Dextran and PEG coated iron oxide nanoparticles (NP), when suitably modified to enable conjugation with molecular targeting agents, provide opportunities to target cancer cells. Monoclonal Antibodies, scFv, and peptides conjugated to 20-nm NP have been reported to target cancer for imaging and alternating magnetic field (AMF) therapy. The physical characteristics of NP's can affect their in vivo performance. Surface morphology, surface charge density, and particle size are considered important factors that determine pharmacokinetics, toxicity, and biodistribution. New NanoFerrite (NF) particles having improved specific AMF absorption rates and diameters of 30 nm and 100 nm were studied to evaluate the variation in their in vitro and in vivo characteristics in comparison to the previously studied 20 nm Superparamagnetic Iron Oxide (SPIO) NP. SPIO NP 20-nm, NF NP 30-and 100-nm were conjugated to 111 In-DOTA-ChL6, a radioimmunoconjugate. Radioimmunoconjugates were conjugated to NP's using 25μg of RIC/mg of NP by carbodiimide chemistry. The radioimmunonanoparticles (RINP) were purified characterized by PAGE, cellulose acetate electrophoresis (CAE), live cell binding assays, and pharmacokinetics in athymic mice bearing human breast cancer (HBT 3477) xenografts. RINP (2.2 mg) were injected iv and whole body, blood and tissue data were collected at 4, 24, and 48 hours. The preparations used for animal study were >90% monomeric by PAGE and CAE. The immunoreactivity of the RINP was 40−60% compared to 111 In-ChL6. Specific activities of the doses were 20−25μCi/2.2 mg and 6−11μg of MAb/2.2 mg of NP. Mean tumor uptakes (% ID/g ± SD) of each SPIO 20nm, NF 30nm, and 100nm RINP at 48h were 9.00 ± 0.8 (20nm), 3.0 ± 0.3 (30nm), and 4.5 ± 0.8 (100nm) respectively; the ranges of tissue uptakes were liver (16−32 ± 1 − 8), kidney (7.0−15 ± 1) spleen (8−17 ± 3 − 8) lymph nodes 5 − 6 ± 1 −2) and lung (2.0− 4 ± 0.1 − 2). In conclusion, this study demonstrated that 100 nm NF NP could be conjugated to 111 In-MAb so that the resulting RINP had characteristics suitable for AMF therapy. Although 100-nm RINP targeted tumor less than 20-nm SPIO RINP, their heating capacity is typically 6 times greater, suggesting the 100-nm NF RINP could still deliver better therapy with AMF.

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We have developed radiolabeling and quality control procedures for melanin-binding (188)Re-6D2 mAb which made possible currently an on-going Phase I clinical trial in patients with metastatic melanoma.

Purpose: More than two decades of research and clinical trials have shown radioimmunotherapy to be a promising approach for treating various forms of cancer. Lym-1antibody, which binds selectively to HLA-DR10 on malignant B-cell lymphocytes, has proved to be effective in delivering radionuclides to non^Hodgkin's lymphoma and leukemia. Using a new approach to create small synthetic molecules that mimic the targeting properties of the Lym-1antibody, a prototype, selective high-affinity ligand (SHAL), has been developed to bind to a unique region located within the Lym-1epitope on HLA-DR10. Experimental Design: Computer docking methods were used to predict two sets of small molecules that bind to neighboring cavities on the h subunit of HLA-DR10 surrounding a critical amino acid in the epitope, and the ligands were confirmed to bind to the protein by nuclear magnetic resonance spectroscopy. Pairs of these molecules were then chemically linked together to produce a series of bidentate and bisbidentate SHALs. Results: These SHALs bind with nanomolar to picomolar K d 's only to cell lines expressing HLA-DR10. Analyses of biopsy sections obtained from patients also confirmed that SHAL bound to both small and large cell non^Hodgkin's lymphomas mimicking the selectivity of Lym-1. Conclusions: These results show that synthetic molecules less than 1/50th the mass of an antibody can be designed to exhibit strong binding to subtle structural features on cell surface proteins similar to those recognized by antibodies.This approach offers great potential for developing small molecule therapeutics that target other types of cancer and disease.

Despite effective therapies for non-Hodgkin's lymphoma (NHL), the majority of patients are not cured. Radioimmunotherapy (RIT) has shown good results in preclinical and clinical trials even in patients that are non-responsive to standard chemotherapy. To make RIT more effective, agents such as paclitaxel (Taxol), that can enhance radiation effects, are being tested. Nude mice bearing human Burkitt's lymphoma (Raji) xenografts were treated with: 1) 150 or 200 microCi (5.5 or 7.3 MBq) of 90Y-2IT-BAD-Lym-1 alone, 2) 600 micrograms of Taxol alone, 3) 150 or 200 microCi of 90Y-2IT-BAD-Lym-1 plus 600 micrograms of Taxol given 24 hours after RIT, or 4) no treatment. Tumor size, survival, mouse weight and blood counts were monitored to assess efficacy and toxicity. Survival for mice treated in this 84 day trial was: 71% for 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol, 29% for Taxol alone, 6% for 90Y-2IT-BAD-Lym-1 (200 microCi) alone and 14% in the untreated group. Average tumor volume in the 90Y-2IT-BAD-Lym-1 (200 microCi) plus Taxol group was reduced by 89 and 99% compared to the RIT alone and Taxol alone groups, respectively. Mice treated with 150 microCi had less toxicity than those treated with 200 microCi of 90Y-2IT-BAD-Lym-1, however, the higher radiation dose, and Taxol, were required for improved survival. Mouse weights and myelotoxicity in the combined modality (RIT plus Taxol) groups were similar to those receiving the same dose of RIT alone. In the Raji tumored nude mouse model, addition of Taxol to 90Y-2IT-BAD-Lym-1, in doses clinically achievable in humans, provided therapeutic synergy without increased or excessive toxicity.