In vitro and in vivo characterization of temoporfin-loaded PEGylated PLGA nanoparticles for use in photodynamic therapy.

AIMS In this study we evaluated temoporfin-loaded polyethylene glycol (PEG) Poly-(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) as a new formulation for potential use in cancer treatment. MATERIALS & METHODS NPs were characterized for their photophysical properties, temoporfin release, cellular uptake and intracellular localization, and dark and photocytotoxicities of temoporfin by using A549, MCF10A neoT and U937 cell lines. In vivo imaging was performed on athymic nude-Foxn1 mice. RESULTS Temoporfin was highly aggregated within the NPs and the release of temoporfin monomers was faster from PEGylated PLGA NPs than from non-PEGylated ones. PEGylation significantly reduced the cellular uptake of NPs by the differentiated promonocytic U937 cells, revealing the stealth properties of the delivery system. Dark cytotoxicity of temoporfin delivered by NPs was less than that of free temoporfin in standard solution (Foscan(®), Biolitec AG [Jena, Germany]), whereas phototoxicity was not reduced. Temoporfin delivered to mice by PEGylated PLGA NPs exhibits therapeutically favorable tissue distribution. CONCLUSION These encouraging results show promise in using PEGylated PLGA NPs for improving the delivery of photosensitizers for photodynamic therapy.

[1]  M. C. Berenbaum,et al.  Photodynamic therapy with chlorins for diffuse malignant mesothelioma: initial clinical results. , 1991, British journal of cancer.

[2]  R. Senior,et al.  12-o-Tetradecanoyl-phorbol-13-acetate-differentiated U937 cells express a macrophage-like profile of neutral proteinases. High levels of secreted collagenase and collagenase inhibitor accompany low levels of intracellular elastase and cathepsin G. , 1986, The Journal of clinical investigation.

[3]  J. Kos,et al.  Poly(lactide-co-glycolide) nanoparticles as a carrier system for delivering cysteine protease inhibitor cystatin into tumor cells. , 2004, Experimental cell research.

[4]  T. Kiesslich,et al.  Comparative in vitro study on the characteristics of different photosensitizers employed in PDT. , 2010, Journal of photochemistry and photobiology. B, Biology.

[5]  P. McCarron,et al.  Photosensitiser delivery for photodynamic therapy. Part 2: systemic carrier platforms , 2008 .

[6]  Jayanth Panyam,et al.  Rapid endo‐lysosomal escape of poly(DL‐lactide‐coglycolide) nanoparticles: implications for drug and gene delivery , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  J. Kos,et al.  Proinflammatory effects of bare and PEGylated ORMOSIL-, PLGA- and SUV-NPs on monocytes and PMNs and their modulation by f-MLP. , 2011, Nanomedicine.

[8]  F. Guillemin,et al.  Correlation between in vivo pharmacokinetics, intratumoral distribution and photodynamic efficiency of liposomal mTHPC. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[9]  L. Bezdetnaya,et al.  Spectroscopic and Biological Testing of Photobleaching of Porphyrins in Solutions * , 1996, Photochemistry and photobiology.

[10]  D. Vernon,et al.  Identification and Partial Characterization of an Unusual Distribution of the Photosensitizer meta‐Tetrahydroxyphenyl Chlorin (Temoporfin) in Human Plasma , 1999, Photochemistry and photobiology.

[11]  K. Avgoustakis,et al.  Biodistribution properties of nanoparticles based on mixtures of PLGA with PLGA-PEG diblock copolymers. , 2005, International journal of pharmaceutics.

[12]  J. Kos,et al.  Nanoscale polymer carriers to deliver chemotherapeutic agents to tumours , 2005, Expert opinion on biological therapy.

[13]  A. Moor,et al.  Signaling pathways in cell death and survival after photodynamic therapy. , 2000, Journal of photochemistry and photobiology. B, Biology.

[14]  R. Gurny,et al.  Toward the understanding of the photodynamic activity of m-THPP encapsulated in PLGA nanoparticles: correlation between nanoparticle properties and in vivo activity , 2009, Journal of drug targeting.

[15]  Robert Gurny,et al.  Enhanced photodynamic activity of meso-tetra(4-hydroxyphenyl)porphyrin by incorporation into sub-200 nm nanoparticles. , 2003, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[16]  N. Oleinick,et al.  The photobiology of photodynamic therapy: cellular targets and mechanisms. , 1998, Radiation research.

[17]  H. Maeda,et al.  Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[18]  Stanley B. Brown,et al.  The high photoactivity of m-THPC in photodynamic therapy. Unusually strong retention of m-THPC by RIF-1 cells in culture. , 1999 .

[19]  K. Avgoustakis,et al.  Effect of copolymer composition on the physicochemical characteristics, in vitro stability, and biodistribution of PLGA-mPEG nanoparticles. , 2003, International journal of pharmaceutics.

[20]  G. Miotto,et al.  The cellular uptake of meta-tetra(hydroxyphenyl)chlorin entrapped in organically modified silica nanoparticles is mediated by serum proteins , 2009, Nanotechnology.

[21]  C. M. Agrawal,et al.  Sterilization, toxicity, biocompatibility and clinical applications of polylactic acid/polyglycolic acid copolymers. , 1996, Biomaterials.

[22]  Kohei Tahara,et al.  Improved cellular uptake of chitosan-modified PLGA nanospheres by A549 cells. , 2009, International journal of pharmaceutics.

[23]  Nicholas A Peppas,et al.  Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. , 2006, International journal of pharmaceutics.

[24]  G. Dolivet,et al.  Temoporfin‐mediated photodynamic therapy in patients with advanced, incurable head and neck cancer: A multicenter study , 2010, Head & neck.

[25]  Stephen G Bown,et al.  Photodynamic therapy for prostate cancer recurrence after radiotherapy: a phase I study. , 2002, The Journal of urology.

[26]  Matthias G. Wacker,et al.  Photosensitizer loaded HSA nanoparticles II: in vitro investigations. , 2011, International journal of pharmaceutics.

[27]  V. Labhasetwar,et al.  Biodegradable nanoparticles for cytosolic delivery of therapeutics. , 2007, Advanced drug delivery reviews.

[28]  Zhiyuan Hu,et al.  Meso-tetra (carboxyphenyl) porphyrin (TCPP) nanoparticles were internalized by SW480 cells by a clathrin-mediated endocytosis pathway to induce high photocytotoxicity. , 2009, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[29]  I. Tan,et al.  mTHPC‐mediated photodynamic therapy for early oral squamous cell carcinoma , 2004, International journal of cancer.

[30]  R. Gurny,et al.  Improved photodynamic activity of porphyrin loaded into nanoparticles: an in vivo evaluation using chick embryos. , 2004, International journal of pharmaceutics.

[31]  Peter H Lin,et al.  Current advances in research and clinical applications of PLGA-based nanotechnology , 2009, Expert review of molecular diagnostics.

[32]  P. Morlière,et al.  Endoplasmic reticulum and Golgi apparatus are the preferential sites of Foscan® localisation in cultured tumour cells , 2003, British Journal of Cancer.

[33]  François Guillemin,et al.  Investigation of Foscan interactions with plasma proteins. , 2005, Biochimica et biophysica acta.

[34]  Yong Zhang,et al.  Nanoparticles in photodynamic therapy: an emerging paradigm. , 2008, Advanced drug delivery reviews.

[35]  R. Gurny,et al.  Encapsulation of p-THPP into Nanoparticles: Cellular Uptake, Subcellular Localization and Effect of Serum on Photodynamic Activity¶ , 2003 .

[36]  G. Jori,et al.  Tumour photosensitizers: approaches to enhance the selectivity and efficiency of photodynamic therapy. , 1996, Journal of photochemistry and photobiology. B, Biology.

[37]  R. Gurny,et al.  In vitro and in vivo activities of verteporfin-loaded nanoparticles. , 2005, Journal of controlled release : official journal of the Controlled Release Society.