title: Ionizing radiation improves glioma-specific targeting of superparamagnetic iron oxide nanoparticles conjugated with cmHsp70.1 monoclonal antibodies (SPION-cmHsp70.1).
abstract: The stress-inducible 72 kDa heat shock protein Hsp70 is known to be expressed on the membrane of highly aggressive tumor cells including high-grade gliomas, but not on the corresponding normal cells. Membrane Hsp70 (mHsp70) is rapidly internalized into tumor cells and thus targeting of mHsp70 might provide a promising strategy for theranostics. Superparamagnetic iron oxide nanoparticles (SPIONs) are contrast negative agents that are used for the detection of tumors with MRI. Herein, we conjugated the Hsp70-specific antibody (cmHsp70.1) which is known to recognize mHsp70 to superparamagnetic iron nanoparticles to assess tumor-specific targeting before and after ionizing irradiation. In vitro experiments demonstrated the selectivity of SPION-cmHsp70.1 conjugates to free and mHsp70 in different tumor cell types (C6 glioblastoma, K562 leukemia, HeLa cervix carcinoma) in a dose-dependent manner. High-resolution MRI (11 T) on T(2)-weighted images showed the retention of the conjugates in the C6 glioma model. Accumulation of SPION-cmHsp70.1 nanoparticles in the glioma resulted in a nearly 2-fold drop of T*(2) values in comparison to non-conjugated SPIONs. Biodistribution analysis using NLR-M(2) measurements showed a 7-fold increase in the tumor-to-background (normal brain) uptake ratio of SPION-cmHsp70.1 conjugates in glioma-bearing rats in comparison to SPIONs. This accumulation within Hsp70-positive glioma was further enhanced after a single dose (10 Gy) of ionizing radiation. Elevated accumulation of the magnetic conjugates in the tumor due to radiosensitization proves the combination of radiotherapy and application of Hsp70-targeted agents in brain tumors.
authors.affiliation: Institute of Cytology of the Russian Academy of Sciences (RAS), Tikhoretsky ave., 4, St. Petersburg, 194064, Russia. shevtsov-max@mail.ru.
authors.forename: Maxim A
authors.initials: MA
authors.lastname: Shevtsov
authors.forename: Boris P
authors.initials: BP
authors.lastname: Nikolaev
authors.forename: Vyacheslav A
authors.initials: VA
authors.lastname: Ryzhov
authors.forename: Ludmila Y
authors.initials: LY
authors.lastname: Yakovleva
authors.forename: Yaroslav Y
authors.initials: YY
authors.lastname: Marchenko
authors.forename: Marina A
authors.initials: MA
authors.lastname: Parr
authors.forename: Valerij I
authors.initials: VI
authors.lastname: Rolich
authors.forename: Anastasiya L
authors.initials: AL
authors.lastname: Mikhrina
authors.forename: Anatolii V
authors.initials: AV
authors.lastname: Dobrodumov
authors.forename: Emil
authors.initials: E
authors.lastname: Pitkin
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000737:chemistry / Q000494:pharmacology; D001932:Brain Neoplasms / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods*; D016503:Drug Delivery Systems / Q000379:methods*; D005720:Gamma Rays / Q000627:therapeutic use*; D005910:Glioma / Q000628:therapy*; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018840:HSP70 Heat-Shock Proteins; D058185:Magnetite Nanoparticles