title: Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery.
abstract: BACKGROUND
  Modular nanotransporters (MNT) are recombinant multifunctional polypeptides created to exploit a cascade of cellular processes, initiated with membrane receptor recognition to deliver selective short-range and highly cytotoxic therapeutics to the cell nucleus. This research was designed for in vivo concept testing for this drug delivery platform using two modular nanotransporters, one targeted to the α-melanocyte-stimulating hormone (αMSH) receptor overexpressed on melanoma cells and the other to the epidermal growth factor (EGF) receptor overexpressed on several cancers, including glioblastoma, and head-and-neck and breast carcinoma cells.
  
  
  METHODS
  In vivo targeting of the modular nanotransporter was determined by immuno-fluorescence confocal laser scanning microscopy and by accumulation of (125)I-labeled modular nanotransporters. The in vivo therapeutic effects of the modular nanotransporters were assessed by photodynamic therapy studies, given that the cytotoxicity of photosensitizers is critically dependent on their delivery to the cell nucleus.
  
  
  RESULTS
  Immunohistochemical analyses of tumor and neighboring normal tissues of mice injected with multifunctional nanotransporters demonstrated preferential uptake in tumor tissue, particularly in cell nuclei. With (125)I-labeled MNT{αMSH}, optimal tumor:muscle and tumor:skin ratios of 8:1 and 9.8:1, respectively, were observed 3 hours after injection in B16-F1 melanoma-bearing mice. Treatment with bacteriochlorin p-MNT{αMSH} yielded 89%-98% tumor growth inhibition and a two-fold increase in survival for mice with B16-F1 and Cloudman S91 melanomas. Likewise, treatment of A431 human epidermoid carcinoma-bearing mice with chlorin e(6)- MNT{EGF} resulted in 94% tumor growth inhibition compared with free chlorin e(6), with 75% of animals surviving at 3 months compared with 0% and 20% for untreated and free chlorin e(6)-treated groups, respectively.
  
  
  CONCLUSIONS
  The multifunctional nanotransporter approach provides a new in vivo functional platform for drug development that could, in principle, be applicable to any combination of cell surface receptor and agent (photosensitizers, oligonucleotides, radionuclides) requiring nuclear delivery to achieve maximum effectiveness.
authors.affiliation: Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Moscow, Russia.
authors.forename: Tatiana A
authors.initials: TA
authors.lastname: Slastnikova
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Rosenkranz
authors.forename: Pavel V
authors.initials: PV
authors.lastname: Gulak
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Schiffelers
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Lupanova
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Khramtsov
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Sobolev
mesh_terms: D000818:Animals; D001709:Biotechnology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000295:instrumentation* / Q000379:methods; D066246:ErbB Receptors / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D050997:Nanomedicine / Q000379:methods*; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry* / Q000633:toxicity; D010316:Particle Size; D010778:Photochemotherapy / Q000379:methods; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D011166:Porphyrins / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000521:alpha-MSH / Q000493:pharmacokinetics
chemical_list: D007457:Iodine Radioisotopes; D017319:Photosensitizing Agents; D011166:Porphyrins; C452433:bacteriochlorin; D000521:alpha-MSH; C541485:EGFR protein, mouse; D066246:ErbB Receptors