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Abstract: The purpose of this study is to evaluate the therapeutic efficacy of the liposome encaged with vinorelbine (VNB) and 111In-oxine on human colorectal adenocarcinoma (HT-29) using HT-29/luc mouse xenografts. HT-29 cells stably transfected with plasmid vectors containing luciferase gene (luc) were transplanted subcutaneously into the male NOD/SCID mice. Biodistribution of the drug was performed when tumor size reached 500–600mm3. The uptakes of 111In-VNB-liposome in tumor and normal tissues/organs at various time points postinjection were assayed. Multimodalities, including gamma scintigraphy, bioluminescence imaging (BLI) and whole-body autoradiography (WBAR), were applied for evaluating the therapeutic efficacy when tumor size was about 100mm3. The tumor/blood ratios of 111In-VNB-liposome were 0.044, 0.058, 2.690, 20.628 and 24.327, respectively, at 1, 4, 24, 48 and 72h postinjection. Gamma scinitigraphy showed that the tumor/muscle ratios were 2.04, 2.25 and 4.39, respectively, at 0, 5 and 10mg/kg VNB. BLI showed that significant tumor control was achieved in the group of 10mg/kg VNB (111In-VNB-liposome). WBAR also confirmed this result. In this study, we have demonstrated a non-invasive imaging technique with a luciferase reporter gene and BLI for evaluation of tumor treatment efficacy in vivo. The SCID mice bearing HT-29/luc xenografts treated with 111In-VNB-liposome were shown with tumor reduction by this technique. [Copyright &y& Elsevier]

Objective: Previous studies have shown that the accumulation level of FMAU in tumor is proportional to its proliferation rate. This study demonstrated that 2′-deoxy-2′-[18F]fluoro-β-d-arabinofuranosyluracil ([18F]FMAU) is a promising PET probe for noninvasively monitoring the therapeutic efficacy of 6% PEGylated liposomal vinorelbine (lipo-VNB) in a subcutaneous murine NG4TL4 sarcoma mouse model. Methods: Female syngenic FVB/N mice were inoculated with NG4TL4 cells in the right flank. After tumor size reached 150±50mm3 (day 0), lipo-VNB (5mg/kg) was intravenously administered on days 0, 3 and 6. To monitor the therapeutic efficacy of lipo-VNB, [18F]FMAU PET was employed to evaluate the proliferation rate of tumor, and it was compared with that observed from [18F]FDG/[18F]fluoroacetate PET. The expression of proliferating cell nuclear antigen (PCNA) in tumor during treatment was determined by semiquantitative analysis of immunohistochemical staining. Results: A significant inhibition (p<0.001) in tumor growth was observed on day 3 after a single dose treatment. The tumor-to-muscle ratio (T/M) derived from [18F]FMAU-PET images of lipo-VNB-treated group declined from 2.33±0.16 to 1.26±0.03 after three doses of treatment, while that of the control remained steady. The retarded proliferation rate of lipo-VNB-treated sarcoma was confirmed by PCNA immunohistochemistry staining. However, both [18F]FDG and [18F]fluoroacetate microPET imaging did not show significant difference in T/M between the therapeutic and the control groups throughout the entire experimental period. Conclusion: Lipo-VNB can effectively impede the growth of NG4TL4 sarcoma. [18F]FMAU PET is an appropriate modality for early monitoring of the tumor response during the treatment course of lipo-VNB. [ABSTRACT FROM AUTHOR]

Abstract: Colorectal carcinoma is a highly prevalent and common cause of cancer in Taiwan. There is still no available cure for this malignant disease. To address this issue, we applied the multimodality of molecular imaging to explore the efficacy of diagnostic and therapeutic nanoradiopharmaceuticals in an animal model of human colorectal adenocarcinoma [colorectal cancer (CRC)] that stably expresses luciferase (luc) as a reporter. In this study, an in vivo therapeutic efficacy evaluation of dual-nanoliposome (100 nm in diameter) encaged vinorelbine (VNB) and 111In-oxine on HT-29/luc mouse xenografts was carried out. HT-29/luc tumor cells were transplanted subcutaneously into male SCID mice. Multimodality of molecular imaging approaches including bioluminescence imaging (BLI), gamma scintigraphy, whole-body autoradiography (WBAR) and in vivo tumor growth tracing, histopathology and biochemistry/hematology analyses were applied on xenografted SCID mice to study the treatments with 6% polyethylene glycol (PEG) of 111In-NanoX/VNB-liposomes. In vivo tumor growth tracing and BLI showed that tumor volume could be completely inhibited by the combination therapy with 111In-VNB-liposomes and by chemotherapy with NanoX/VNB-liposomes (i.e., without Indium-111) (P<.01). The nuclear medicine images of gamma scintigraphy and WBAR also revealed the conspicuous inhibition of tumor growth by the combination therapy with 111In-VNB-liposomes. Animal body weights, histopathology and biochemistry/hematology analyses were used to confirm the safety and feasibility of radiopharmaceuticals. A synergistic therapeutic effect on CRC xenografted SCID mice was proven by combining an Auger electron-emitting radioisotope (Indium-111) with an anticancer drug (VNB). This study further demonstrates the beneficial potential applications of multimodality molecular imaging as part of the diagnostic and therapeutic approaches available for the evaluation of new drugs and other strategic approaches to disease treatment. [Copyright &y& Elsevier]

Abstract: In vivo characterization and dosimetric analysis has been performed to evaluate the potential of pegylated liposomes as carriers of radionuclides in tumor internal radiotherapy. Methods: The DTPA/PEG-liposomes were synthesized with a medium size of 110nm, conjugated with 111In/177Lu-(oxine)3 to afford 111In/177Lu-liposome. The stability of 111In/177Lu-liposome in serum was investigated. The biodistribution, scintigraphic imaging and pharmacokinetics of 111In/177Lu-liposomes after intravenous(i.v.) injection into C-26 tumor-bearing BALB/cByJ mice were studied. Radiation dose was estimated by MIRD-III program. Results: The incorporation efficiency of 111In/177Lu into liposomes was 95%. After incubation at 37°C for 72h in serum, more than 83% of radioactivity was still retained in the intact 111In/177Lu-liposomes. The biodistribution of 111In-liposomes showed that the radioactivity in the blood decreased from 23.14±8.16%ID/g at 1h to 0.02±0.00%ID/g at 72h post-injection (p.i.), while reaching its maximum accumulation in tumors at 48h p.i., with half-life in blood of 10.2h. The results were supported by that of 177Lu-liposomes. Scintigraphic imaging with 111In-liposomes showed unambiguous tumor images at 48h p.i. Dose estimation showed that the absorbed dose in tumor from 177Lu-liposomes was 5.74×10−5 Gy/MBq. Conclusions: This study provides an in vivo characterization and dosimetric evaluation for the use of liposome systems as carriers in targeted radionuclide therapy. The results suggest that adequate tumor targeting as well as dose delivered to tumors could be achieved by the use of radionuclide targeted liposomes. [Copyright &y& Elsevier]

Liposomes modified with a high concentration of polyethylene glycol (PEG) could significantly prolong the retention time of the carried drug in the circulation, thus improving the drug accumulation in the tumor. In this study, 6 mol% rather than 0.9 mol% PEGylated liposomes (100 nm in diameter) encapsulated with indium-111 were used in a human colorectal carcinoma HT-29/luc tumor-bearing mouse model for comparing the PEGylation effect. Pharmacokinetics, biodistribution, passive-targeted assay, bioluminescence imaging (BLI) and tumor growth measurements were used for the spatial and temporal distribution, tumor localization and therapeutic evaluation of the drug. Pharmacokinetic studies indicated that the terminal half-life (T((1/2))lambdaz) and C(max) of 6 mol% PEG (111)In liposomes were similar to those of 0.9 mol% PEG (111)In liposomes. In the blood, the total body clearance (Cl) of 6 mol% PEG (111)In liposomes was about 1.7-fold lower and the area under the curve (AUC) was 1.7-fold higher than those of 0.9 mol% PEG (111)In liposomes. These results showed that the long-term circulation and localization of 6 mol% PEGylated liposomes was more appropriate for use in the tumor-bearing animal model. In addition, the biodistribution of 6 mol% PEG (111)In liposomes showed significantly lower uptake in the liver, spleen, kidneys, small intestine and bone marrow than those of 0.9 mol% PEG (111)In liposomes. The clearance rate of both drugs from the blood decreased with time, with the maximum at 24 h post intravenous (i.v.) injection. Prominent tumor uptake and the highest tumor/muscle ratios were found at 48 h post injection. Both AUC and relative ratio of the AUCs (RR-AUC) also showed that 6 mol% PEGylated liposomes significantly reduced the uptake of drugs in the reticuloendothelial system (RES), yet enhanced the uptake in the tumor. Gamma scintigraphy at 48 h post injection also demonstrated more distinct tumor uptake with 6 mol% PEG (111)In liposomes as compared to that of 0.9 mol% PEGylated liposomes (p<0.01). BLI and in vivo tumor growth tracing showed that growth in tumor volume could largely be inhibited by 6 mol% PEG (111)In liposomes. The results suggest that 6 mol% PEGylated liposomes might be a more suitable liposomal carrier for drug delivery than 0.9 mol% PEGylated liposomes, not only by reducing the drug accumulation in the RES or its related organs, but by prolonging drug circulation and eventually enhancing the targeting efficiency in the tumor to reach a better therapeutic index.

Unlike conventional liposomes, sterically stabilized liposomes, with their smaller volume of distribution and reduced clearance, preferentially convey encapsulated drugs into tumor sites. Despite these improvements, intracellular delivery is hampered by the stable drug retention of the liposomes, which diminishes the efficacy of the liposomal drug. To facilitate uptake of liposomal drugs into cells, two cell-penetrating peptides, penetratin (PEN) and TAT, derived from the HIV-1 TAT protein, were studied. In contrast to control peptides, both TAT and PEN enhanced the translocation efficiency of liposomes in proportion to the number of peptides attached to the liposomal surface. A peptide number of as few as five could enhance the intracellular delivery of liposomes. The kinetics of uptake was peptide- and cell-type dependent. Intracellular accumulation of TAT-liposomes increased with incubation time, but PEN-liposomes peaked at 1 h and then declined gradually. After treatment with 1 microg/ml doxorubicin equivalents of liposome for 2 h, TAT increased the doxorubicin uptake of A431 cells by 12-fold. However, the improvement of uptake of liposomal doxorubicin was not reflected by cytotoxicity in vitro or tumor control in vivo. Our results demonstrated that merely adding CPP to a liposome encapsulating anticancer drug was inadequate in improving its antitumor activity. An additional approach to enhance the intracellular release of the encapsulated drug is obviously necessary.