title: Mixed Nanosized Polymeric Micelles as Promoter of Doxorubicin and miRNA-34a Co-Delivery Triggered by Dual Stimuli in Tumor Tissue.
abstract: Dual stimuli-sensitive mixed polymeric micelles (MM) are developed for co-delivery of the endogenous tumor suppressor miRNA-34a and the chemotherapeutic agent doxorubicin (Dox) into cancer cells. The novelty of the system resides in two stimuli-sensitive prodrugs, a matrix metalloproteinase 2 (MMP2)-sensitive Dox conjugate and a reducing agent (glutathione, GSH)-sensitive miRNA-34a conjugate, self-assembled in a single particle decorated with a polyethylene glycol corona for longevity, and a cell-penetrating peptide (TATp) for enhanced intracellular delivery. The MMP2-sensitivity of the system results in threefold higher cytotoxicity in MMP2-overexpressing HT1080 cells compared to low MMP2-expressing MCF7 cells. Cellular internalization of Dox increases by more than 70% after inclusion of TATp to the formulation. MMP2-sensitive MM also inhibits proliferation and migration of HT1080 cells. Moreover, GSH-sensitive MM allows for an efficient downregulation of Bcl2, survivin, and notch1 (65%, 55%, and 46%, respectively) in HT1080 cells. Combination of both conjugates in dual sensitive MM reduces HT1080 cell viability to 40% and expression of Bcl2 and survivin. Finally, 50% cell death is observed in 3D models of tumor mass. The results confirm the potential of the MM to codeliver miRNA-34a and doxorubicin triggered by dual stimuli inherent of tumor tissues.
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, 02115, USA.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Salzano
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, 02115, USA.|CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, 70040-020, Brazil.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Costa
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, 02115, USA.
authors.forename: Can
authors.initials: C
authors.lastname: Sarisozen
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA.
authors.forename: Ed
authors.initials: E
authors.lastname: Luther
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA.
authors.forename: George
authors.initials: G
authors.lastname: Mattheolabakis
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, 02115, USA.
authors.forename: Pooja P
authors.initials: PP
authors.lastname: Dhargalkar
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, 02115, USA. v.torchilin@neu.edu.|Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia. v.torchilin@neu.edu.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018014:Gene Transfer Techniques; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008823:Micelles; D035683:MicroRNAs / Q000008:administration & dosage* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010316:Particle Size; D011108:Polymers / Q000737:chemistry*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism
chemical_list: C522425:MIRN34 microRNA, human; D008823:Micelles; D035683:MicroRNAs; D011108:Polymers; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2; D005978:Glutathione
keywords: doxorubicin; miRNA-34a; mixed micelles; spheroid; stimuli-sensitive, cancer therapy