Translating Research for the Radiotheranostics of Nanotargeted 188Re-Liposome

Abstract

Nanoliposomes are one of the leading potential nano drug delivery systems capable of targeting chemotherapeutics to tumor sites because of their passive nano-targeting capability through the enhanced permeability and retention (EPR) effect for cancer patients. Recent advances in nano-delivery systems have inspired the development of a wide range of nanotargeted materials and strategies for applications in preclinical and clinical usage in the cancer field. Nanotargeted ¹⁸⁸Re-liposome is a unique internal passive radiotheranostic agent for nuclear imaging and radiotherapeutic applications in various types of cancer. This article reviews and summarizes our multi-institute, multidiscipline, and multi-functional studied results and achievements in the research and development of nanotargeted ¹⁸⁸Re-liposome from preclinical cells and animal models to translational clinical investigations, including radionuclide nanoliposome formulation, targeted nuclear imaging, biodistribution, pharmacokinetics, radiation dosimetry, radiation tumor killing effects in animal models, nanotargeted radionuclide and radio/chemo-combination therapeutic effects, and acute toxicity in various tumor animal models. The systemic preclinical and clinical studied results suggest ¹⁸⁸Re-liposome is feasible and promising for in vivo passive nanotargeted radionuclide theranostics in future cancer care applications.

Keywords: liposome; nanoliposome; nuclear imaging; radiotheranostics; rhenium-188.

Figure 1

An overview of radiation killing mechanisms of preclinical tumor animal models in internal radiotherapy of nanotargeted ¹⁸⁸Re-liposome. TUNEL: Terminal deoxynucleotidyl transferase dUTP nick end labeling.

Figure 2

Chemical structure of BMEDA (A) and ¹⁸⁸Re-BMEDA (B). Diagram (C) depicting after-loading method for liposomes containing ammonium sulfate pH gradient radiolabeled with ¹⁸⁸Re-BMEDA. The lipophilic form of BMEDA at pH 7.2 crosses the lipid bilayer. Once inside the liposome interior, BMEDA becomes protonated at pH 5.1 and trapped within the hydrophilic liposome interior as ¹⁸⁸Re-BMEDA-H⁺ form. This research was originally published in JNM [19].

Figure 3

Chemical flowsheet for the preparation of ¹⁸⁸Re-liposomes. DSPC: 1,2-Distearoyl-sn-Glycero-3-Phosphocholine; HSPC: Hydrogen Soybean Phosphotidylcholine. Figure adapted with permission from [32].

Figure 4

Micro-SPECT/CT imaging of ¹⁸⁸Re-BMEDA (A), ¹⁸⁸Re-liposome (B) and ¹⁸⁸Re-DXR-liposome (C) in C26 tumor-bearing mice. (D) Correlation of tumor uptake ¹⁸⁸Re-liposome analyzed by microSPECT imaging and biodistribution. Arrows indicate positions of subcutaneous tumors. Figures adapted with permission from [30,34].

Figure 5

Tumor volume (A) and survival ratio (B) versus time following administering ¹⁸⁸Re-DXR-liposome (22.2 MBq of ¹⁸⁸Re and 2 mg/kg DXR) (●), ¹⁸⁸Re-liposome (22.2 MBq of ¹⁸⁸Re) (∇), Lipo-Dox (2 mg/kg DXR) (■) and normal saline (♢) by triple intravenous injection on Day 0, 4 and 8 in C26 murine colon tumor-bearing mice. (C) MicroSPECT/CT image of ¹⁸⁸Re-DXR-liposome at 120 day after treatment. (D) Statistics of therapeutic efficacy of ¹⁸⁸Re-liposome compared with Lipo-DOX. CI: Combination Index; MGI: Mean Growth Inhibition. Figures adapted with permission from [34].

Figure 6

Tumor volume (A) and survival ratio (B) versus time following administering ¹⁸⁸Re-liposome (80% MTD, 29.6 MBq) or 5-FU (80% MTD, 144 mg/kg) by single intravenous injection in C26 murine colon tumor-bearing mice. (C) Statable 188. Re-liposome compared with 5-FU. Figures adapted with permission from [22].

Figure 7

The total ascites weight (A), tumors weight (B) and survival ratio (C) following administering ¹⁸⁸Re-liposome (80% MTD, 29.6 MBq), 5-FU (80% MTD, 144 mg/kg), and normal saline, respectively by single intravenous injection in C26 peritoneal metastatic tumor-bearing mice. *: significant difference between ¹⁸⁸Re-liposome- and normal saline-treated groups; ◆: significant difference between ¹⁸⁸Re-liposome- and 5-FU-treated groups. (D) Statistics of therapeutic efficacy of ¹⁸⁸Re-liposome compared with 5-FU. Figures adapted with permission from [36].

Figure 8

Combination therapy of ¹⁸⁸Re-liposome with Lipo-Dox, EBRT or Nexavar. Measurements of tumor growth (A) and survival ration (B) in C26 tumor-bearing mice responded to a treatment regimen in which the mice were injected with either saline or Lipo-Dox (2.5 mg/kg) prior to an injection of the ¹⁸⁸Re-liposome (22.2 MBq) on day 0. (C) Therapeutic effect of EBRT and ¹⁸⁸Re-liposome. For combination treatment, BE-3 tumor-bearing mice received EBRT (IR, 3 Gy) followed by ¹⁸⁸Re-liposome (13.2 MBq). Single treatment of EBRT, ¹⁸⁸Re-liposome, liposome and normal saline were used for comparison. EBRT: external beam radiotherapy; IR: ionizing radiation. (D) Therapeutic effect of Nexavar and ¹⁸⁸Re-liposome. For combination treatment, C26-luc murine colon tumor-bearing mice received ¹⁸⁸Re-liposome (29.6 MBq) and Nexavar (10 mg/kg, once every other day for 1 week) by intrasplenic injection. ¹⁸⁸Re-liposome or Nexavar treatment only was used for comparison. Figures adapted with permission from [42,43,44].

Figure 9

Phase 0 clinical studies of ¹⁸⁸Re-liposome SPECT/CT imaging showing tumor targeting and uptake in a NPC patient (Pt. 14) with pulmonary and mediastinal metastasis: (A) One month before ¹⁸⁸Re-liposome injection, MRI shows there is a soft tissue lesion (blue arrow) in the left nasopharynx, (B) SPECT/CT 24 h after ¹⁸⁸Re-liposome injection as seen on the MRI, (C) Anterior upper-body images at six different time points after ¹⁸⁸Re-liposome injection (blue arrows indicate the lesion over the left nasopharynx), (D) The nasopharyncoscopic examination one month before ¹⁸⁸Re-liposome injection shows the left nasopharyngeal mass with a crust and mucoid (yellow arrow), (E) Two months after ¹⁸⁸Re-liposome injection, there are engorged blood vessels and irregular surface over the left nasopharynx (yellow arrow) and (F) One year after the trial, the nasopharyngoscopic study shows fibrosis over the left nasopharynx (yellow arrow). Figures adapted with permission from [29].