Folate Receptor-Targeted Multimodality Imaging of Ovarian Cancer in a Novel Syngeneic Mouse Model

Abstract

A new transplantable ovarian tumor model is presented using a novel folate receptor (FR) positive, murine ovarian cancer cell line that emulates the human disease and induces widespread intraperitoneal (i.p.) tumors in immunocompetent mice within 4–8 weeks of implantation. Tumor development was monitored using a new positron emission tomography (PET) FR-targeting reporter with PET/computerized tomography (PET/CT) and fluorescence molecular tomography (FMT) using a commercial FR-targeting reporter. Conventional structural magnetic resonance imaging (MRI) was also performed. Adult female C57BL/6 mice were injected i.p. with 6 × 106 MKP-L FR+ cells. Imaging was performed weekly beginning 2 weeks after tumor induction. The albumin-binding, FR-targeting ligand cm09 was radiolabeled with the positron emitter 68Ga and used to image the tumors with a small animal PET/CT. The FR-reporter FolateRSense 680 (PerkinElmer) was used for FMT and flow cytometry. Preclinical MRI (7 T) without FR-targeting was compared with the PET and FMT molecular imaging. Tumors were visible by all three imaging modalities. PET/CT had the highest imaging sensitivity at 3–3.5 h postadministration (mean %IA/g mean > 6) and visualized tumors earlier than the other two modalities with lower kidney uptake (mean %IA/g mean < 17) than previously reported FR-targeting agents in late stage disease. FMT showed relatively low FR-targeted agent in the bladder and kidneys, but yielded the lowest anatomical image resolution. MRI produced the highest resolution images, but it was difficult to distinguish tumors from abdominal organs during early progression since a FR-targeting MRI reporter was not used. Nevertheless, there was good correlation of imaging biomarkers between the three modalities. Tumors in the mouse ovarian cancer model could be detected using FR-targeted imaging as early as 2 weeks post i.p. injection of tumor cells. An imaging protocol should combine one or more of the modalities, e.g., PET/CT or PET/MRI for optimal tumor detection and delineation from surrounding tissues.

Hypocrellin B‐loaded, folate‐conjugated polymeric micelle for intraperitoneal targeting of ovarian cancer in vitro and in vivo

“…Folic acid can conjugate with folate receptor (FR), which is overexpressed in many types of tumors including ovarian, endometrial, breast, renal cell carcinomas, and so forth. Targeting the folate receptor has shown considerable promise in mediating uptake of a variety of drugs, gene therapy products, and radiopharmaceuticals …”

“…Targeting the folate receptor has shown considerable promise in mediating uptake of a variety of drugs, gene therapy products, and radiopharmaceuticals. [12][13][14] Therefore, we have explored a new folic acid-conjugated PEG-PLA micelle delivery system for HB (HB/FA-PEG-PLA micelle). In the present study, the stability and drug release of the HB/FA-PEG-PLA micelles either in vitro or in vivo were studied.…”

Molecular Imaging of Ovarian Cancer

“…Notably, this agent is capable of delineating the metastatic spread of OVCAR3 tumors along the ipsilateral chain of lymph nodes. Ocak et al recently used a 68 Ga-DOTA-albumin–folate conjugate and FR680 for the multimodal PET/fluorescence molecular tomographic imaging of the intraperitoneal spread of folate receptor–positive MKP-L cells (25). Similarly, Liu et al reported on the multimodal PET/optical imaging of metastatic ovarian tumors within the peritoneum of mice using a 64 Cu-labeled pyropheophorbide–folate conjugate (26).…”

Riboflavin immobilized Fe 3 O 4 magnetic nanoparticles carried with n -butylidenephthalide as targeting-based anticancer agents

“…To limit the potential damage caused by these treatments, targeting-based cancer treatments have become alternatives [1]. Certain receptors and transporters, such as folate receptors [2][3][4][5][6][7][8][9][10][11][12][13][14], glucose transporters [15][16][17], transferrin receptors (TfR) [18][19][20][21] and riboflavin (RF) receptors [22][23][24][25], are highly overexpressed on the surface of certain cancer cells. Thus, these receptors can be used as target sites when employing targeting-based cancer therapy.…”

“…For example, folate receptors are overexpressed on the cell membrane of ovarian [2], cervical [3], breast [4], lung [5], kidney [6], colon/rectum [7] and brain tumor cells [8]. Thus, folate receptors have been used as targets in studies on drug delivery [9,10] and cell imaging against these target cancer cells [11][12][13][14]. In addition, Warburg effect describes the phenomenon that cancer cells consume a larger amount of glucose and have a higher aerobic glycolysis rate than normal cells [15,16].…”