Metronomic Photodynamic Therapy with Conjugated Polymer Nanoparticles in Glioblastoma Tumor Microenvironment

Alternative therapies such as photodynamic therapy (PDT) that combine light, oxygen and photosensitizers (PSs) have been proposed for glioblastoma (GBM) management to overcome conventional treatment issues. An important disadvantage of PDT using a high light irradiance (fluence rate) (cPDT) is the abrupt oxygen consumption that leads to resistance to the treatment. PDT metronomic regimens (mPDT) involving administering light at a low irradiation intensity over a relatively long period of time could be an alternative to circumvent the limitations of conventional PDT protocols. The main objective of the present work was to compare the effectiveness of PDT with an advanced PS based on conjugated polymer nanoparticles (CPN) developed by our group in two irradiation modalities: cPDT and mPDT. The in vitro evaluation was carried out based on cell viability, the impact on the macrophage population of the tumor microenvironment in co-culture conditions and the modulation of HIF-1α as an indirect indicator of oxygen consumption. mPDT regimens with CPNs resulted in more effective cell death, a lower activation of molecular pathways of therapeutic resistance and macrophage polarization towards an antitumoral phenotype. Additionally, mPDT was tested in a GBM heterotopic mouse model, confirming its good performance with promising tumor growth inhibition and apoptotic cell death induction.

[1]  H. Stepp,et al.  Interstitial Photodynamic Therapy of Glioblastomas: A Long-Term Follow-up Analysis of Survival and Volumetric MRI Data , 2023, Cancers.

[2]  L. E. Ibarra,et al.  Exploring Monocytes-Macrophages in Immune Microenvironment of Glioblastoma for the Design of Novel Therapeutic Strategies , 2023, Brain sciences.

[3]  O. Tillement,et al.  Targeting Glioblastoma-Associated Macrophages for Photodynamic Therapy Using AGuIX®-Design Nanoparticles , 2023, Pharmaceutics.

[4]  M. Jager,et al.  Current Challenges and Opportunities of Photodynamic Therapy against Cancer , 2023, Pharmaceutics.

[5]  Qiong Yuan,et al.  A pH-Responsive Drug Delivery System Based on Conjugated Polymer for Effective Synergistic Chemo-/Photodynamic Therapy , 2023, Molecules.

[6]  Seung-Jin Jung,et al.  Conjugated Polymer Nanoparticles: Photothermal and Photodynamic Capabilities According to Molecular Ordering in Their Assembly Structures , 2022, Macromolecules.

[7]  F. Alustiza,et al.  Development and biological evaluation of pNIPAM-based nanogels as vaccine carriers. , 2022, International journal of pharmaceutics.

[8]  Y. Muragaki,et al.  Photodynamic therapy for malignant brain tumors in children and young adolescents , 2022, Frontiers in Oncology.

[9]  D. Aebisher,et al.  The Use of Photodynamic Therapy in the Treatment of Brain Tumors—A Review of the Literature , 2022, Molecules.

[10]  Emmanuel Odella,et al.  Sweet light o' mine: Photothermal and photodynamic inactivation of tenacious pathogens using conjugated polymers. , 2022, Journal of photochemistry and photobiology. B, Biology.

[11]  L. Cerchia,et al.  Selective Photo-Assisted Eradication of Triple-Negative Breast Cancer Cells through Aptamer Decoration of Doped Conjugated Polymer Nanoparticles , 2022, Pharmaceutics.

[12]  J. Hossain,et al.  Tumor-Associated Macrophages in Gliomas—Basic Insights and Treatment Opportunities , 2022, Cancers.

[13]  S. Vanzulli,et al.  Photosensitization of a subcutaneous tumour by the natural anthraquinone parietin and blue light , 2021, Scientific Reports.

[14]  L. E. Ibarra.  Development of nanosystems for active tumor targeting in photodynamic therapy. , 2021, Therapeutic delivery.

[15]  N. Reyns,et al.  Interstitial Photodynamic Therapy for Glioblastomas: A Standardized Procedure for Clinical Use , 2021, Cancers.

[16]  Nicola H. Green,et al.  In Vitro Low-Fluence Photodynamic Therapy Parameter Screening Using 3D Tumor Spheroids Shows that Fractionated Light Treatments Enhance Phototoxicity. , 2021, ACS biomaterials science & engineering.

[17]  S. Gibson,et al.  Reactive Oxygen Species (ROS) Regulates Different Types of Cell Death by Acting as a Rheostat , 2021, Oxidative medicine and cellular longevity.

[18]  P. López-Larrubia,et al.  Iron Oxide Incorporated Conjugated Polymer Nanoparticles for Simultaneous Use in Magnetic Resonance and Fluorescent Imaging of Brain Tumors , 2021, Pharmaceutics.

[19]  I. S. Cogno,et al.  Light-activated green drugs: How we can use them in photodynamic therapy and mass-produce them with biotechnological tools , 2021 .

[20]  E. Terreno,et al.  Sonodynamic Treatment Induces Selective Killing of Cancer Cells in an In Vitro Co-Culture Model , 2021, Cancers.

[21]  J. F. Algorri,et al.  Light Technology for Efficient and Effective Photodynamic Therapy: A Critical Review , 2021, Cancers.

[22]  Zhihong Chen,et al.  Macrophage-tumor cell intertwine drives the transition into a mesenchymal-like cellular state of glioblastoma. , 2021, Cancer cell.

[23]  E. A. Carrera Silva,et al.  A Heterotypic Tridimensional Model to Study the Interaction of Macrophages and Glioblastoma In Vitro , 2021, International journal of molecular sciences.

[24]  H. Nishie,et al.  Photodynamic therapy exploiting the anti-tumor activity of mannose-conjugated chlorin e6 reduced M2-like tumor-associated macrophages , 2021, Translational oncology.

[25]  L. E. Ibarra,et al.  Understanding the glioblastoma tumor biology to optimize photodynamic therapy: From molecular to cellular events , 2020, Journal of neuroscience research.

[26]  K. Sakanoue,et al.  Metronomic photodynamic therapy using an implantable LED device and orally administered 5-aminolevulinic acid , 2020, Scientific Reports.

[27]  C. Chesta,et al.  Photodynamic therapy of Glioblastoma cells using doped conjugated polymer nanoparticles: An in vitro comparative study based on redox status. , 2020, Journal of photochemistry and photobiology. B, Biology.

[28]  H. Gerhardt,et al.  Long-lived tumor-associated macrophages in glioma , 2020, Neuro-oncology advances.

[29]  A. Lourdusamy,et al.  Investigating Glioblastoma Response to Hypoxia , 2020, Biomedicines.

[30]  P. López-Larrubia,et al.  Trojan-horse monocyte-mediated delivery of conjugated polymer nanoparticles for improved photodynamic therapy of glioblastoma. , 2020, Nanomedicine.

[31]  C. Chesta,et al.  Photodynamic inactivation of ESKAPE group bacterial pathogens in planktonic and biofilm cultures using metallated porphyrin-doped conjugated polymer nanoparticles. , 2020, ACS infectious diseases.

[32]  C. Chesta,et al.  Conjugated Polymer Nanoparticles as Unique Coinitiator-Free, Water-Soluble, Visible-Light Photoinitiators of Vinyl Polymerization. , 2020, Macromolecular rapid communications.

[33]  M. Lamberti,et al.  Recapitulation of Hypoxic Tumor–stroma Microenvironment to Study Photodynamic Therapy Implications , 2020, Photochemistry and photobiology.

[34]  A. Darafsheh,et al.  Light Sources and Dosimetry Techniques for Photodynamic Therapy , 2020, Photochemistry and photobiology.

[35]  Weichao Liu,et al.  Metronomic photodynamic therapy with 5-aminolevulinic acid induces apoptosis and autophagy in human SW837 colorectal cancer cells. , 2019, Journal of photochemistry and photobiology. B, Biology.

[36]  E. Khaydukov,et al.  Photodynamic therapy of melanoma by blue-light photoactivation of flavin mononucleotide , 2019, Scientific Reports.

[37]  Zhihong Chen,et al.  Intravital 2-photon imaging reveals distinct morphology and infiltrative properties of glioblastoma-associated macrophages , 2019, Proceedings of the National Academy of Sciences.

[38]  A. Giordano,et al.  Targeted therapy based on p53 reactivation reduces both glioblastoma cell growth and resistance to temozolomide. , 2019, International journal of oncology.

[39]  P. Bednarski,et al.  Comparison of Cellular Death Pathways after mTHPC-mediated Photodynamic Therapy (PDT) in Five Human Cancer Cell Lines , 2019, Cancers.

[40]  E. Esin,et al.  Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience , 2019, Journal of oncology.

[41]  N. Cruickshanks,et al.  The p53 Pathway in Glioblastoma , 2018, Cancers.

[42]  U. Sunar,et al.  Measurement of Cyanine Dye Photobleaching in Photosensitizer Cyanine Dye Conjugates Could Help in Optimizing Light Dosimetry for Improved Photodynamic Therapy of Cancer , 2018, Molecules.

[43]  Hizuru Amano,et al.  Tissue-adhesive wirelessly powered optoelectronic device for metronomic photodynamic cancer therapy , 2018, Nature Biomedical Engineering.

[44]  Tregei Starr,et al.  The phorbol 12-myristate-13-acetate differentiation protocol is critical to the interaction of THP-1 macrophages with Salmonella Typhimurium , 2018, PloS one.

[45]  C. Chesta,et al.  Amplified singlet oxygen generation in metallated-porphyrin doped conjugated polymer nanoparticles , 2018 .

[46]  V. Rivarola,et al.  Metallated porphyrin-doped conjugated polymer nanoparticles for efficient photodynamic therapy of brain and colorectal tumor cells. , 2018, Nanomedicine.

[47]  M. Lamberti,et al.  Transcriptional activation of HIF-1 by a ROS-ERK axis underlies the resistance to photodynamic therapy , 2017, PloS one.

[48]  Zhihong Chen,et al.  Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma. , 2017, Cancer research.

[49]  Sang Y Lee.  Temozolomide resistance in glioblastoma multiforme , 2016, Genes & diseases.

[50]  J. Akimoto.  Photodynamic Therapy for Malignant Brain Tumors , 2016, Neurologia medico-chirurgica.

[51]  G. Bergers,et al.  Glioblastoma: Defining Tumor Niches. , 2015, Trends in cancer.

[52]  M. Baptista,et al.  Photodynamic Efficiency: From Molecular Photochemistry to Cell Death , 2015, International journal of molecular sciences.

[53]  M. Raes,et al.  M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide , 2015, BMC Cancer.

[54]  V. Bagnato,et al.  Validation of Photodynamic Action via Photobleaching of a New Curcumin-Based Composite with Enhanced Water Solubility , 2014, Journal of Fluorescence.

[55]  T. Friedrich,et al.  Reactive oxygen species: re-evaluation of generation, monitoring and role in stress-signaling in phototrophic organisms. , 2014, Biochimica et biophysica acta.

[56]  Jennie W. Taylor,et al.  Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma. , 2013, Neuro-oncology.

[57]  Elisabete C. Costa,et al.  Evaluation of Nanoparticle Uptake in Co-culture Cancer Models , 2013, PloS one.

[58]  B. Cornelissen,et al.  Subcutaneous tumor volume measurement in the awake, manually restrained mouse using MRI , 2013, Journal of magnetic resonance imaging : JMRI.

[59]  J. Králová,et al.  Role of ER Stress Response in Photodynamic Therapy: ROS Generated in Different Subcellular Compartments Trigger Diverse Cell Death Pathways , 2012, PloS one.

[60]  Shaoshan Hu,et al.  Effect of photodynamic therapy and endostatin on human glioma xenografts in nude mice. , 2011, Photodiagnosis and photodynamic therapy.

[61]  S. Lorkowski,et al.  Selection of reliable reference genes during THP-1 monocyte differentiation into macrophages , 2010, BMC Molecular Biology.

[62]  K. Christensen,et al.  Mechanism of cellular uptake of highly fluorescent conjugated polymer nanoparticles. , 2010, Biomacromolecules.

[63]  Marc Daigneault,et al.  The Identification of Markers of Macrophage Differentiation in PMA-Stimulated THP-1 Cells and Monocyte-Derived Macrophages , 2010, PloS one.

[64]  M. Kuimova,et al.  Singlet oxygen in a cell: spatially dependent lifetimes and quenching rate constants. , 2009, Journal of the American Chemical Society.

[65]  B. Wilson,et al.  Interstitial in vivo ALA-PpIX mediated metronomic photodynamic therapy (mPDT) using the CNS-1 astrocytoma with bioluminescence monitoring. , 2007, Photodiagnosis and photodynamic therapy.

[66]  J. Gallo,et al.  Preclinical Pharmacokinetic and Pharmacodynamic Evaluation of Metronomic and Conventional Temozolomide Dosing Regimens , 2007, Journal of Pharmacology and Experimental Therapeutics.

[67]  Theresa M Busch,et al.  Fluence rate as a modulator of PDT mechanisms , 2006, Lasers in surgery and medicine.

[68]  T. Busch,et al.  Local physiological changes during photodynamic therapy , 2006, Lasers in surgery and medicine.

[69]  L. Lilge,et al.  Fluorescence image-guided brain tumour resection with adjuvant metronomic photodynamic therapy: pre-clinical model and technology development , 2005, Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology.

[70]  Lothar Lilge,et al.  Metronomic Photodynamic Therapy as a New Paradigm for Photodynamic Therapy: Rationale and Preclinical Evaluation of Technical Feasibility for Treating Malignant Brain Tumors¶ , 2004, Photochemistry and photobiology.

[71]  A. Obwegeser,et al.  Photodynamic therapy in neurosurgery: a review. , 1996, Journal of photochemistry and photobiology. B, Biology.

[72]  M. Lamberti,et al.  Direct and indirect photodynamic therapy effects on the cellular and molecular components of the tumor microenvironment. , 2013, Biochimica et biophysica acta.

[73]  Herwig Kostron,et al.  Photodynamic diagnosis and therapy and the brain. , 2010, Methods in molecular biology.

[74]  E. Eruslanov,et al.  Identification of ROS using oxidized DCFDA and flow-cytometry. , 2010, Methods in molecular biology.