title: Nanoparticulate carriers for photodynamic therapy of cholangiocarcinoma: In vitro comparison of various polymer-based nanoparticles.
abstract: The photodynamic therapy with porphyrin derivatives is an established approach to targeted tumor therapy, but is still afflicted with disadvantages of the physicochemical characteristics of the photosensitizer. To overcome drug-related restrictions in photodynamic therapy, three 5,10,15,20-tetrakis(m-hydroxyphenyl) porphyrin (mTHPP)-loaded nanoparticulate formulations based on poly(dl-lactide-co-glycolide) (PLGA), poly(d,l-lactide) (PLA), and Eudragit(®) E were prepared in a consistent diameter range and compared with free mTHPP in vitro. Formulation behavior was investigated in two different cholangiocellular cell lines, EGI-1 and TFK-1. High cytotoxicity was shown for all photosensitizer loaded nanoparticle (NP) formulations and free mTHPP, with EC50 values ranging from 0.2 to 1.3μM. PLA based NP were not as effective in all performed tests as other formulations. Nanoparticulate embedded mTHPP remained photodynamically active and resulted in caspase-3 activation even at low concentrations of 250nM. PLGA based NP exhibited highest caspase-3 activation. For all formulations an effective intracellular accumulation of mTHPP was observed, whereby for mTHPP-Eudragit(®) E-NP a 200-fold drug accumulation was shown. Polymer based nanoparticles were shown to be an effective and highly active transport vehicle for the photosensitizer mTHPP in vitro. Problems like low solubility of free drug can be circumvented by successful embedding into nanoparticulate carrier systems, maintaining therapeutic effects of the photosensitizer.
authors.affiliation: Institute of Pharmaceutical Technology and Biopharmacy, University of Muenster, Corrensstraße 48, 48149 Münster, Germany. Electronic address: j.gruenebaum@wwu.de.
authors.forename: Jonas
authors.initials: J
authors.lastname: Grünebaum
authors.affiliation: Institute of Pharmaceutical Technology and Biopharmacy, University of Muenster, Corrensstraße 48, 48149 Münster, Germany. Electronic address: j.soebbing@wwu.de.
authors.forename: Judith
authors.initials: J
authors.lastname: Söbbing
authors.affiliation: Institute of Pharmaceutical Technology and Biopharmacy, University of Muenster, Corrensstraße 48, 48149 Münster, Germany. Electronic address: mulac.dennis@wwu.de.
authors.forename: Dennis
authors.initials: D
authors.lastname: Mulac
authors.affiliation: Institute of Pharmaceutical Technology and Biopharmacy, University of Muenster, Corrensstraße 48, 48149 Münster, Germany. Electronic address: k.langer@wwu.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Langer
mesh_terms: D001650:Bile Duct Neoplasms / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D018281:Cholangiocarcinoma / Q000188:drug therapy*; D002843:Chromatin / Q000737:chemistry; D004337:Drug Carriers; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D010778:Photochemotherapy; D011108:Polymers / Q000737:chemistry*
chemical_list: D002843:Chromatin; D004337:Drug Carriers; D011108:Polymers; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3
keywords: Cholangiocarcinoma; Cytotoxicity; Drug delivery system; Nanoparticle; Photodynamic therapy; Polymer influence