Therapeutic efficacy evaluation of 111In-labeled PEGylated liposomal vinorelbine in murine colon carcinoma with multimodalities of molecular imaging.
In our previous studies using combined radioisotopes with chemotherapeutic liposomal drugs (i.e., (111)In-labeled polyethylene glycol (PEG)ylated liposomal vinorelbine) we have reported possible therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this chemotherapy has a therapeutic effect as good as that of combination therapy. The goal of this study was to investigate the real therapeutic effectiveness of 6 mol% PEG (111)In-vinorelbine liposomes via the elevation of the radiation dosage and reduction in the concentration of chemotherapeutic agents.


METHODS
Murine colon carcinoma cells transfected with dual-reporter genes (CT-26/tk-luc) were xenografted into BALB/c mice. The biodistribution was estimated to determine the drug profile and targeting efficiency of (111)In-vinorelbine liposomes. Bioluminescence imaging and (18)F-FDG small-animal PET were applied to monitor the therapeutic response after drug administration. The survival in vivo was estimated and linked with the toxicologic and histopathologic analyses to determine the preclinical safety and feasibility of the nanomedicine.


RESULTS
Effective long-term circulation of radioactivity in the plasma was achieved by 6 mol% PEG (111)In-vinorelbine liposomes, and this dose showed significantly lower uptake in the reticuloendothelial system than that of 0.9 mol% PEG (111)In-vinorelbine liposomes. Selective tumor uptake was represented by cumulative deposition, and the maximum accumulation was at 48 h after injection. The combination therapy exhibited an additive effect for tumor growth suppression as tracked by caliper measurement, bioluminescence imaging, and small-animal PET. Furthermore, an improved survival rate and reduced tissue toxicity were closely correlated with the toxicologic and histopathologic results.


CONCLUSIONS
The results demonstrated that the use of 6 mol% PEG (111)In-vinorelbine liposomes for passively targeted tumor therapy displayed an additive effect with combined therapy, not only by prolonging the circulation rate because of a reduction in the phagocytic effect of the reticuloendothelial system but also by enhancing tumor uptake. Thus, this preclinical study suggests that 6 mol% PEG (111)In-vinorelbine liposomes have the potential to increase the therapeutic index and reduce the toxicity of the passively nanotargeted chemoradiotherapies.
Chow
Tong-Hsien
TH
Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
Lin
Yi-Yu
YY
Hwang
Jeng-Jong
JJ
Wang
Hsin-Ell
HE
Tseng
Yun-Long
YL
Pang
Victor Fei
VF
Liu
Ren-Shyan
RS
Lin
Wuu-Jyh
WJ
Yang
Chung-Shi
CS
Ting
Gann
G
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D004305:Dose-Response Relationship, Drug; D019788:Fluorodeoxyglucose F18; D007205:Indium Radioisotopes / Q000737:chemistry*; D007553:Isotope Labeling; D008081:Liposomes; D008163:Luminescent Measurements; D051379:Mice; D008807:Mice, Inbred BALB C; D057054:Molecular Imaging; D011092:Polyethylene Glycols / Q000737:chemistry*; D049268:Positron-Emission Tomography; D011829:Radiation Dosage; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000077235:Vinorelbine
D007205:Indium Radioisotopes; D008081:Liposomes; D019788:Fluorodeoxyglucose F18; D011092:Polyethylene Glycols; D014747:Vinblastine; D000077235:Vinorelbine