Translating Research for the Radiotheranostics of Nanotargeted 188Re-Liposome.

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.

Evaluation of Nanotargeted 111In-Cyclic RGDfK-Liposome in a Human Melanoma Xenotransplantation Model.

Nanotargeted liposomes may be modified with targeting peptide on the surface of a prepared liposome to endow specificity and elevate targeting efficiency. The aim of this study was to develop a radioactive targeted nanoparticle, the 111In-cyclic RGDfK-liposome, and its advantage of recognizing the αVß3 integrin was examined. The cyclic RGDfK modified liposomes were demonstrated the ability to bind the αVß3 integrin expressed on the surface of human melanoma cell in vitro and in vivo. The effects of the cyclic RGDfK-liposome on the functioning of phagocytes was also examined, showing no considerable negative effects on the engulfment of bacteria and the generation of reactive oxygen species. Based upon these findings, the cyclic RGDfK- liposome is said to be a promising agent for tumor imaging.

Bi-Functional Radiotheranostics of 188Re-Liposome-Fcy-hEGF for Radio- and Chemo-Therapy of EGFR-Overexpressing Cancer Cells.

Epidermal growth factor receptor (EGFR) specific therapeutics is of great importance in cancer treatment. Fcy-hEGF fusion protein, composed of yeast cytosine deaminase (Fcy) and human EGF (hEGF), is capable of binding to EGFR and enzymatically convert 5-fluorocytosine (5-FC) to 1000-fold toxic 5-fluorocuracil (5-FU), thereby inhibiting the growth of EGFR-expressing tumor cells. To develop EGFR-specific therapy, 188Re-liposome-Fcy-hEGF was constructed by insertion of Fcy-hEGF fusion protein onto the surface of liposomes encapsulating of 188Re. Western blotting, MALDI-TOF, column size exclusion and flow cytometry were used to confirm the conjugation and bio-activity of 188Re-liposome-Fcy-hEGF. Cell lines with EGFR expression were subjected to treat with 188Re-liposome-Fcy-hEGF/5-FC in the presence of 5-FC. The 188Re-liposome-Fcy-hEGF/5-FC revealed a better cytotoxic effect for cancer cells than the treatment of liposome-Fcy-hEGF/5-FC or 188Re-liposome-Fcy-hEGF alone. The therapeutics has radio- and chemo-toxicity simultaneously and specifically target to EGFR-expression tumor cells, thereby achieving synergistic anticancer activity.

188Re-Liposome Can Induce Mitochondrial Autophagy and Reverse Drug Resistance for Ovarian Cancer: From Bench Evidence to Preliminary Clinical Proof-of-Concept.

Despite standard treatment, about 70% of ovarian cancer will recur. Cancer stem cells (CSCs) have been implicated in the drug-resistance mechanism. Several drug resistance mechanisms have been proposed, and among these, autophagy plays a crucial role for the maintenance and tumorigenicity of CSCs. Compared to their differentiated counterparts, CSCs have been demonstrated to display a significantly higher level of autophagy flux. Moreover, mitophagy, a specific type of autophagy that selectively degrades excessive or damaged mitochondria, is shown to contribute to cancer progression and recurrence in several types of tumors. Nanomedicine has been shown to tackle the CSCs problem by overcoming drug resistance. In this work, we developed a nanomedicine, 188Re-liposome, which was demonstrated to target autophagy and mitophagy in the tumor microenvironment. Of note, the inhibition of autophagy and mitophagy could lead to significant tumor inhibition in two xenograft animal models. Lastly, we presented two cases of recurrent ovarian cancer, both in drug resistance status that received a level I dose from a phase I clinical trial. Both cases developing drug resistance showed drug sensitivity to 188Re-liposome. These results suggest that inhibition of autophagy and mitophagy by a nanomedicine may be a novel strategy to overcome drug resistance in ovarian cancer.

Single dose acute toxicity testing for N,N-bis(2-mercaptoethyl)-N',N' diethylethylenediamine in beagles.

N,N-Bis(2-mercaptoethyl)-N',N'-diethylenediamine (BMEDA) is used in the preparation of the (188)Re-BMEDA-liposome as a chelator to deliver rhenium 188 into liposomes. Although the safety of the (188)Re-BMEDA-liposome had been established, the use of BMEDA in preparing the liposome is of interest; however, an assessment of its safety is warranted. In this present work, we report on the acute toxicity study of BMEDA in beagles to identify doses causing no adverse effect and doses causing life-threatening toxicity. In a single dose 14-day systemic toxicity study conducted in beagles, BMEDA was without compound-related adverse effects at doses of up to 2mg/kg in a series of clinical observations and clinical pathology examinations. The results of these studies could aid in choosing doses for repeat-dose studies and in the selection of starting doses for Phase 1 human studies.

Pharmacokinetics of BMEDA after intravenous administration in beagle dogs.

The pharmacokinetics of N,N-bis(2-mercapatoethly)-N',N'-diethylenediamine (BMEDA), a molecule that can form a chelate with rhenium-188 (188Re) to produce the 188Re-BMEDA-liposomes, was studied. In this work, beagles received a single injection of BMEDA, at doses of 1, 2, or 5 mg/kg; the concentration of BMEDA in the beagles' plasma was then analyzed and determined by liquid chromatography-mass spectrometry/mass spectrometry. Based on the pharmacokinetic parameters of BMEDA, we found that male and female animals shared similar patterns indicating that the pharmacokinetics of BMEDA is independent of gender differences. In addition, the pharmacokinetics of BMEDA was seen to be non-linear because the increase of mean AUC0-t and AUC0-∞ values tend to be greater than dose proportional while the mean Vss and CL values of BMEDA appeared to be dose dependent. The information on the pharmacokinetics of BMEDA generated from this study will serve as a basis to design appropriate pharmacology and toxicology studies for future human use.

Therapeutic efficacy of 188Re-liposome in a C26 murine colon carcinoma solid tumor model.

Nanoliposomes are good drug delivery systems that allow the encapsulation of drugs into vesicles for their delivery. The objective of this study is to investigate the therapeutic efficacy of a new radio-therapeutics of (188)Re-labeled pegylated liposome in a C26 murine colon carcinoma solid tumor model. The safety of (188)Re-liposome was evaluated before radiotherapy treatment. The anti-tumor effect of (188)Re-liposome was assessed by tumor growth inhibition, survival ratio and ultrasound imaging. Apoptotic marker in tumor was also evaluated by the TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling) method after injection of (188)Re-liposome. The group treated with (188)Re-liposome displayed slight loss in body weight and decrease in white blood cell (WBC) count 7 to 14 days post-injection. With respect to therapeutic efficacy, the tumor-bearing mice treated with (188)Re-liposome showed better mean tumor growth inhibition rate (MGI) and longer median survival time (MGI = 0.140; 80 day) than those treated with anti-cancer drug 5-FU (MGI = 0.195; 69 day) and untreated control mice (MGI = 0.413; 48 day). The ultrasound imaging showed a decrease in both tumor volume and number of blood vessels. There were significantly more apoptotic nuclei (TUNEL-positive) in (188)Re-liposome-treated mice at 8 h after treatment than in control mice. These results evidenced the potential benefits achieved by oncological application of the radio-therapeutics (188)Re-liposome for adjuvant cancer treatment.

Acute intravenous injection toxicity of BMEDA in mice.

(188)Re/(186)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine-labeled pegylated liposome ((188)Re-BMEDA-liposome) has been proven as a promising candidate for cancer therapy in tumor-rodent models. (188)Re-BMEDA complexes should be prepared for the radiolabeling of liposomes. This article describes the acute toxicity of BMEDA in Imprinting Control Region (ICR) mice. Treated mice were administered with BMEDA at dose levels of 3, 6, 9, and 12 mg/kg, with a dose volume of 10 mL/kg. The control mice were administered 10 mL/kg of vehicle control. The mice were observed for 14 days. Observations included mortality, clinical signs, total body-weight gains, food consumption, and gross necropsy findings. BMEDA exerted no adverse toxic effects in ICR mice at dose levels 3 mg/kg, which are up to 360,000 times higher than the intended human dose. The lethal-dose (LD(50)) value of BMEDA was 8.13 and 8.68 mg/kg in male and female mice, respectively.

Preliminary evaluation of acute toxicity of (188) Re-BMEDA-liposome in rats.

Liposomes can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness and reducing toxicity. To evaluate therapeutic strategies, it is essential to use animal models reflecting important safety aspects before clinical application. The objective of this study was to investigate acute radiotoxicity of ¹88Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (¹88Re-BMEDA-liposome) in Sprague-Dawley rats. Rats were administered with ¹88Re-BMEDA-liposome, normal saline as blank or non-radioactive liposome as vehicle control via intravenous injection and observed for 14 days. Examinations were conducted with respect to mortality, clinical signs, food consumption, body weight and hematological and biochemical analyses. In addition, gross necropsy, histopathological examinations and cytogenetic analyses were also performed. None of the rats died and no clinical sign was observed during the 14-day study period. Rats administered with ¹88Re-BMEDA-liposome at dosage of 185 MBq displayed a significant weight loss compared with the control from study day (SD) 1 to SD 4, and the white blood cell count reduced to 5-10% of initial value (female: 18.55 ± 6.58 to 0.73 ± 0.26 x 10³ µl⁻¹; male: 14.52 ± 5.12 to 1.43 ± 0.54 x 10³ µl⁻¹) 7 days-post injection, but were found to have recovered on SD 15. There were no significant differences in biochemical parameters and histopathological assessments between the ¹88Re-BMEDA-liposome-treated and control groups. The frequencies of dicentric chromosomes were associated with dosage of ¹88Re-BMEDA-liposome. The information generated from this study on acute toxicity will serve as a safety reference for further subacute toxicity study in rats and human clinical trials.

Pharmacokinetics, micro-SPECT/CT imaging and therapeutic efficacy of (188)Re-DXR-liposome in C26 colon carcinoma ascites mice model.

The pharmacokinetics and internal radionuclide therapy of intraperitoneally administrated (188)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomal doxorubicin ((188)Re-DXR-liposome) were investigated in the C26 murine colon carcinoma ascites mouse model. After intraperitoneal administration of the nanotargeted bimodality (188)Re-DXR-liposome, the ascites and tumor accumulation of the radioactivity were observed, the levels of radioactivity within the ascites were maintained at relatively higher levels before 48 h and the levels of radioactivity in the tumor were maintained at steady levels after 4 h. The AUC((o-->infinity)) of (188)Re-DXR-liposome in blood, ascites and tumor was 9.3-, 4.2- and 4.7-fold larger than that of (188)Re-BMEDA, respectively. The maximum tolerated dose of intraperitoneally administrated (188)Re-DXR-liposome was determined in normal BALB/c mice. The survival, tumor and ascites inhibition of mice after (188)Re-DXR-liposome (22.2 MBq of (188)Re, 5 mg/kg of DXR) treatment were evaluated. Consequently, radiochemotherapeutics of (188)Re-DXR-liposome attained better survival time, tumor and ascites inhibition (decreased by 49% and 91% at 4 days after treatment; P<.05) in mice than radiotherapeutics of (188)Re-liposome or chemotherapeutics of Lipo-Dox did. Therefore, intraperitoneal administration of novel (188)Re-DXR-liposome could provide a benefit and promising strategy for delivery of passive nanotargeted bimodality radiochemotherapeutics in oncology applications.

Biodistribution, pharmacokinetics and imaging of (188)Re-BMEDA-labeled pegylated liposomes after intraperitoneal injection in a C26 colon carcinoma ascites mouse model.

Nanoliposomes are important carriers capable of packaging drugs for various delivery applications through passive targeting tumor sites by enhanced permeability and retention effect. Radiolabeled liposomes have potential applications in radiotherapy and diagnostic imaging. The purpose of this study was to investigate the biodistribution, pharmacokinetics and imaging of nanotargeted (188)Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (RBLPL) and unencapsulated (188)Re-BMEDA after intraperitoneal (ip) injection in a C26 colon carcinoma ascites mouse model. The nanopegylated liposomes were labeled with (188)Re-BMEDA. The labeling efficiency of RBLPL was 82.3+/-4.5%. In vitro stability of RBLPL in normal saline at room temperature and in rat plasma at 37 degrees C for 72 h was 92.01+/-1.31% and 82.4+/-1.64%, respectively. The biodistribution studies indicated that the radioactivity in ascites was 69.96+/-14.08 percentage injected dose per gram (% ID/g) at 1h to 5.99+/-1.97% ID/g at 48 h after ip administration of RBLPL. The levels of radioactivity in tumor were progressive accumulation to a maximum of 6.57+/-1.7% ID/g at 24 h. The radioactivity of (188)Re-BMEDA in ascites reached the maximum level of 54.89+/-5.91% ID/g at 1 h and declined rapidly with time. Pharmacokinetic studies revealed that the terminal half-life, total body clearance and area under the curve of RBLPL were 5.3-, 9.5- and 9.4-fold higher than that of (188)Re-BMEDA in blood, respectively. These results suggested that the long circulation, bioavailability and localization of RBLPL in tumor and ascites sites, which also demonstrate that the ip administration of RBLPL is a potential multifunctional nanoradiotherapeutics and imaging agents on a C26 colon carcinoma ascites mouse model.

Biodistribution, pharmacokinetics and microSPECT/CT imaging of 188Re-bMEDA-liposome in a C26 murine colon carcinoma solid tumor animal model.

Nanoliposomes are useful carriers in drug delivery. Radiolabeled nanoliposomes have potential applications in radiotherapy and diagnostic imaging. In this study, the biodistribution and pharmacokinetics of 188Re-BMEDA-labelled pegylated liposomes (RBLPL) and unencapsulated 188Re-BMEDA administered by the i.v. route in murine C26-colon tumour-bearing mice were investigated. MicroSPECT/CT images were performed to evaluate the distribution and tumor targeting of RBLPL in mice. For the biodistribution study, the highest uptake of liposome in tumors was 3.62% +/- 0.73% at 24 h after RBLPL administration, and the tumor to muscle ratio of RBLPL was 7.1-fold higher than that of 188Re-BMEDA. With image analysis, the highest SUV in tumor was 2.81 +/- 0.26 at 24 h after injection of RBLPL. The Pearson correlation analysis showed a positive correlation of tumor targeting or uptake of RBLPL between biodistribution and microSPECT semi-quantification imaging analysis (r = 0.633). The results of the pharmacokinetics revealed that the area under the tissue concentration-time curve (AUC) of RBLPL was 4.7-fold higher than that of unencapsulated 188Re-BMEDA. These results suggested the potential benefit and advantage of 188Re-labeled nanoliposomes for imaging and treatment of malignant diseases.

Intraperitoneal (188)Re-Liposome delivery switches ovarian cancer metabolism from glycolysis to oxidative phosphorylation and effectively controls ovarian tumour growth in mice.

BACKGROUND AND PURPOSE: Cancer stem cells exhibit distinctive cellular metabolism compared with the more differentiated counterparts or normal cells. We aimed to investigate the impact of a novel radionuclide anti-cancer agent (188)Re-Liposome on stemness markers' expression and cellular metabolism in an ovarian cancer model. MATERIAL AND METHODS: A 2×2 factorial experiment was designed in which factor 1 represented the drug treatment comparing (188)Re-BMEDA, a free form of (188)Re, with (188)Re-Liposome, a nanoparticle-encapsulated form of (188)Re. Factor 2 represented the delivery route, comparing intravenous with intraperitoneal delivery. RESULTS: Intraperitoneal delivery of (188)Re-Liposome predominantly killed the CSCs-like cells in tumours and switched metabolism from glycolysis to oxidative phosphorylation. Further, intraperitoneal delivery of (188)Re-Liposome treatment was able to block epithelial-to-mesenchymal transition (EMT) and reactivate p53 function. Collectively, these molecular changes led to a striking tumour-killing effect. CONCLUSIONS: Radionuclides encapsulated in liposomes may represent a novel treatment for ovarian cancer when delivered intraperitoneally (a type of loco-regional delivery). In the future, this concept may be further extended for the treatment of several relevant cancers that have been proved to be suitable for loco-regional delivery of therapeutic agents, such as colon cancer, gastric cancer, and pancreatic cancer.

Involvement of let-7 microRNA for the therapeutic effects of Rhenium-188-embedded liposomal nanoparticles on orthotopic human head and neck cancer model.

Human head and neck squamous cell carcinoma (HNSCC) is usually treated by surgical resection with adjuvant radio-chemotherapy. In this study, we examined whether the radiopharmaceutical 188Re-liposome could suppress the growth of HNSCC followed by an investigation of molecular mechanisms. The orthotopic HNSCC tumor model was established by human hypopharyngeal FaDu carcinoma cells harboring multiple reporter genes. The drug targeting and therapeutic efficacy of 188Re-liposome were examined using in vivo imaging, bio-distribution, pharmacokinetics, and dosimetry. The results showed that 188Re-liposome significantly accumulated in the tumor lesion compared to free 188Re. The circulation time and tumor targeting of 188Re-liposome were also longer than that of free 188Re in tumor-bearing mice. The tumor growth was suppressed by 188Re-liposome up to three weeks using a single dose treatment. Subsequently, microarray analysis followed by Ingenuity Pathway Analysis (IPA) showed that tumor suppressor let-7 microRNA could be an upstream regulator induced by 188Re-liposome to regulate downstream genes. Additionally, inhibition of let-7i could reduce the effects of 188Re-liposome on suppression of tumor growth, suggesting that let-7 family was involved in 188Re-liposome mediated suppression of tumor growth in vivo. Our data suggest that 188Re-liposome could be a novel strategy for targeting HNSCC partially via induction of let-7 microRNA.

Structure-based optimization of GRP78-binding peptides that enhances efficacy in cancer imaging and therapy.

It is more challenging to design peptide drugs than small molecules through molecular docking and in silico analysis. Here, we developed a structure-based approach with various computational and analytical techniques to optimize cancer-targeting peptides for molecular imaging and therapy. We first utilized a peptide-binding protein database to identify GRP78, a specific cancer cell-surface marker, as a target protein for the lead, L-peptide. Subsequently, we used homologous modeling and molecular docking to identify a peptide-binding domain within GRP78 and optimized a series of peptides with a new protein-ligand scoring program, HotLig. Binding of these peptides to GRP78 was confirmed using an oriented immobilization technique for the Biacore system. We further examined the ability of the peptides to target cancer cells through in vitro binding studies with cell lines and clinical cancer specimens, and in vivo tumor imaging and targeted chemotherapeutic studies. MicroSPECT/CT imaging revealed significantly greater uptake of (188)Re-liposomes linked to these peptides as compared with non-targeting (188)Re-liposomes. Conjugation with these peptides also significantly increased the therapeutic efficacy of Lipo-Dox. Notably, peptide-conjugated Lipo-Dox significantly reduced stem-cell subpopulation in xenografts of breast cancer. The structure-based optimization strategy for peptides described here may be useful for developing peptide drugs for cancer imaging and therapy.

Cytotoxic Effects of PEGylated Anti-EGFR Immunoliposomes Combined with Doxorubicin and Rhenium-188 Against Cancer Cells.

BACKGROUND/AIM: We aimed to construct epidermal growth factor receptor (EGFR)-targeting cetuximab-immunoliposomes (IL-C225) for targeted delivery of doxorubicin and rhenium-188 (Re-188) to EGFR(+) cancer cells. MATERIALS AND METHODS: Synthesized IL-C225 was analyzed by dynamic light scattering, transmission electron microscopy, and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy. Cell binding and internalization were examined using doxorubicin-loaded IL-C225 (DXR-IL-C225) with confocal microscopy. IL-C225 combined with doxorubicin and Re-188 ((188)Re-DXR-IL-C225) was synthesized, and the cytotoxic effects of (188)Re-DXR-IL-C225 were analyzed in EGFR(+) cancer cells using cell viability assays. RESULTS: IL-C225 bound to EGFR on A431 cancer cells and was rapidly internalized. Furthermore, IL-C225 localized within the tumor cells efficiently. (188)Re-DXR-IL-C225 exhibited outstanding cytotoxic effects against EGFR(+) cancer cells in vitro and showed superior cytotoxic effects compared to DXR-IL-C225 or (188)Re-IL-C225 alone. CONCLUSION: The new formulation of (188)Re-DXR-IL-C225 may be a potential theranostic vehicle for delivery of drugs in the treatment of EGFR-overexpressing human cancer.

Evaluation of 188Re-labeled PEGylated nanoliposome as a radionuclide therapeutic agent in an orthotopic glioma-bearing rat model.

PURPOSE: In this study, the (188)Re-labeled PEGylated nanoliposome ((188)Re-liposome) was prepared and evaluated as a therapeutic agent for glioma. MATERIALS AND METHODS: The reporter cell line, F98(luc) was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of (188)Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered (188)Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the (188)Re-liposome-treated rats. RESULTS: By using bioluminescent imaging, the well-established reporter cell line (F98(luc)) showed a high relationship between cell number and its bioluminescent intensity (R(2)=0.99) in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of (188)Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the (188)Re-liposome-treated group than the control group (P<0.05). As a result, the lifespan of glioma-bearing rats treated with (188)Re-liposome was prolonged 10.67% compared to the control group. CONCLUSION: The radiotherapeutic evaluation by dosimetry and survival studies have demonstrated that passive targeting (188)Re-liposome via systemic administration can significantly prolong the lifespan of orthotopic glioma-bearing rats while maintaining reasonable systemic radiation safety. Therefore, (188)Re-liposome could be a potential therapeutic agent for glioblastoma multiforme treatment.

External beam radiotherapy synergizes ¹88Re-liposome against human esophageal cancer xenograft and modulates ¹88Re-liposome pharmacokinetics.

External beam radiotherapy (EBRT) treats gross tumors and local microscopic diseases. Radionuclide therapy by radioisotopes can eradicate tumors systemically. Rhenium 188 ((188)Re)-liposome, a nanoparticle undergoing clinical trials, emits gamma rays for imaging validation and beta rays for therapy, with biodistribution profiles preferential to tumors. We designed a combinatory treatment and examined its effects on human esophageal cancer xenografts, a malignancy with potential treatment resistance and poor prognosis. Human esophageal cancer cell lines BE-3 (adenocarcinoma) and CE81T/VGH (squamous cell carcinoma) were implanted and compared. The radiochemical purity of (188)Re-liposome exceeded 95%. Molecular imaging by NanoSPECT/CT showed that BE-3, but not CE81T/VGH, xenografts could uptake the (188)Re-liposome. The combination of EBRT and (188)Re-liposome inhibited tumor regrowth greater than each treatment alone, as the tumor growth inhibition rate was 30% with EBRT, 25% with (188)Re-liposome, and 53% with the combination treatment at 21 days postinjection. Combinatory treatment had no additive adverse effects and significant biological toxicities on white blood cell counts, body weight, or liver and renal functions. EBRT significantly enhanced the excretion of (188)Re-liposome into feces and urine. In conclusion, the combination of EBRT with (188)Re-liposome might be a potential treatment modality for esophageal cancer.

The PEGylated liposomal doxorubicin improves the delivery and therapeutic efficiency of 188Re-Liposome by modulating phagocytosis in C26 murine colon carcinoma tumor model.

Liposome in delivering radionuclide for cancer therapy has been expansively studied; however, liposome itself can be deliberately entrapped and destroyed by the reticuloendothelial system, causing an insufficiency of the drug delivery, which in turn would restrict the effectiveness of the drug. In this study, mice with subcutaneous implantation of C26 murine colon cancer received an experimental treatment regimen in which mice took delivery of PEGylated liposomal doxorubicin (LipoDox) first, after a three-day interval, of Rhenium-188 encapsulated into PEGylated liposome ((188)Re-Liposome) subsequently and by which suppressed the functioning of reticuloendothelial system for the short term. The data showed that based upon the biodistribution assay and the evaluation of the therapeutic efficacy, (188)Re-Liposome was more sufficiently delivered to tumor sites in mice with this treatment regimen than mice without the regimen, and that cancer mortalities in mice with the treatment regimen were much lower than the mortalities in mice without the regimen. Taken together, a new strategy proposed in this study significantly improved both the (188)Re-Liposome delivery and the effectiveness of (188)Re-Liposome, suggesting that the strategy can be an ideal treatment for cancer.

Evaluation of the therapeutic and diagnostic effects of PEGylated liposome-embedded 188Re on human non-small cell lung cancer using an orthotopic small-animal model.

UNLABELLED: Non-small cell lung cancer (NSCLC) is a highly morbid and mortal cancer type that is difficult to eradicate using conventional chemotherapy and radiotherapy. Little is known about whether radionuclide-based pharmaceuticals can be used for treating NSCLC. Here we embedded the therapeutic radionuclide (188)Re in PEGylated (PEG is polyethylene glycol) liposomes and investigated the biodistribution, pharmacokinetics, and therapeutic efficacy of this nanoradiopharmaceutical on NSCLC using a xenograft lung tumor model and the reporter gene imaging techniques. METHODS: Human NSCLC NCI-H292 cells expressing multiple reporter genes were used in this study. (188)Re was conjugated to N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA) and loaded into the PEGylated liposome to form a (188)Re-liposome. The tumor growth rates and localizations were confirmed using bioluminescent imaging and SPECT/CT after the (188)Re-BMEDA or (188)Re-liposome was intravenously injected. The accumulation of the nanodrug in various organs was determined by the biodistribution analysis and the nano-SPECT/CT system. The pharmacokinetic and dosimetric analyses were further determined using WinNonlin and OLINDA/EXM, respectively. RESULTS: The biodistribution and nano-SPECT/CT imaging showed that PEGylated (188)Re-liposome could efficiently accumulate in xenograft tumors formed by NCI-H292 cells that were subcutaneously implanted in nude mice. Pharmacokinetic analysis also showed that the retention of (188)Re-liposome was longer than that of (188)Re-BMEDA. In an orthotopic tumor model, ex vivo γ counting revealed that the uptake of (188)Re-liposome was detected in tumor lesions but not in surrounding normal lung tissues. Moreover, we evaluated the therapeutic efficacy using bioluminescent imaging and showed that the lung tumor growth was suppressed but not eradicated by (188)Re-liposome. The life span of (188)Re-liposome-treated mice was 2-fold longer than that of untreated control mice. CONCLUSION: The results of biodistribution, pharmacokinetics, estimated dosimetry, nano-SPECT/CT, and bioluminescent imaging suggest that the PEGylated liposome-embedded (188)Re could be used for the treatment of human lung cancers.