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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 NPs 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 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 and NF NP 30 and 100 nm were conjugated to (111)In-DOTA-ChL6, a radioimmunoconjugate. Radioimmunoconjugates were conjugated to NPs using 25 microg of RIC/mg of NP by carbodiimide chemistry. The radioimmunonanoparticles (RINP) were purified and 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 h. The preparations used for animal study were90% monomeric by PAGE and CAE. The immunoreactivity of the RINP was 40-60% compared to (111)In-ChL6. Specific activities of the doses were 20-25 microCi/2.2 mg and 6-11 microg of mAb/2.2 mg of NP. Mean tumor uptakes (% ID/g +/- SD) of each SPIO 20 nm, NF 30 nm, and 100 nm RINP at 48 h were 9.00 +/- 0.8 (20 nm), 3.0 +/- 0.3 (30 nm), and 4.5 +/- 0.8 (100 nm), 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.

Purpose: Radioactivity deposition in normal tissues limits the dose deliverable by radiopharmaceuticals (RP) in radioimmunotherapy (RIT). This study investigated the absorbed radiation dose in normal tissues for prostate cancer patients in comparison to breast cancer patients for 2 RPs using the monoclonal antibody (MAb) m170. Methods and Materials: 111 In-DOTA-glycylglycylglycyl-l-p-isothiocyanatophenylalanine amide (GGGF)-m170 and 111 In-1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA) 2-iminothiolane (2IT)-m170, representing the same MAb and chelate with and without a cleavable linkage, were studied in 13 breast cancer and 26 prostate cancer patients. Dosimetry for 90 Y was calculated using 111 In MAb pharmacokinetics from the initial imaging study for each patient, using reference man– and patient-specific masses. Results: The reference man–specific radiation doses (cGy/MBq) were not significantly different for the breast and the prostate cancer patients for both RPs in all but one tissue-RP combination (liver, DOTA-2IT). The patient-specific doses had differences between the groups most of which can be related to weight differences. Conclusions: Similar normal tissue doses were calculated for two groups of patients having different cancers and genders. This similarity combined with continued careful analysis of the imaging data might allow the use of higher starting doses in early phase RIT studies.

Purpose: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer. Experimental Design: Patients were imaged with indium-111 (111In)-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-peptide-m170. One week later, yttrium-90 (90Y)-m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody. Results: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine. Conclusions: 111In/90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, “fractionated” therapy that could enhance clinical response.

Purpose: Paclitaxel synergized radiolabeled monoclonal antibodies, enhancing therapeutic effect in studies in mice with human xenografts. Paclitaxel was also observed to increase tumor uptake in imaging studies of 111In-DOTA-Gly3Phe-m170 in patients with breast and prostate cancers. Further evaluations of tissue-cumulated activities, therapeutic indices, and pharmacokinetics were done using data for patients with breast and prostate cancer and for mice with human breast cancer xenografts. Experimental Design: In radioimmunotherapy trials, 12 patients with breast or prostate cancer were given two imaging doses (5 mCi each) of 111In-DOTA-Gly3Phe-m170 1 week apart. Five of these patients were given a single dose of paclitaxel i.v. (75 mg/m2) 2 days after the second dose of 111In. In a subsequent study, athymic mice with human breast cancer xenografts were given 111In-DOTA-Gly3Phe-ChL6 alone, or in combination with daily paclitaxel i.p. (300 μg) one or more times. Pharmacokinetics were studied for at least 6 days in patients and 5 days in mice. Cumulated activities were determined for tumors and normal tissues. Results: Tumor-cumulated activity for every patient in the paclitaxel-treated group increased for the second dose of 111In-DOTA-Gly3Phe-m170. The median ratio of cumulated activities in tumors for imaging dose 2 to those for dose 1 was 1.0 (0.8-1.3) in patients that were not given paclitaxel and 1.3 (1.2-1.4) in patients given paclitaxel. Normal tissue-cumulated activities were not different for the two doses. Mice given paclitaxel 1 day after 111In-DOTA-Gly3Phe-ChL6 also showed an increase in tumor-cumulated activity, 22.9 (± 1.3) versus 19.4 (± 3.3) μCi h/g/μCi (P = 0.05). Cumulated activities of normal tissues were similar for all groups of mice. Conclusions: Paclitaxel given 1 to 2 days after 111In-DOTA-Gly3Phe-monoclonal antibody increased the tumor-cumulated activity in patients and in mice with epithelial cancers and did not alter cumulated activities in normal tissues.

Purpose: New strategies that target selected molecular characteristics and result in an effective therapeutic index are needed for metastatic, hormone-refractory prostate cancer. Experimental Design: A series of preclinical and clinical studies were designed to increase the therapeutic index of targeted radiation therapy for prostate cancer. 111In/90Y-monoclonal antibody (mAb), m170, which targets aberrant sugars on abnormal MUC1, was evaluated in androgen-independent prostate cancer patients to determine the maximum tolerated dose and efficacy of nonmyeloablative radioimmunotherapy and myeloablative combined modality radioimmunotherapy with paclitaxel. To enhance the tumor to liver therapeutic index, a cathepsin degradable mAb linkage (111In/90Y-peptide-m170) was used in the myeloablative combined modality radioimmunotherapy protocol. For tumor to marrow therapeutic index improvement in future studies, anti-MUC1 scFvs modules were developed for pretargeted radioimmunotherapy. Anti-MUC1 and anti-DOTA scFvs were conjugated to polyethylene glycol scaffolds tested on DU145 prostate cancer cells and prostate tissue arrays, along with mAbs against MUC1 epitopes. Results: The nonmyeloablative maximum tolerated dose of 90Y-m170 was 0.74 GBq/m2 for patients with not more than 10% axial skeleton involvement. Metastatic prostate cancer was targeted in all 17 patients; mean radiation dose was 10.5 Gy/GBq and pain response occurred in 7 of 13 patients reporting pain. Myeloablative combined modality radioimmunotherapy with 0.4 GBq/m2 of 90Y-peptide-m170 and paclitaxel showed therapeutic effects in 4 of 6 patients and 30% less radiation to the liver per unit of activity. Neutropenia was dose limiting without marrow support and patient eligibility was a major limitation to dose escalation. Hypoglycosylated MUC1 epitopes were shown to be abundant in prostate cancer and to increase with disease grade. Anti-MUC1 scFvs binding to prostate cancer tissue and live cells were developed into di-scFv binding modules. Conclusions: The therapeutic index enhancement for prostate radioimmunotherapy was achieved in clinical studies by the addition of cathepsin cleavable linkers to 90Y-conjugated mAbs and the use of paclitaxel. However, the need for marrow support in myeloablative combined modality radioimmunotherapy restricted eligible patients. Therefore, modular pretargeted radioimmunotherapy, aiming at improving the tumor to marrow therapeutic index, is being developed.

Myelotoxicity can be ameliorated by peripheral blood stem cell (PBSC) infusion. Continuous irradiation by radioactivity retained in the body after high-dose radioimmunotherapy can damage PBSCs if they are transfused too early. Previously, infusion time was predetermined using the radioactivity concentration in the blood. This study proposes to plan PBSC infusion time based on noninvasive dosimetry that considers damage of PBSCs during PBSC circulation and residence in organs with high radioactivity.The method considers a time-varying distribution of PBSCs and radioactivity in tissues. Five breast cancer patients received (111)In-2IT-BAD-m170 for imaging, and 3 of the 5 received high doses of (90)Y-2IT-BAD-m170 therapy followed by PBSC infusion. (90)Y concentrations in tissues were extrapolated from quantitative imaging of (111)In, and (90)Y blood concentrations were determined from (90)Y in serial blood samples. The radiation dose to PBSCs was determined by time integration of the organ dose rate and PBSC distribution rate. The radiosensitivity of PBSCs was determined by measuring survival of granulocyte-macrophage colony-forming units with (90)Y in cell culture.The mean effective half-life of (90)Y within the imaging period (up to 6 d) was 3.7 d for liver, 2.4 d for spleen, 2.1 d for kidneys, 1.8 d for lungs, and 1.6 d for blood. The survival fractions of PBSCs in patients were determined as functions of the infusion time and the injected dose of (90)Y-2IT-BAD-m170. To achieve 90% PBSC survival rate for a 2.0-GBq injection dose, PBSC dosimetry suggested a time interval of 13 d after radioimmunotherapy for PBSC infusion. In contrast, the simple blood concentration method suggested an interval about 7 d for the same PBSC survival rate. In our clinical practice, an interval of 2 wk has been used and worked well.A noninvasive dosimetry method was developed for optimizing the time interval for PBSC infusion after high-dose radionuclide therapy. Our studies suggested that the PBSC dosimetry method was more effective than the blood concentration method in determining the optimal time to reinfuse PBSCs for radiopharmaceuticals that have much a higher activity concentration in organs than that in the blood.

Radioimmunoimaging and radioimmunotherapy with radioiodinated anti-(hepatocellular carcinoma ferritin) antibody (131I- or 125I-FtAb) have been applied in patients with primary liver cancer. A total of 41 patients with surgically unresectable hepatocellular carcinoma (HCC) and receiving hepatic artery ligation and cannulation during exploratory laparotomy were treated with this regimen by intrahepatic arterial infusion. Compared with the control group, a decline of serum alpha-fetoprotein (65.7% versus 42.9%) and shrinkage of tumor (68.3% versus 33.9%) were observed in the treated group, and a higher second-look resection rate (31.7% versus 5.1%) and longer survival (1-year: 61.0% versus 37.3%, 3-year: 25.0% versus 6.9%) resulted. The administration of antibody through a hepatic arterial catheter (n = 16) was compared with intravenous injection (n = 17) in terms of the tumor-imaging sensitivity in 33 patients with liver cancer. The results indicated that hepatic arterial infusion was superior to intravenous injection. The sensitivity 7 days after the administration was 100% in the i.a. group and 76.5% in the i.v. group, the uptake ratio of tumor to liver being 1.74 +/- 0.57 in the former and 1.34 +/- 0.29 in the latter. Furthermore, intrahepatic arterial infusion revealed a lower anti-antibody detection rate than intravenous injection (0/14 versus 4/11).