Hsin-Ell Wang

Transarterial radioembolization (TARE) is an emerging treatment for patients with unresectable hepatocellular carcinoma (HCC). This study successfully developed radiometal-labeled chitosan microspheres (¹¹¹In/¹⁷⁷Lu-DTPA-CMS) with a diameter of 36.5 ± 5.3 μm for TARE. The radiochemical yields of ¹¹¹In/¹⁷⁷Lu-DTPA-CMS were greater than 90% with high radiochemical purities (>98%). Most of the ¹¹¹In/¹⁷⁷Lu-DTPA-CMS were retained in the hepatoma and liver at 1 h after intraarterial (i.a.) administration. Except for liver accumulation, radioactivity in each normal organ was less than 1% of the injected radioactivity (%IA) at 72 h after injection. At 10 days after injection of ¹⁷⁷Lu-DTPA-CMS (18.6 ± 1.3 MBq), the size of the hepatoma was significantly reduced by around 81%, while that of the rats in the control group continued to grow. This study demonstrated the effectiveness of ¹⁷⁷Lu-DTPA-CMS in the treatment of N1-S1 hepatoma. ¹¹¹In/¹⁷⁷Lu-DTPA-CMS have the potential to be a superior theranostic pair for the treatment of clinical hepatoma.

Regarding the increased incidence and high mortality rate of malignant melanoma, practical early-detection methods are essential to improve patients’ clinical outcomes. In this study, we successfully prepared novel picolinamide–benzamide (¹⁸F-FPABZA) and nicotinamide–benzamide (¹⁸F-FNABZA) conjugates and determined their biological characteristics. The radiochemical yields of ¹⁸F-FPABZA and ¹⁸F-FNABZA were 26 ± 5% and 1 ± 0.5%, respectively. ¹⁸F-FPABZA was more lipophilic (log P = 1.48) than ¹⁸F-FNABZA (log P = 0.68). The cellular uptake of ¹⁸F-FPABZA in melanotic B16F10 cells was relatively higher than that of ¹⁸F-FNABZA at 15 min post-incubation. However, both radiotracers did not retain in amelanotic A375 cells. The tumor-to-muscle ratios of ¹⁸F-FPABZA-injected B16F10 tumor-bearing mice increased from 7.6 ± 0.4 at 15 min post-injection (p.i.) to 27.5 ± 16.6 at 3 h p.i., while those administered with ¹⁸F-FNABZA did not show a similarly dramatic increase throughout the experimental period. The results obtained from biodistribution studies were consistent with those derived from microPET imaging. This study demonstrated that ¹⁸F-FPABZA is a promising melanin-targeting positron emission tomography (PET) probe for melanotic melanoma.

Malignant melanoma is the most harmful type of skin cancer and its incidence has increased in this past decade. Early diagnosis and treatment are urgently desired. In this study, we conjugated picolinamide/nicotinamide with the pharmacophore of ¹³¹I-MIP-1145 to develop ¹³¹I-iodofluoropicolinamide benzamide (¹³¹I-IFPABZA) and ¹³¹I-iodofluoronicotiamide benzamide (¹³¹I-IFNABZA) with acceptable radiochemical yield (40 ± 5%) and high radiochemical purity (>98%). We also presented their biological characteristics in melanoma-bearing mouse models. ¹³¹I-IFPABZA (Log P = 2.01) was more lipophilic than ¹³¹I-IFNABZA (Log P = 1.49). B16F10-bearing mice injected with ¹³¹I-IFNABZA exhibited higher tumor-to-muscle ratio (T/M) than those administered with ¹³¹I-IFPABZA in planar γ-imaging and biodistribution studies. However, the imaging of ¹³¹I-IFNABZA- and ¹³¹I-IFPABZA-injected mice only showed marginal tumor uptake in A375 amelanotic melanoma-bearing mice throughout the experiment period, indicating the high binding affinity of these two radiotracers to melanin. Comparing the radiation-absorbed dose of ¹³¹I-IFNABZA with the melanin-targeted agents reported in the literature, ¹³¹I-IFNABZA exerts lower doses to normal tissues on the basis of similar tumor dose. Based on the in vitro and in vivo studies, we clearly demonstrated the potential of using ¹³¹I-IFNABZA as a theranostic agent against melanoma.

Microbial proteins have recently been found to have more benefits in clinical disease treatment because of their better-developed strategy and properties than traditional medicine. In this study, we investigated the effectiveness of a truncated peptide synthesized from the C-terminal sequence of pneumolysin, i.e., C70PLY4, in Streptococcus pneumoniae, in treating chronic inflammatory conditions. It has been shown that C70PLY4 significantly blocks the transendothelial migration of neutrophils and attenuates the formation of atherosclerotic plaque and the secretion of soluble forms of the intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule 1 (VCAM-1), and E-selectin in high-fat-diet/streptozotocin-induced inflammatory rats. The mechanism and the docking simulation analysis further indicated that C70PLY4 might serve as a Toll-like receptor 4 (TLR4) antagonist by competing for the binding site of MD2, an indispensable protein for lipopolysaccharide (LPS)–TLR4 interaction signaling, on the TLR4 structure. Moreover, compared to the full-length PLY, C70PLY4 seems to have no cytotoxicity in human vascular endothelial cells. Our study elucidated a possible therapeutic efficacy of C70PLY4 in reducing chronic inflammatory conditions and clarified the underlying mechanism. Thus, our findings identify a new drug candidate that, by blocking TLR4 activity, could be an effective treatment for patients with chronic inflammatory diseases.

Prodrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV-based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and E. coli nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV-RRV achieved highly efficient delivery of these prodrug activator genes to RG-2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5-fluorocytosine and CB1954 in vitro. In an immune-competent intracerebral RG-2 glioma model, GALV-mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV-NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV-NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV-RRV enabled high-efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV-RRV, and opens the door to the possibility of future combination gene therapy with CD-armed MLV-RRV, as the latter vector is currently being evaluated in clinical trials.

PEGylated gold nanostars (pAuNSs) and their radioactive surrogate (¹¹¹In–DTPA–pAuNS), with unique physiochemical properties, are thought to be a promising agent for image-guided photothermal therapy (PTT).

The efficacy of gold nanoparticle (AuNP)-assisted radiofrequency (RF)-induced hyperthermia employing the Kanzius device remains controversial. Different from the Kanzius device, modulated electro-hyperthermia (mEHT) utilizes the capacitive-impedance coupled 13.56 MHz radiofrequency (RF) current and has been approved for clinical cancer treatment. In this study, we investigated the heating characteristics of spherical-, urchin-, and rod-like AuNPs of a similar 50 nm size upon exposure to a 13.56 MHz radiofrequency using the LabEHY-105CL, an in vivo mEHT device. We found that, regardless of the AuNPs’ sphere-, urchin- or rod-like shape, purified gold nanoparticle solution would not promote heat generation. The temperature elevation during radiofrequency irradiation was solely attributed to the ionic background of the solution. The AuNPs present in the medium (≤25 ppm) showed no effect on selective cell killing of malignant cells, whereas the AuNPs incorporated in the cells diminished the cell selectivity as well as cell death and acted as protectors in mEHT cancer treatment. Our study suggested that (1) the temperature elevation induced by 50 nm AuNPs in the 13.56 MHz radiofrequency field was negligible and was shape-independent, and (2) the presence of AuNPs would alter the cell-killing effect of modulated electro-hyperthermia.

Colorectal cancer is one of the major causes of cancer-related death in Taiwan and worldwide. Patients with peritoneal metastasis from colorectal cancer have reduced overall survival and poor prognosis. Hybrid protein-inorganic nanoparticle systems have displayed multifunctional applications in solid cancer theranostics. In this study, a gold nanocore-encapsulated human serum albumin nanoparticle (Au@HSANP), which is a hybrid protein-inorganic nanoparticle, and its radioactive surrogate ¹¹¹In-labeled Au@HSANP (¹¹¹In-Au@HSANP), were developed and their biological behaviors were investigated in a tumor/ascites mouse model. ¹¹¹In-Au@HSANP was injected either intravenously (iv) or intraperitoneally (ip) in CT-26 tumor/ascites-bearing mice. After ip injection, a remarkable and sustained radioactivity retention in the abdomen was noticed, based on microSPECT images. After iv injection, however, most of the radioactivity was accumulated in the mononuclear phagocyte system. The results of biodistribution indicated that ip administration was significantly more effective in increasing intraperitoneal concentration and tumor accumulation than iv administration. The ratios of area under the curve (AUC) of the ascites and tumors in the ip-injected group to those in the iv-injected group was 93 and 20, respectively. This study demonstrated that the ip injection route would be a better approach than iv injections for applying gold-albumin nanoparticle in peritoneal metastasis treatment.