title: Application of vasoactive and matrix-modifying drugs can improve polyplex delivery to tumors upon intravenous administration.
abstract: Low efficacy of cationic polymer-based formulations (polyplexes) for systemic gene delivery to tumors remains the crucial concern for their clinical translation. Here we show that modulating the physiological state of a tumor using clinically approved pharmaceuticals can improve delivery of intravenously injected polyplexes to murine melanoma tumors with different characteristics. Direct comparison of drugs with different mechanisms of action has shown that application of nitroglycerin or losartan improved extravasation and tumor uptake of polyplex nanoparticles, whereas angiotensin II had almost no effect on polyplex accumulation and microdistribution in the tumor tissue. Application of nitroglycerin and losartan caused from 2- to 6-fold enhanced efficacy of polyplex-mediated gene delivery depending on the tumor model. The results obtained on polyplex behavior in tumor tissues depending on physiological state of the tumor can be relevant to optimize delivery of polyplexes and other nanomedicines with similar physicochemical properties.
authors.affiliation: Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, Ul. Vavilova, 34/5, 119334 Moscow, Russia.
authors.forename: Mikhail O
authors.initials: MO
authors.lastname: Durymanov
authors.affiliation: Faculty of Biology, Moscow State University, Leninskie Gory, 1-12, 119234 Moscow, Russia.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Yarutkin
authors.affiliation: Faculty of Biology, Moscow State University, Leninskie Gory, 1-12, 119234 Moscow, Russia; Scientific Research Institute of Physical-Chemical Medicine, Ul. Malaya Pirogovskaya, 1a, 119435 Moscow, Russia.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Bagrov
authors.affiliation: Scientific Research Institute of Physical-Chemical Medicine, Ul. Malaya Pirogovskaya, 1a, 119435 Moscow, Russia.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Klinov
authors.affiliation: P.K. Anokhin Research Institute of Normal Physiology, Ul. Baltiyskaya, 8, 125315 Moscow, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kedrov
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Ul. Institutskaya, 3, 142290 Pushchino, Moscow Region, Russia.
authors.forename: Nikolay K
authors.initials: NK
authors.lastname: Chemeris
authors.affiliation: Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, Ul. Vavilova, 34/5, 119334 Moscow, Russia; Faculty of Biology, Moscow State University, Leninskie Gory, 1-12, 119234 Moscow, Russia.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Rosenkranz
authors.affiliation: Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, Ul. Vavilova, 34/5, 119334 Moscow, Russia; Faculty of Biology, Moscow State University, Leninskie Gory, 1-12, 119234 Moscow, Russia. Electronic address: sobolev@igb.ac.ru.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Sobolev
mesh_terms: D061605:Administration, Intravenous; D000804:Angiotensin II / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage; D016503:Drug Delivery Systems; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D019808:Losartan / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D049409:Luciferases, Firefly / Q000235:genetics; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D053758:Nanoparticles / Q000008:administration & dosage; D005996:Nitroglycerin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D011094:Polyethyleneimine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D024042:Collagen Type I; D009842:Oligopeptides; D044102:Receptor, Melanocortin, Type 1; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C485184:enhanced green fluorescent protein; C544016:poly(ethylene glycol)-co-poly(ethyleneimine); D000804:Angiotensin II; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D004247:DNA; D049409:Luciferases, Firefly; D005996:Nitroglycerin; D019808:Losartan
keywords: Gene delivery; Nanoparticle extravasation; Polyplexes; Tumor uptake; Tumor vasculature