the last decade.
We and others are working toward cost-effective treatment methods based on non-conventional combinations of known and proven techniques. We asked whether it is possible to achieve cancer localization by using porphyrin labels for the delivery of iron-containing superparamagnetic nanoparticles to tumor tissue. Tumor cells selectively uptake porphyrins, which they need as prosthetic groups in their elevated sugar metabolism, via over-expression of porphyrin receptors in their cell membranes . There is a strong positive correlation between the cell uptake of a variety of chemically defined, synthetic and natural porphyrins and their octanol/water distribution coefficients [3, 4]. These findings support the paradigm that there indeed exists a porphyrin uptake mechanism other than endocytosis in cancer cells. The LDL (lowdensity lipoprotein) receptor, which is over-expressed in cancer cells, has the ability to take up porphyrins as well, either alone or simultaneously with other porphyrin receptors. Localized hyperthermia is a powerful therapeutic modality. When administered selectively, hyperthermia treatment can be very potent against many types of cancer because it is not based on the intake of drugs by cancer cells, but on the application of heat. When heated to 45°C, vital proteins of the cancer cell become damaged (e.g. misfolded) and/or the cell membrane partially dissolves in the surrounding aqueous medium . A multitude of heat-induced deviations from the "normal" metabolism of a cancer cell can eventually lead to apoptosis (programmed cell death). Although many cancer types are slightly more susceptible to hyperthermia than healthy cells, the latter essentially share the same fate when heated . Therefore, the development of methods to localize hyperthermia to cancer cells remains one of the challenges in this field. This is important when attempting to treat solid tumors within the human body as well as for treatment of metastasizing cancers. The use of tethered porphyrins as "bait" may provide an effective (and low cost) alternative to using antibodies for getting magnetic nanoparticles effectively into tumors, which is currently a common tumor targeting method.
Magnetic nanoparticles dump thermal energy into the system, therefore providing heating (magnetic hyperthermia) . Heating takes place by power absorption of magnetic particles due to an A/C magnetic field . The important factor for magnetic heating experiments is the specific absorption rate (SAR), which is determined by SAR = C × ΔT/Δt, where C is the specific heat capacity of the sample and T and t are the temperature and time, respectively. SAR is very sensitive to the material properties. While in multi-domain particles the dominant heating is hysteresis loss due to the movement of domain walls, this is not the case with small, single domain particles. The two main contributing mechanisms of SAR in single domain magnetic NPs are the Brownian (rotation of the entire nanoparticle) and Néel (random flipping of the spin without rotation of the particle) relaxations [9, 10]. The transition between the two mechanisms occurs between 5-12 nm for various materials, but it also varies with frequency 
Melanoma incidence has reached almost epidemic proportions worldwide. When it is present as disseminated metastatic disease it is not curable using current clinical tools; traditional chemotherapy is often ineffective due to inherent drug resistance . We have selected the B16-F10 melanoma model in syngeneic C57BL/6 female mice because this type of melanoma has proven to be quite resistant to treatment. In order to evaluate the efficacy of hyperthermia treatment against cancer, we did not want to select a less resistant cancer cell line/host system. In addition, since hyperthermia often enhances the immune response, an immunocompetent host was desirable.
In the work reported here, we have used (bi)magnetic iron/iron oxide core/shell nanoparticles, synthesized by NanoScale Corporation (Manhattan, KS), for A/C (alternating current)-magnetic cancer therapy, because they exhibit superior properties in several areas: The nanoscopic size (d<15 nm) of the stealth-protected Fe/Fe3O4 core/shell nanoparticles will permit passive tumor targeting from the bloodstream by using the EPR (enhanced permeation and retention) effect [13, 14]. In addition, we surmise that our porphyrin coating may enhance MNP uptake in tumors, because cancer cells are in constant need of porphyrins as prosthetic groups in their elevated sugar metabolism  and overexpress the LDL(low-density lipoprotein) receptor. This remains an area for future clarification. Here, we compared the effects of intratumoral (IT) and intravenous (IV) core/shell porphyrin-tethered nanoparticle treatment followed by A/C exposure on B16-F10 melanoma growth in a mouse model.