Radiolabeled liposome imaging determines an indication for liposomal anticancer agent in ovarian cancer mouse xenograft models

Abstract

Liposomal anticancer agents can effectively deliver drugs to tumor lesions, but their therapeutic effects are enhanced in only limited number of patients. Appropriate biomarkers to identify responder patients to these liposomal agents will improve their treatment efficacies. We carried out pharmacological and histopathological analyses of mouse xenograft models bearing human ovarian cancers (Caov‐3, SK‐OV‐3, KURAMOCHI, and TOV‐112D) to correlate the therapeutic effects of doxorubicin‐encapsulated liposome (Doxil®) and histological characteristics linked to the enhanced permeability and retention effect. We next generated 111In‐encapsulated liposomes to examine their capacities to determine indications for Doxil® treatment by single‐photon emission computed tomography (SPECT)/CT imaging. Antitumor activities of Doxil® were drastically enhanced in Caov‐3, moderately in SK‐OV‐3, and minimally in KURAMOCHI and TOV‐112D when compared to doxorubicin. Microvessel density and vascular perfusion were high in Caov‐3 and SK‐OV‐3, indicating a close relation with the enhanced antitumor effects. Next, 111In‐encapsulated liposomes were given i.v. to the animals. Their tumor accumulation and area under the curve values over 72 h were high in Caov‐3, relatively high in SK‐OV‐3, and low in two other tumors. Importantly, as both Doxil® effects and liposomal accumulation varied in the SK‐OV‐3 group, we individually obtained SPECT/CT images of SK‐OV‐3‐bearing mouse (n = 11) before Doxil® treatment. Clear correlation between liposomal tumor accumulation and effects of Doxil® was confirmed (R 2 = 0.73). Taken together, our experiments definitely verified that enhanced therapeutic effects through liposomal formulations of anticancer agents depend on tumor accumulation of liposomes. Tumor accumulation of the radiolabeled liposomes evaluated by SPECT/CT imaging is applicable to appropriately determine indications for liposomal antitumor agents.

Antitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models

“…PEGylated liposomes encapsulating 111 In-diethylene-triamine-penta-acetic acid ( 111 In-DTPA) were prepared by the lipid film hydration extrusion method as described previously. (14,19) In brief, the dried films were dispersed in 50 mM HEPES buffer (pH 7.4) containing 5% mannitol and 10 mM DTPA at 60°C and then repeatedly extruded through polycarbonate membrane filters (0.4-, 0.2-and 0.05-lm pore sizes) (GE Healthcare, Buckinghamshire, UK) to adjust their diameters to approximately 80 nm. Unencapsulated DTPA was removed by passage through a Sephadex G-50 column (GE Healthcare Japan Ltd, Tokyo, Japan).…”

Nanoparticle Interactions with the Immune System: Clinical Implications for Liposome-Based Cancer Chemotherapy

“…For example, in the phase 3 study of PLD against doxorubicin single agent in metastatic breast cancer, no survival advantage was observed (4) despite the clear superiority of PLD in animal tumor models. Recent studies in mouse models using radionuclide SPECT imaging with In 111 -labeled liposomes and PET imaging with Zr 89 -labeled liposomes admixed with PLD have observed that higher tumor uptake of liposomes correlates with greater antitumor activity at the individual level (44, 45). These studies also show a correlation between tumor uptake and tumor microvessel density and reveal remarkable heterogeneity in liposomal tumor accumulation.…”

Liposomes: Clinical Applications and Potential for Image-Guided Drug Delivery

“…As a representation of the study, Harrington et al presented gamma camera images of three patients with three different cancers at 72 h post 111 In-DTPA labeled pegylated liposomes that showed clear depiction of tumors in all three images [ 109 ]. Molecular imaging using SPECT enabling liposomes are increasingly being investigated to diagnose various diseases including inflammation, plaques, cancers and many more [ 110 , 111 , 112 , 113 , 114 , 115 ]. Molecular imaging using radiolabeled nanoparticles is also aimed at facilitating better delivery, in vivo pharmacokinetics monitoring, as well controlled release.…”