title: pH-Switch Nanoprecipitation of Polymeric Nanoparticles for Multimodal Cancer Targeting and Intracellular Triggered Delivery of Doxorubicin.
abstract: Theranostic nanoparticles are emerging as potent tools for noninvasive diagnosis, treatment, and monitoring of solid tumors. Herein, an advanced targeted and multistimuli responsive theranostic platform is presented for the intracellular triggered delivery of doxorubicin. The system consists of a polymeric-drug conjugate solid nanoparticle containing encapsulated superparamagnetic iron oxide nanoparticles (IO@PNP) and decorated with a tumor homing peptide, iRGD. The production of this nanosystem is based on a pH-switch nanoprecipitation method in organic-free solvents, making it ideal for biomedical applications. The nanosystem shows sufficient magnetization saturation for magnetically guided therapy along with reduced cytotoxicity and hemolytic effects. IO@PNP are largely internalized by endothelial and metastatic cancer cells and iRGD decorated IO@PNP moderately enhance their internalization into endothelial cells, while no enhancement is found for the metastatic cancer cells. Poly(ethylene glycol)-block-poly(histidine) with pH-responsive and proton-sponge properties promotes prompt lysosomal escape once the nanoparticles are endocyted. In addition, the polymer-doxorubicin conjugate solid nanoparticles show both intracellular lysosomal escape and efficient translocation of doxorubicin to the nuclei of the cells via cleavage of the amide bond. Overall, IO@PNP-doxorubicin and the iRGD decorated counterpart demonstrate to enhance the toxicity of doxorubicin in cancer cells by improving the intracellular delivery of the drug carried in the IO@PNP.
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E (P. O. Box 56), 00014, Helsinki, Finland.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Herranz-Blanco
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E (P. O. Box 56), 00014, Helsinki, Finland.
authors.forename: Mohammad-Ali
authors.initials: MA
authors.lastname: Shahbazi
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E (P. O. Box 56), 00014, Helsinki, Finland.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Correia
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E (P. O. Box 56), 00014, Helsinki, Finland.
authors.forename: Vimalkumar
authors.initials: V
authors.lastname: Balasubramanian
authors.affiliation: Department of Physics, University of Helsinki, Gustaf Hällströmin katu 2a (P. O. Box 64), 00560, Helsinki, Finland.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Kohout
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E (P. O. Box 56), 00014, Helsinki, Finland.
authors.forename: Jouni
authors.initials: J
authors.lastname: Hirvonen
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E (P. O. Box 56), 00014, Helsinki, Finland.
authors.forename: Hélder A
authors.initials: HA
authors.lastname: Santos
mesh_terms: D045744:Cell Line, Tumor; D020099:Coated Materials, Biocompatible / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D058185:Magnetite Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D020099:Coated Materials, Biocompatible; D058185:Magnetite Nanoparticles; C569656:N-end cysteine peptide tumor-homing peptide; D009842:Oligopeptides; D004317:Doxorubicin
keywords: SPION; iRGD; lysosomal escape; poly(histidine); theranostic nanoparticles