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. 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 Reliposome. 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-liposometreated 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.

Radionuclide imaging of liposomal drug delivery

“…Dosimetric analysis indicated an effective dose of 3.3 × 10 -2 mSv/MBq for 64 Cu-labeled PEGylated-liposomes, which would be acceptable for using these liposomes as a diagnostic imaging agent in patients [84]. Liposomes have been labeled with 89 Zr to evaluate their pharmacokinetics over a week with PET [6]. Recently, PEGylated-liposomes labeled with 89 Zr as well as with gadolinium ions have been developed.…”

“…Liposomes have been labeled with 89 Zr to evaluate their pharmacokinetics over a week with PET [6]. Recently, PEGylated-liposomes labeled with 89 Zr as well as with gadolinium ions have been developed. This resulted in a liposomal formulation that enabled combined PET and MR imaging.…”

“…In addition, these liposomes were surface-coated with octreotide, a peptide targeting the human somatostatin receptor type II, for specific tumor targeting [85]. In vitro serum protein studies and bone uptake of 89 Zr uptake indicated limited stability of these radiolabeled liposomes. Still, dual PET/MR tracking of the liposomes was feasible and specific tumor uptake was observed.…”

“…To be able to image at later time points to evaluate the dynamics of the accumulation in tumors, liposomes labeled with radionuclides with longer half-lives should be used. Liposomes labeled with 64 Cu (t ½ = 12.7 h) and 89 Zr (t ½ = 78.4 h) have been developed. These liposomes allow for tracking of liposomes for a longer period of time, up to 2 weeks after injection for 89 Zr-labeled liposomes.…”

“…Liposomes labeled with 64 Cu (t ½ = 12.7 h) and 89 Zr (t ½ = 78.4 h) have been developed. These liposomes allow for tracking of liposomes for a longer period of time, up to 2 weeks after injection for 89 Zr-labeled liposomes. PEGliposomes labeled with 64 Cu were used to evaluate PET imaging of cancer lesions and tumor-associated macrophages [56,83,84].…”