title: Nanocarriers for photodynamic therapy-rational formulation design and medium-scale manufacture.
abstract: The development and manufacture of novel nanocarriers for drug delivery has proved challenging with regards to scale-up and pharmaceutical quality. Polymeric nanocarriers composed of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-PEG) were prepared and the photosensitizer meso-tetrakis(3-hydroxyphenyl) chlorin (mTHPC) was effectively encapsulated. Furthermore, the interplay of various process and formulation parameters and their impact on the most important product specifications were investigated by using a factorial design and a central composite design in a microfluidic manufacturing process. These nanoparticles for intravenous administration with a size of 97 ± 0.13 nm, narrow size distribution, and an encapsulation efficiency of more than 80% were produced at high throughput. In vitro stability and in vitro drug release testing were applied for quality control purposes. Finally, the toxicity of the photosensitizer was tested in vitro. The cytotoxicity was successfully reduced while the efficacy of the formulation was maintained. First observations using in vivo imaging suggest effective distribution of the nanocarrier system after injection into rodents. Thus, further in vivo testing of the beneficial effects of nanoencapsulation into the matrix system and its formulation will be considered for the delivery of mTHPC to tumor tissues during photodynamic therapy.
authors.affiliation: Laboratory of R&D of Drug Delivery Systems, Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacy, State University of Maringá, Av. Colombo, 5790, Maringá, Paraná, Brazil.
authors.forename: Mônica
authors.initials: M
authors.lastname: Villa Nova
authors.affiliation: Institute of Pharmaceutical Technology, Goethe University, 60438 Frankfurt (Main), Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Janas
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project group for Translational Medicine & Pharmacology (TMP), 60596 Frankfurt/ Main, Germany.
authors.forename: Mike
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project group for Translational Medicine & Pharmacology (TMP), 60596 Frankfurt/ Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ulshoefer
authors.affiliation: biolitec research GmbH, Otto-Schott-Str. 15, 07745 Jena, Germany.
authors.forename: Susanna
authors.initials: S
authors.lastname: Gräfe
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project group for Translational Medicine & Pharmacology (TMP), 60596 Frankfurt/ Main, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schiffmann
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project group for Translational Medicine & Pharmacology (TMP), 60596 Frankfurt/ Main, Germany.
authors.forename: Natasja
authors.initials: N
authors.lastname: de Bruin
authors.affiliation: biolitec research GmbH, Otto-Schott-Str. 15, 07745 Jena, Germany.
authors.forename: Arno
authors.initials: A
authors.lastname: Wiehe
authors.affiliation: biolitec research GmbH, Otto-Schott-Str. 15, 07745 Jena, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Albrecht
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project group for Translational Medicine & Pharmacology (TMP), 60596 Frankfurt/ Main, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parnham
authors.affiliation: Laboratory of R&D of Drug Delivery Systems, Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacy, State University of Maringá, Av. Colombo, 5790, Maringá, Paraná, Brazil.
authors.forename: Marcos
authors.initials: M
authors.lastname: Luciano Bruschi
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project group for Translational Medicine & Pharmacology (TMP), 60596 Frankfurt/ Main, Germany. Electronic address: matthias.wacker@ime.fraunhofer.de.
authors.forename: Matthias G
authors.initials: MG
authors.lastname: Wacker
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D015195:Drug Design; D004345:Drug Industry / Q000379:methods; D006801:Humans; D008652:Mesoporphyrins / Q000737:chemistry; D051379:Mice; D046210:Microfluidic Analytical Techniques; D049329:Nanostructures / Q000737:chemistry*; D010316:Particle Size; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D008652:Mesoporphyrins; D017319:Photosensitizing Agents; D011091:Polyesters; C558447:methoxypolyethyleneglycol-poly(lactic-co-glycolic acid); D011092:Polyethylene Glycols; C072269:temoporfin
keywords: Experimental design; Microreactor technology; PLGA–PEG; Photodynamic therapy; Photosensitizer; mTHPC