title: Polymeric nanotheranostics for real-time non-invasive optical imaging of breast cancer progression and drug release.
abstract: Polymeric nanocarriers conjugated with low molecular weight drugs are designed in order to improve their efficacy and toxicity profile. This approach is particularly beneficial for anticancer drugs, where the polymer-drug conjugates selectively accumulate at the tumor site, due to the enhanced permeability and retention (EPR) effect. The conjugated drug is typically inactive, and upon its pH- or enzymatically-triggered release from the carrier, it regains its therapeutic activity. These settings lack information regarding drug-release time, kinetics and location. Thereby, real-time non-invasive intravital monitoring of drug release is required for theranostics (therapy and diagnostics). We present here the design, synthesis and characterization of a theranostic nanomedicine, based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer, owing its fluorescence-based monitoring of site-specific drug release to a self-quenched near-infrared fluorescence (NIRF) probe. We designed two HPMA copolymer-based systems that complement to a theranostic nanomedicine. The diagnostic system consists of self-quenched Cy5 (SQ-Cy5) as a reporter probe and the therapeutic system is based on the anticancer agent paclitaxel (PTX). HPMA copolymer-PTX/SQ-Cy5 systems enable site-specific release upon enzymatic degradation in cathepsin B-overexpressing breast cancer cells. The release of the drug occurs concomitantly with the activation of the fluorophore to its Turn-ON state. HPMA copolymer-SQ-Cy5 exhibits preferable body distribution and drug release compared with the free drug and probe when administered to cathepsin B-overexpressing 4T1 murine mammary adenocarcinoma-bearing mice. This approach of co-delivery of two complementary systems serves as a proof-of-concept for real-time deep tissue intravital orthotopic monitoring and may have the potential use in clinical utility as a theranostic nanomedicine.
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Ferber
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Hemda
authors.initials: H
authors.lastname: Baabur-Cohen
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Blau
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Yana
authors.initials: Y
authors.lastname: Epshtein
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Einat
authors.initials: E
authors.lastname: Kisin-Finfer
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Redy
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Shabat
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: ronitsf@post.tau.ac.il.
authors.forename: Ronit
authors.initials: R
authors.lastname: Satchi-Fainaro
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003952:Diagnostic Imaging; D004337:Drug Carriers; D005260:Female; D005456:Fluorescent Dyes; D008689:Methacrylates; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D049329:Nanostructures; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D005456:Fluorescent Dyes; D008689:Methacrylates; D017239:Paclitaxel; C032802:hydroxypropyl methacrylate
keywords: Breast cancer; NIR fluorophore; Paclitaxel; Polymeric nanomedicines; Theranostics; Tumor targeting