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.

Abstract

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. 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. 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. 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.