NanoCarrier (Japan)

Abstract Purpose: The abnormal function of tumor blood vessels causes hypoxia fueling disease progression and conferring treatment resistance. The local level of oxygen experienced by a cell will determine its response, making it critical to understand tissue oxygen levels with a spatial resolution on the order of the size of a cell. While microenvironment normalization strategies alleviate global hypoxia, how local oxygen levels change are not known because there are no in vivo techniques to longitudinally assess tumor vessels and interstitial oxygen in tumors with sufficient resolution. Understanding the heterogeneity of oxygen levels after microenvironmental normalization will help improve the efficacy of various normalization strategies. Experimental Design: We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular weight palladium porphyrin probe to measure perfused vessels, oxygen tension and their spatial correlations in vivo in mouse skin, bone marrow, and tumors. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to microenvironmental normalization. Results: We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen carrying ability than normal skin, most tumors had inefficient vessels. Further, inter-vessel heterogeneity in tumors coincided with heterogeneous response to microenvironmental normalizing agents. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persist, even with global reductions in hypoxia. Conclusions: We present the first study to examine the high-resolution spatial and temporal response of tumor vessels to two agents known to improve vascular perfusion globally. Our measurements demonstrate that the heterogeneities in the local imbalance of pro- and anti-angiogenic signaling lead to spatially heterogeneous changes in vessel structure and function. Microscale dynamic vascular changes should be considered in optimizing the dose and schedule of microenvironment normalizing therapies to improve function. Citation Format: John Martin, Ryan Lanning, Dai Fukumura, Timothy Padera, Rakesh Jain. Multiphoton phosphorescence quenching microscopy reveals kinetics of tumor oxygenation during anti-angiogenesis and angiotensin signaling inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB557.

La gestión de la información para representar distancias y altimetrías encontradas en los mapas de ruta permite visibilizar datos por medio de tablas, gráficas, fotografías, perfiles e imágenes. A partir de lo anterior surge el siguiente interrogante: ¿Es clara la información de distancias y altimetría en los mapas de ruta para un grupo de usuarios de varios niveles? Para dar respuesta en este artículo se propone un ejercicio investigativo de tipo mixto, en el que se utilizó material cartográfico en formato análogo de cuadros de distancias y perfiles de altimetría de los mapas de ruta Bogotá-Medellín y una encuesta semiestructurada. El objetivo de la investigación fue analizar la lectura en los mapas de ruta de la vía Bogotá-Medellín de 1997, 2006 y 2010 realizada por un grupo de usuarios e indagar la claridad, dificultad y formas de lectura de los cuadros de distancias y perfiles de altimetría.

This study aimed to examine whether DC101 (anti-VEGFR2 antibody)- modified micelles have applications as novel drug delivery devices, which allow small molecule antiangiogenic agents to deliver to angiogenic sites on a murine laser-induced choroidal neovascularization (CNV) model. CNV was induced by photocoagulation on the unilateral eye of each mouse under anesthesia. Immediately after laser coagulation, E7974-loaded DC101-modified micelles and motesanib-loaded DC101-modified micelles were intravitreally administrated. Two weeks after photocoagulation, CNV was visualized using fluorescein-conjugated dextran (MW=2,000 kDa), and the CNV area was measured in retinal pigment epithelium (RPE)-choroidal flat mounts. Intravitreal administration of both DC101-modified micelles loaded with E7974 at 2 µM and motesanib at 2 µM significantly reduced CNV area in the murine laser-induced CNV model at a clearly lower concentration than the effective dose of each agent. These results suggest that DC101-modified micelle might be effective drug carrier system for treating CNV and other ocular angiogenic diseases.

Purpose: NC-6004, a novel cisplatin nanoparticle developed using micellar technology exhibits sustained release of cisplatin and selective distribution to tumors. Preclinical data demonstrated a favorable tolerability profile and preserved or improved antitumor activity compared with cisplatin across animal models. We evaluated the safety and tolerability of NC-6004 and gemcitabine using a Bayesian continual reassessment model (N-CRM) to determine the optimal dose.Experimental Design: Patients with advanced solid tumors received NC-6004 at 60 to 180 mg/m2 on day 1 and gemcitabine at 1,250 mg/m2 on days 1 and 8 every 3 weeks. Dose escalation of NC-6004 began with a single patient run-in until a dose-limiting toxicity occurred at 180 mg/m2 Cohorts of four patients were enrolled at doses predicted by the N-CRM. The maximum tolerated dose (MTD) was defined as having the greatest probability of target toxicity <25%. Quality of life was assessed using EORTC-QLQ-C30.Results: Among 22 patients, the most common grade III/IV hematologic adverse events were leukopenia (68%) and thrombocytopenia (59%). Of 20 pretreated patients evaluable for response, half were previously exposed to a platinum agent. The MTD was 135 mg/m2 Nine patients were treated at the MTD with median treatment duration of 15 weeks (range, 3-50). Tumor shrinkage occurred in 11 (55%), partial responses in 3 (15%), and stable disease in 14 (70%). Most patients reported stable or improved EORTC QLQ-C30 scores.Conclusions: Greater cisplatin equivalent doses were achieved with no clinically significant neuro-, oto-, or nephrotoxicity. These data demonstrate tolerability and promising activity of NC-6004 in combination with gemcitabine. Clin Cancer Res; 24(1); 43-51. ©2017 AACR.

Abstract Background: Antibody-drug conjugates (ADCs) have been recognized as a promising anticancer agent. There have been a lot of registered clinical trials for ADCs. However, not all ADC compounds were successful. To overcome the difficulties and drive the next generation of ADCs, we have recently developed Antibody/Drug-Conjugated Micelle (ADCM) system. ADCM is composed of polyethylene glycol-poly (amino acid derivative) polymers, which can form a micellar nanoparticle spontaneously in aqueous media with a diameter of 20-100 nm. Antibodies are attached to the surface of the nanoparticle, while payloads are incorporated in the inner core at a payload-to-antibody molecular ratio of 100-200. In this study, anti-EGFR monoclonal antibody NCAB001 and novel hemiasterlin analogue E7974 were used as a targeting sensor and a payload of the ADCM (NC-6201), respectively. Here we report the results of in vitro evaluation and in vivo efficacy and toxicity studies. Methods: NC-6201 was prepared as described previously (Japan Patent No.4538666) with slight modification. The antigen affinity and the cytotoxicity of NC-6201 were evaluated using a Biacore system and Cell Counting Kit-8, respectively. NC-6201 was administered intravenously to BALB/c-nu/nu mice xenografted with various human tumor cell lines. Tumor volumes and animal body weights were monitored 2 or 3 times a week. Also, the dose- and schedule-dependency of the antitumor effect were evaluated. Single-dosed toxicological studies of NC-6201 in SD rats and cynomolgus monkeys were performed. Results: NC-6201 showed similar antigen affinity to the unconjugated NCAB001 and had a broad range of in vitro cytotoxicity against a panel of tumor cells. NC-6201 potently suppressed tumor growth in nude mice bearing subcutaneous human tumor xenografts expressing EGFR, such as BxPC-3 (pancreas) and MDA-MB-231 (triple-negative breast) tumor models. The efficacious NC-6201 dose schedules were achieved at one tenth or two fifth of its MTD. In an EGFR-null tumor model, NC-6201 and untargeted micelle incorporating E7974 showed comparable tumor growth inhibition. Overall, NC-6201 at efficacious doses was well tolerated without significant body weight loss, indicating that NC-6201 has an excellent therapeutic window. Relative to E7974, NC-6201 showed an unaltered toxicity profile in rats and monkeys, and the potential for reduced toxicity and an improved therapeutic window. Conclusion: Based on these promising results, NC-6201 is advanced in our project pipeline as a clinical candidate for cancer therapy. Citation Format: Mitsunori Harada, Masami Tsuchiya, Ryusuke Miyazaki, Tadashi Inoue, Ryosuke Tanaka, Yuuki Yanagisawa, Masayoshi Ito, Yu Ito, Kenichiro Naito. Preclinical evaluation of NC-6201, an antibody/drug-conjugated micelle incorporating novel hemiasterlin analogue E7974. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1368.

For the creation of a successful antibody–drug conjugate (ADC), both scientific and clinical evidence has indicated that highly toxic anticancer agents (ACA) should be conjugated to a monoclonal antibody (mAb) to administer a reasonable amount of ADC to patients without compromising the affinity of the mAb. For ordinary ACA, the conjugation of a mAb to ACA-loaded micellar nanoparticles is clinically applicable. Tissue factor (TF) is often overexpressed in various cancer cells and tumor vascular endothelium. Accordingly, anti-TF-NC-6300, consisting of epirubicin-incorporating micelles (NC-6300) conjugated with the F(ab')2 of anti-TF mAb was developed. The in vitro and in vivo efficacy and pharmacokinetics of anti-TF-NC-6300 were compared to NC-6300 using two human pancreatic cancer cell lines, BxPC3 (high TF expression) and SUIT2 (low TF expression), and a gastric cancer cell line, 44As3 (high TF expression). The intracellular uptake of epirubicin was faster and greater in BxPC3 cells treated with anti-TF-NC-6300, compared with NC-6300. Anti-TF-NC-6300 showed a superior antitumor activity in BxPC3 and 44As3 xenografts, compared with NC-6300, while the activities of both micelles were similar in the SUIT2 xenograft. A higher tumor accumulation of anti-TF-NC-6300 compared to NC-6300 was seen, regardless of the TF expression levels. However, anti-TF-NC-6300 appeared to be localized to the tumor cells with high TF expression. These results indicated that the enhanced antitumor effect of anti-TF-NC6300 may be independent of the tumor accumulation but may depend on the selective intratumor localization and the preferential internalization of anti-TF-NC-6300 into high TF tumor cells.

2573 Background: NC-6004 contains cisplatin derivatives in micellar nanoparticles. Preclinical activity was seen in platinum resistant cell lines. We report a phase I trial of NC-6004 with doses from 10–120mg/m2 cisplatin equivalent. Methods: NC-6004 dose was escalated in patients with refractory solid tumors according to toxicity with 1 patient per dose level until grade 2 toxicity observed then 3–6 evaluable patients per dose level. Eligible patients had adequate bone marrow, hepatic and renal function. NC-6004 was administered as a 1 hour intravenous infusion on day 1 of a 21 day cycle (C). Patients were monitored for usual dose-limiting toxicities (DLT) and renal function assessed by EDTA GFR. Pharmacokinetics (PK) of cisplatin were characterized by atomic absorption spectrometry for total platinum, micellar component by gel-filtration, inductively-coupled plasma mass spectrometry for free platinum species. Patients were restaged every 2 cycles and treatment continued if clinical benefit and acceptabl...