M@C(60) and related endohedral metallofullerenes comprise a significant portion of the metallofullerene yield in the traditional arc synthesis, but their chemistry and potential applications have been largely overlooked because of their sparse solubility. In this work, procedures are described to solublize Gd@C(60) species for the first time by forming the derivative, Gd@C(60)[C(COOCH(2)CH(3))(2)](10), and its hydrolyzed water-soluble form, Gd@C(60)[C(COOH)(2)](10). Imparting water solubility to Gd@C(60) permits its evaluation as a magnetic resonance imaging (MRI) contrast agent. Relaxometry measurements for Gd@C(60)[C(COOH)(2)](10) reveal it to possess a relaxivity (4.6 mM(-1) s(-1) at 20 MHz and 40 degrees C) comparable to that of commercially available Gd(III) chelate-based MRI agents. An in vivo MRI biodistribution study in a rodent model reveals Gd@C(60)[C(COOH)(2)](10) to possess the first non-reticuloendothelial system (RES) localizing behavior for a water-soluble endohedral metallofullerene species, consistent with its lack of intermolecular aggregation in solution as determined by light-scattering measurements. This first derivatization and use of a M@C(60) species suggests new potential for metallofullerene technologies by reducing reliance on the chromatographic purification procedures normally employed for the far less abundant M@C(82) and related endohedrals. The recognition that water-soluble fullerene derivatives can be designed to avoid high levels of RES uptake is an important step toward fullerene-based pharmaceutical development.

Targeted drug delivery aims to increase the therapeutic index by making more drug molecules available at the diseased sites while reducing systemic drug exposure. In this update, we provide an overview of polymer-drug conjugates that have advanced into the clinical trials. These systems use synthetic water-soluble polymers as the drug carriers. The preclinical pharmacology and recent data in clinical trials with poly(L-glutamic acid)-paclitaxel (PG-TXL) are discussed first. This is followed by a summary of conjugates of a variety of polymeric conjugates with chemotherapeutic agents. Results from early clinical trials of these polymer-drug conjugates have demonstrated several advantages over the corresponding parent drugs, including fewer side effects, enhanced therapeutic efficacy, ease of drug administration, and improved patient compliance. Collectively, these data warrant further clinical development of polymer-drug conjugates as a new class of anticancer agents.

Doxorubicin (Adriamycin) was administered by continuous infusion to reduce peak plasma levels and thus lessen cardiac toxicity. Cardiotoxicity was monitored by noninvasive methods, and endomyocardial biopsy specimens were studied by electronmicroscopy. Cardiotoxicity was compared in 21 patients receiving doxorubicin intravenously over 48 or 96 hours and in 30 control patients treated by standard intravenous injection. Both groups were studied prospectively and were well matched by risk factors for doxorubicin cardiotoxicity. The median cumulative dose for those receiving continuous infusion was 600 mg/m2 body surface area (range, 360 to 1500 mg/m2) compared with 465 mg/m2 (range 290 to 680 mg/m2) in the control group (p = 0.002). Fourteen of the 30 patients in the control group showed severe morphologic changes in the biopsy specimens, precluding further doxorubicin administration, as compared with two of 21 patients receiving the drug by continuous infusion (p less than 0.02). The mean pathologic score for the infusion group, 0.9, was lower than the mean for the control group, 1.6 (p = 0.004). Antitumor activity was not compromised. Decreasing peak plasma levels of doxorubicin by continuous infusion reduces cardiotoxicity.

This study indicates that the distribution to tumor tissue was enhanced when [3H]TXL was administered as a macromolecular conjugate, and that free TXL was released and maintained within the tumor for a prolonged period. Thus, the antitumor activity of PG-TXL observed in preclinical studies may be attributed in part to enhanced tumor uptake of PG-TXL.

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BACKGROUND Giant cell tumors of the bone can behave as aggressive and sometimes lethal tumors. In the sacrum, the tumor can be extremely difficult to manage. Standard treatments, including surgery and radiation, are associated with significant complications and recurrence rates. The goal of this study is to evaluate the long‐term outcome of selective arterial embolization as an alternative treatment modality. METHODS From 1975 to 2001, 18 patients were treated with selective intraarterial embolization. The embolization method was a combination of Gelfoam particles and coils for peripheral and central occlusions, respectively. The number of embolizations was based on clinical symptoms, radiographic response, and the vascularity of the tumor. Nine patients received intraarterial cisplatin as part of their treatment. The median follow‐up was 105 months. RESULTS Of 18 patients, 14 responded favorably to embolization with improvement in pain and neurologic symptoms. Computed tomographic and magnetic resonance imaging scans showed reossification and stabilization of tumor size. Arteriograms showed diminished vascularity. With long‐term follow‐up, three patients developed late disease recurrences within the sacrum. Kaplan–Meier analysis showed that the risk of local recurrence is 31% at 10 years and 43% at 15 and 20 years. The long‐term outcome was not affected by intraarterial cisplatin. There was one death that occurred 1 day after embolization. CONCLUSIONS Most patients demonstrate an objective early radiographic response to embolization. Long‐term follow‐up shows that the response is durable in approximately one half of the patients. Given the potential morbidity of other treatments, embolization should be included in the armamentarium of treatment for this difficult disease. Embolization may be used alone or in conjunction with other therapy. Long‐term follow‐up is recommended for all patients because late disease recurrence or sarcomatous change can occur. Cancer 2002;95:1317–25. © 2002 American Cancer Society. DOI 10.1002/cncr.10803

Hepatic artery collaterals in 40 patients who had had hepatic artery occlusion following peripheral or central embolization, surgical ligation, intra-arterial chemotherapy, or intimal injury from catheterization were studied. The collaterals were classified as intrahepatic or extrahepatic collaterals. Intrahepatic arterial collaterals develop in the portal triads and subcapsular area between the lobes of the liver. Extrahepatic arterial collaterals develop in the ligaments that suspend the liver in the peritoneal cavity and through the structures that are closely attached to the liver. A simplified angiographic classification of hepatic arterial collaterals is presented.

Seventy-two hepatic artery embolizations were performed in 47 patients to treat hepatic neoplasms. Hepatic artery embolization creates tumor devascularization, but the portal flow prevents infarction of liver parenchyma because of the single vascular supply from the hepatic artery to a neoplasm, in contrast to the dual vascular supply to the liver parenchyma. Indications for the use of hepatic artery embolization are failure of chemotherapy, either systemic or intra-arterial infusion, vascular anomalies requiring combined lobar embolization and lobar infusion, and lack of effective treatment. Three types of embolization were performed: peripheral embolization using Gelfoam, proximal embolization using coils, and combined peripheral and proximal embolization. The complications after embolization were pain, fever, and transient liver function changes. No death or hepatic abscess occurred. The median survival duration of the group was 11.5 months from the time of embolization. Hepatic artery embolization is an effective treatment of hepatic neoplasm.