title: Unravelling "off-target" effects of redox-active polymers and polymer multilayered capsules in prostate cancer cells.
abstract: Redox-active polymers and carriers are oxidizing nanoagents that can potentially trigger intracellular off-target effects. In the present study, we investigated the occurrence of off-target effects in prostate cancer cells following exposure to redox-active polymer and thin multilayer capsules with different chemical properties. We show that, depending on the intracellular antioxidant capacity, thiol-functionalized poly(methacrylic acid), PMA(SH) triggers cell defense responses/perturbations that result in off-target effects (i.e., induction of autophagy and down-regulation of survivin). Importantly, the conversion of the carboxyl groups of PMA(SH) into the neutral amides of poly(hydroxypropylmetacrylamide) (pHPMA(SH)) nullified the off-target effects and cytotoxicity in tested cell lines. This suggests that the simultaneous action of carboxyl and disulfide groups in PMA(SH) polymer or capsules may play a role in mediating the intracellular off-target effects. Our work provides evidence that the rational design of redox-active carriers for therapeutic-related application should be guided by a careful investigation on potential disturbance of the cellular machineries related to the carrier association.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Amadeo 42, 20133 Milan, Italy. nadia.zaffaroni@istitutotumori.mi.it.
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Beretta
authors.forename: Marco
authors.initials: M
authors.lastname: Folini
authors.forename: Francesca
authors.initials: F
authors.lastname: Cavalieri
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.forename: Enrico
authors.initials: E
authors.lastname: Fresch
authors.forename: Subramanian
authors.initials: S
authors.lastname: Kaliappan
authors.forename: Christoph
authors.initials: C
authors.lastname: Hasenöhrl
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Richardson
authors.forename: Stella
authors.initials: S
authors.lastname: Tinelli
authors.forename: Andreas
authors.initials: A
authors.lastname: Fery
authors.forename: Frank
authors.initials: F
authors.lastname: Caruso
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D000178:Acrylamides / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D002214:Capsules; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008422:Materials Testing; D010084:Oxidation-Reduction; D011109:Polymethacrylic Acids / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D000178:Acrylamides; D000975:Antioxidants; D002214:Capsules; D011109:Polymethacrylic Acids; C030613:polymethacrylic acid; C032976:N-(2-hydroxypropyl)methacrylamide