7-Ethyl-10-hydroxy-camptothecin (SN-38), a biological active metabolite of irinotecan hydrochloride (CPT-11), has potent antitumor activity but has not been used clinically because it is a water-insoluble drug. For delivery by i.v. injection, we have successfully developed NK012, a SN-38-releasing nanodevice. The purpose of this study is to investigate the pharmacologic character of NK012 as an anticancer agent, especially in a vascular endothelial growth factor (VEGF)-secreting tumor model. The particle size of NK012 was f20 nm with a narrow size distribution. NK012 exhibited a much higher cytotoxic effect against lung and colon cancer cell lines as compared with CPT-11. NK012 showed significantly potent antitumor activity against a human colorectal cancer HT-29 xenograft as compared with CPT-11. Enhanced and prolonged distribution of free SN-38 in the tumor was observed after the injection of NK012. NK012 also had significant antitumor activity against bulky SBC-3/Neo (1,533

Purpose: We conducted a first-in-human phase I study to determine the dose-limiting toxicity (DLT), evaluate the pharmacokinetic profile, and document any antitumor activity of NK012, a novel SN-38-incorporating micellar nanoparticle.Experimental Design: Patients with solid tumors refractory to standard therapy, or for which no standard therapy is available, were enrolled. NK012 was administered as a 30-minute infusion every 3 weeks. The starting dose was 2 mg/m 2 as SN-38 equivalent, and an accelerated titration schedule was used. Pharmacokinetic analysis was conducted in cycles 1 and 2. Results: Twenty-four patients were enrolled in the study. No UGT1A1*28 homozygous patients were enrolled. Predominant toxicity was neutropenia. Nonhematologic toxicity, especially diarrhea, was mostly grade 1 or 2 during study treatments. Two of nine patients had DLT during cycle 1 at the 28 mg/m 2 dose level. DLTs were mostly neutropenia or a related event. Polymer-bound SN-38 (NK012) and SN-38 released from NK012 were slowly eliminated from the plasma, with a terminal-phase half-life of approximately 140 and 210 hours, respectively. Systemic exposure to both polymer-bound SN-38 and SN-38 increased in proportion to the dose. A refractory esophageal cancer patient and a lung carcinoid tumor patient had an objective response and continued the study treatment for 5 and 12 months, respectively.Conclusions: NK012 was well tolerated and showed antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing. Clin Cancer Res; 16(20); 5058-66. ©2010 AACR.Irinotecan hydrochloride (CPT-11) has proven to be active against colorectal, lung, and ovarian cancers (1-5). CPT-11 is a prodrug that is converted to a biologically active metabolite, 7-ethyl-10-hydroxy-CPT (SN-38), by carboxylesterase (CE) enzymes. SN-38 is an analogue of the plant alkaloid camptothecin, which targets DNA topoisomerase I. Compared with CPT-11, SN-38 exhibits up to 1,000-fold more potent cytotoxic activity against various cancer cells in vitro (6). Although CPT-11 is converted to SN-38 in the liver and tumor, the metabolic conversion rate is <10% of the original volume of 8). Moreover, the conversion of CPT-11 to SN-38 depends on the genetic interindividual variability of CE activity (9). Thus, more efficient use of SN-38 might be highly advantageous and quite attractive for cancer treatment.Drugs categorized under the drug delivery system (DDS) are made primarily by using nanotechnology (10). In the field of oncology, DDS drugs have been produced and evaluated in preclinical or clinical trials, with some already approved for clinical use (11,12). NK012 categorized in DDS is a micelle-forming macromolecular prodrug prepared by binding SN-38 to the polyglutamate of a block copolymer via an ester bond (Fig. 1). The amphiphilic block copolymers consist of polyethylene glycol and partially SN-38-bound polyglutamate. Polyethylene glycol is hydrophilic a...

MCC-465 was well tolerated. The recommended dose for a phase II study of MCC-465, for a 3-week schedule, is considered to be 32.5 mg/m2 in an equivalent amount of DXR.

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A platinum-based intermetallic phase with an early d-metal, Pt(3)Ti, has been synthesized in the form of nanoparticles (NPs) dispersed on silica (SiO(2)) supports. The organometallic Pt and Ti precursors, Pt(1,5-cyclooctadiene)Cl(2) and TiCl(4)(tetrahydrofuran)(2), were mixed with SiO(2) and reduced by sodium naphthalide in tetrahydrofuran. Stoichiometric Pt(3)Ti NPs with an average particle size of 2.5 nm were formed on SiO(2) (particle size: 20-200 nm) with an atomically disordered FCC-type structure (Fm3m; a = 0.39 nm). A high dispersivity of Pt(3)Ti NPs was achieved by adding excessive amounts of SiO(2) relative to the Pt precursor. A 50-fold excess of SiO(2) resulted in finely dispersed, SiO(2)-supported Pt(3)Ti NPs that contained 0.5 wt % Pt. The SiO(2)-supported Pt(3)Ti NPs showed a lower onset temperature of catalysis by 75 degrees C toward the oxidation reaction of CO than did SiO(2)-supported pure Pt NPs with the same particle size and Pt fraction, 0.5 wt %. The SiO(2)-supported Pt(3)Ti NPs also showed higher CO conversion than SiO(2)-supported pure Pt NPs even containing a 2-fold higher weight fraction of Pt. The SiO(2)-supported Pt(3)Ti NPs retained their stoichiometric composition after catalytic oxidation of CO at elevated temperatures, 325 degrees C. Pt(3)Ti NPs show promise as a catalytic center of purification catalysts for automobile exhaust due to their high catalytic activity toward CO oxidation with a low content of precious metals.