Microdistribution of MC1R-targeted polyplexes in murine melanoma tumor tissue.
Targeted sodium-iodide symporter (NIS) gene transfer can be considered as a promising approach for diagnostics of specific types of cancer. For this purpose we used targeted polyplexes based on PEI-PEG-MC1SP block-copolymer containing MC1SP-peptide, a ligand specific for melanocortin receptor-1 (MC1R) overexpressed on melanoma cells. Targeted polyplexes demonstrated enhanced NIS gene transfer compared to non-targeted (lacking MC1SP) ones in vitro. Using dorsal skinfold chamber and intravital microscopy we evaluated accumulation and microdistribution of quantum dot-labeled polyplexes in tumor and normal subcutaneous tissues up to 4 h after intravenous injection. Polyplexes demonstrated significantly higher total accumulation in tumor tissue in comparison with subcutaneous ones (control). Targeted and non-targeted polyplexes extravasated and penetrated into the tumor tissue up to 20 μm from the vessel walls. In contrast, in normal subcutaneous tissue polyplexes penetrated not more than 3 μm from the vessel walls with the level of extravasated polyplexes 400-fold less than in tumor. Accumulated polyplexes in tumor tissue caused NIS gene expression. Subsequent (123)I(-) intravenous injection resulted in 6.8 ± 1.1 and 4.5 ± 0.8% ID/g (p < 0.001) iodide accumulation in tumors in the case of targeted and non-targeted polyplexes, respectively, as was shown using SPECT/CT.
Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5, Vavilov St., 119334 Moscow, Russia; Department of Biophysics, Faculty of Biology, Moscow State University, 1-12, Leninskie Gory, 119991 Moscow, Russia. Electronic address: mdurymanov@gmail.com.
Mikhail O
MO
Durymanov
Tatiana A
TA
Slastnikova
Alexey I
AI
Kuzmich
Yuri V
YV
Khramtsov
Alexey V
AV
Ulasov
Andrey A
AA
Rosenkranz
Sergey Y
SY
Egorov
Eugene D
ED
Sverdlov
Alexander S
AS
Sobolev
D000818:Animals; D002460:Cell Line; D018014:Gene Transfer Techniques; D008545:Melanoma / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000378:metabolism*
D011108:Polymers; D044102:Receptor, Melanocortin, Type 1
Block-copolymer; Confocal microscopy; Intratumoral distribution; Nanoparticles; Targeted gene transfer; Tumor diagnostics