An overview of translational (radio)pharmaceutical research related to certain oncological and non-oncological applications

Figure 1 Schematic structure of the translational research activities covered by the overview article. ^99mTc-sestamibi: Technetium-99m labeled-hexakis (2-methoxyisobutylisonitrile); ^99mTcDMP-HSA: Technetium-99m dimercaptopropionyl human serum albumin; ^123/131I-Hyp: Iodine-123/iodine-131 labeled monoiodohypericin; MI: Myocardial infarction; VDA: Vascular disrupting agent.

Figure 2 Flow diagram of the included research topics. ^99mTc: Technetium-99m; ¹¹¹In: indium-111; ¹²³I: Iodine-123; ¹³¹I: Iodine-131; C₂H₆O: Ethanol; DTPA: Diethylene triamine pentaacetic acid; Fab: Antigen-binding fragment; Gd: Gadolinium; ROS: Reactive oxygen species; SPECT: Single photon emission computed tomography; TNT: Tumor necrosis treatment.

Figure 3 Schematic representation of the etiology of necrosis. ROS: Reactive oxygen species; TNT: Tumor necrosis treatment; RIPK1/3: Receptor-interacting protein kinase 1 and 3; TNFR1: Tumor-necrosis factor receptors 1.

Figure 4 Macroscopic digital imaging of a mouse with acute ethanol-induced necrosis in the liver and muscle having received 5. 0 mg/kg hypericin in DMSO/PEG400/water (25:60:15, v/v/v). Under normal tungsten light, viable liver, intestines and muscle show normal appearances whereas hepatic infarction and muscle necrosis appear as white cheesy tissue (A₁, B₁, C₁). With a UV light of 254 nm, a bright red fluorescence from liver (A₂, B₂) and muscle necrosis (C₂) but a lack of fluorescent signal from the liver (A₂, B₂), viable muscle (C₂) and other abdominal structures were observed (A₂). DMSO: Dimethyl sulfoxide; PEG400: Polyethylene glycol 400; UV: Ultraviolet.

Figure 5 High performance liquid chromatographic analysis of the non-purified iodine-123 labeled hypericin with Ultraviolet (254 nm) and radiometric detection. A: Ultraviolet-chromatogram of the starting reagent hypericin (Hyp) with a retention time of 19.18 min (upper part) and radiochromatogram (lower part) of ¹²³I-Hyp eluting at 22.13 min with a mean radiochemical yield of 95.4%; B: High performance liquid chromatographic analysis of the non-purified ¹²³I-Hyp at 48 h after labeling. A single narrow peak coming out at 21.90 min (lower part) suggests the in vitro stability of ¹²³I-Hyp over time. CPS: Count per second.

Figure 6 Post-mortem analysis of infarcts and viable heart tissues from rabbits with acute reperfused myocardial infarction having intravenously received iodine-123 labeled hypericin/hypericin dissolved in a 0. 07 mol/L solution of the liver-produced surfactant sodium cholate. A: A typical autoradiogram of 50-μm-thick sections reveals higher tracer uptake in infarction than in viable myocardium. The color code bar indicates the coding scheme for the radioactivity; B: Microscopic images of 50-μm-thick sections confirm the selective affinity of the highly fluorescent iodine-123-labeled-hypericin/hypericin for acute myocardial infarction in contrast to the low fluorescent signal found in viable myocardium; C: The H and E-stained section corroborates the location of the viable myocardium tissue and the presence of myocardial necrosis characterized by scattered hemorrhage.

Figure 7 Post-mortem study of necrotic and viable tissues in the liver and muscle from animal models either of reperfused partial liver infarction or ethanol-induced muscle necrosis pre-injected with iodine-123 labeled hypericin/hypericin followed by 1% Evans blue solution. A, B: Muscle; C, D: Liver. The hepatic infarction (A₁) and necrotic muscle (B₁) retain Evans blue as blue hyper intense areas, with viable liver (C₁) and normal muscle (D₁) without staining. Autoradiograms of 50-μm-thick sections show high tracer uptake in hepatic infarction (A₂) and muscle necrosis (B₂) but low accumulation either in viable liver (C₂) or muscle (D₂). The color code bar represents the code for the radioactivity concentration. By histology, the presence of hepatic infarction (A₃) and muscle necrosis (B₃) and the location of the viable liver (C₃) and muscle (D₃) tissues are verified.

Figure 8 Difference in accumulation patterns of iodine-123/131 labeled hypericin/hypericin in tumor necrosis over time. Case 1: Ex-vivo analysis of necrotic tumors from rats with hepatic rhabdomyosarcoma (R1) in the first 24 h after the administration of iodine-123 labeled hypericin/hypericin (¹²³I-Hyp/Hyp) in DMSO/PEG 400/propylene glycol/water (25:25:25:25, v/v/v/v) followed by 1% Evans blue solution. At 24 h after ¹²³I-Hyp/Hyp injection, the tumor necrosis is perfectly outlined by the Evans blue as a blue rim, with viable tumor residues and normal liver with almost no staining (A₁). On the autoradiogram, a perfect match was seen between the high levels of ¹²³I-Hyp/Hyp accumulated in the ring (A₂) and the rim of Evans blue previously observed (A₁). Histology analysis confirms the regions of the liver, necrotic and viable tumors (A₃). Case 2: Single-photon emission computed tomography (SPECT), autoradiograms and histology in severe combined immunodeficiency mice bearing bilateral radiation-induced fibrosarcoma-1 subcutaneously having received combretastatin A-4 phosphate (CA4P) to induce tumor necrosis followed 24 h later by ¹³¹I-Hyp/Hyp in DMSO/PEG 400/water (25:60:15, v/v/v). Twelve days after ¹³¹I-Hyp/Hyp administration, SPECT detects a persistent intense high radioactivity mainly inside the tumor necrotic core (arrow). Autoradiography (B₂)¹ and histology (B₃) of the tumor after 30 d of tracer injection correspond well with the hotspot imaging on tumor (B₁). ¹The color code bar indicates the coding scheme for the radioactivity. DMSO: Dimethyl sulfoxide; PEG 400: Polyethylene glycol 400.

Figure 9 Macroscopic digital imaging of gallbladder stones which were extracted from patients. Stones previously incubated in DMSO/PEG400/water (25:60:15, v/v/v) for 72 h and set as control (A₁, A₂) lack of fluorescent properties (A₃, A₄). Stones treated for 72 h with a solution of Hyp in DMSO/PEG400/water (25:60:15, v/v/v) (B₁, B₂) reveals fluorescence (B₃, B₄) under the UV light of 254 nm. DMSO: Dimethyl sulfoxide; PEG 400: Polyethylene glycol 400; UV: Ultraviolet.