Polymeric Encapsulation of a Ruthenium Polypyridine Complex for Tumor Targeted 1- and 2-Photon Photodynamic Therapy

Photodynamic therapy is a medical technique, which is gaining increasing attention to treat various types of cancer. Among the investigated classes of photosensitizers, the use of Ru(II) polypyridine complexes is gaining momentum. However, the currently investigated compounds generally show poor cancer cell selectivity. As a consequence, high drug doses are needed, which can cause side effects. To overcome this limitation, there is a need for the development of a suitable drug delivery system to increase the amount of PS delivered to the tumor. Herein, we report on the encapsulation of a promising Ru(II) polypyridyl complex into polymeric nanoparticles with terminal biotin groups. Thanks to this design, the particles showed much higher selectivity for cancer cells in comparison to non-cancerous cells in a 2D monolayer and 3D multicellular tumor spheroid model. As a highlight, upon intravenous injection of an identical amount of the Ru(II) polypyridine complex, an improved accumulation inside an adenocarcinomic human alveolar basal epithelial tumor of a mouse by a factor of 8.7 compared to the Ru complex itself was determined. The nanoparticles were found to have a high phototoxic effect upon 1-photon (500 nm) or 2-photon (800 nm) excitation with an eradication of an adenocarcinomic human alveolar basal epithelial tumor inside a mouse. Overall, this work describes, to the best of our knowledge, the first <i>in vivo</i> study demonstrating the cancer cell selectivity of a very promising Ru(II)-based PDT photosensitizer encapsulated into polymeric nanoparticles with terminal biotin groups.

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Ruthenium Complexes for 1- and 2-Photon Photodynamic Therapy: From In Silico Prediction to In Vivo Applications

10.26434/chemrxiv.11767995 ◽

2020 ◽

Author(s):

Johannes Karges ◽

Shi Kuang ◽

Federica Maschietto ◽

Olivier Blacque ◽

Ilaria Ciofini ◽

...

Keyword(s):

Photodynamic Therapy ◽

In Silico ◽

Aqueous Solubility ◽

The Body ◽

Photon Absorption ◽

Multicellular Tumor Spheroids ◽

Spectral Window ◽

Photon Excitation ◽

Polypyridine Complexes

<div>The use of photodynamic therapy (PDT) against cancer has received increasing attention overthe recent years. However, the application of the currently approved photosensitizers (PSs) is somehow limited by their poor aqueous solubility, aggregation, photobleaching and slow clearance from the body. To overcome these limitations, there is a need for the development of new classes of PSs with ruthenium(II) polypyridine complexes currently gaining momentum. However, these compounds generally lack significant absorption in the biological spectral window, limiting their application to treat deep-seated or large tumors. To overcome this drawback, ruthenium(II) polypyridine complexes designed in silico with (E,E’)-4,4´-bisstyryl 2,2´-bipyridine ligands showed impressive 1- and 2-Photon absorption up to a magnitude higher than the ones published so far. While non-toxic in the dark, these compounds were found phototoxic in various 2D monolayer cells, 3D multicellular tumor spheroids and be able to eradicate a multiresistant tumor inside a mouse model upon clinically relevant 1-Photon and 2 Photon excitation.</div>

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Biomimetic oxygen delivery nanoparticles for enhancing photodynamic therapy in triple-negative breast cancer

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00827-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Hanyi Fang ◽

Yongkang Gai ◽

Sheng Wang ◽

Qingyao Liu ◽

Xiao Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Photodynamic Therapy ◽

Cancer Cell ◽

Triple Negative Breast Cancer ◽

Oxygen Delivery ◽

Therapeutic Efficacy ◽

Triple Negative ◽

Oxygen Solubility ◽

Post Injection

Abstract Background Triple-negative breast cancer (TNBC) is a kind of aggressive breast cancer with a high rate of metastasis, poor overall survival time, and a low response to targeted therapies. To improve the therapeutic efficacy and overcome the drug resistance of TNBC treatments, here we developed the cancer cell membrane-coated oxygen delivery nanoprobe, CCm–HSA–ICG–PFTBA, which can improve the hypoxia at tumor sites and enhance the therapeutic efficacy of the photodynamic therapy (PDT), resulting in relieving the tumor growth in TNBC xenografts. Results The size of the CCm–HSA–ICG–PFTBA was 131.3 ± 1.08 nm. The in vitro 1O2 and ROS concentrations of the CCm–HSA–ICG–PFTBA group were both significantly higher than those of the other groups (P < 0.001). In vivo fluorescence imaging revealed that the best time window was at 24 h post-injection of the CCm–HSA–ICG–PFTBA. Both in vivo 18F-FMISO PET imaging and ex vivo immunofluorescence staining results exhibited that the tumor hypoxia was significantly improved at 24 h post-injection of the CCm–HSA–ICG–PFTBA. For in vivo PDT treatment, the tumor volume and weight of the CCm–HSA–ICG–PFTBA with NIR group were both the smallest among all the groups and significantly decreased compared to the untreated group (P < 0.01). No obvious biotoxicity was observed by the injection of CCm–HSA–ICG–PFTBA till 14 days. Conclusions By using the high oxygen solubility of perfluorocarbon (PFC) and the homologous targeting ability of cancer cell membranes, CCm–HSA–ICG–PFTBA can target tumor tissues, mitigate the hypoxia of the tumor microenvironment, and enhance the PDT efficacy in TNBC xenografts. Furthermore, the HSA, ICG, and PFC are all FDA-approved materials, which render the nanoparticles highly biocompatible and enhance the potential for clinical translation in the treatment of TNBC patients.

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Biomimetic Oxygen Delivery Nanoparticles for Enhancing Photodynamic Therapy in Triple-negative Breast Cancer

10.21203/rs.3.rs-195157/v1 ◽

2021 ◽

Author(s):

Hanyi Fang ◽

Yongkang Gai ◽

Sheng Wang ◽

Qingyao Liu ◽

Xiao Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Photodynamic Therapy ◽

Cancer Cell ◽

Triple Negative Breast Cancer ◽

Oxygen Delivery ◽

Therapeutic Efficacy ◽

Triple Negative ◽

Oxygen Solubility ◽

Post Injection

Abstract Background Triple-negative breast cancer (TNBC) is a kind of aggressive breast cancer with a high rate of metastasis, poor overall survival time, and a low response to targeted therapies. To improve the therapeutic efficacy and overcome the drug resistance of TNBC treatments, here we developed the cancer cell membrane-coated oxygen delivery nanoprobe, CCm-HSA-ICG-PFTBA, which can improve the hypoxia at tumor sites and enhance the therapeutic efficacy of the photodynamic therapy (PDT), resulting in relieving the tumor growth in TNBC xenografts. Results The size of the CCm-HSA-ICG-PFTBA was 131.3 ± 1.08 nm. The in vitro 1O2 and ROS concentrations of the CCm-HSA-ICG-PFTBA group were both significantly higher than those of the other groups (P < 0.001). In vivo fluorescence imaging revealed that the best time window was at 24 h post-injection of the CCm-HSA-ICG-PFTBA. Both in vivo 18F-FMISO PET imaging and ex vivo immunofluorescence staining results exhibited that the tumor hypoxia was significantly improved at 24 h post-injection of the CCm-HSA-ICG-PFTBA. For in vivo PDT treatment, the tumor volume and weight of the CCm-HSA-ICG-PFTBA with NIR group were both the smallest among all the groups and significantly decreased compared to the untreated group (P < 0.01). No obvious biotoxicity was observed by the injection of CCm-HSA-ICG-PFTBA till 14 days. Conclusions By using the high oxygen solubility of perfluorocarbon (PFC) and the homologous targeting ability of cancer cell membranes, CCm-HSA-ICG-PFTBA can target tumor tissues, mitigate the hypoxia of the tumor microenvironment, and enhance the PDT efficacy in TNBC xenografts. Furthermore, the HSA, ICG, and PFC are all FDA-approved materials, which render the nanoparticles highly biocompatible and enhance the potential for clinical translation in the treatment of TNBC patients.

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Effect of Photodynamic Therapy in Melanoma Skin Cancer Cell Line A375: in vivo Study

Medical Lasers ◽

10.25289/ml.2014.3.1.27 ◽

2014 ◽

Vol 3 (1) ◽

pp. 27-30 ◽

Cited By ~ 2

Author(s):

Phil-Sang Chung ◽

Jin-Chul Ahn ◽

Sang Joon Lee ◽

Peijie HE ◽

Jeong Hwan Moon

Keyword(s):

Photodynamic Therapy ◽

Skin Cancer ◽

Cell Line ◽

Cancer Cell ◽

Cancer Cell Line ◽

In Vivo Study ◽

Melanoma Skin

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Intracellular tracking of drug release from pH-sensitive polymeric nanoparticles via FRET for synergistic chemo-photodynamic therapy

Journal of Nanobiotechnology ◽

10.1186/s12951-019-0547-2 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 7

Author(s):

Chen Du ◽

Yan Liang ◽

Qingming Ma ◽

Qianwen Sun ◽

Jinghui Qi ◽

...

Keyword(s):

Photodynamic Therapy ◽

Drug Release ◽

Real Time ◽

Polymeric Nanoparticles ◽

Drug Loading ◽

Tumor Therapy ◽

Resonance Energy Transfer ◽

Resonance Energy

Abstract Background Synergistic therapy of tumor is a promising way in curing cancer and in order to achieve effective tumor therapy with real-time drug release monitoring, dynamic cellular imaging and antitumor activity. Results In this work, a polymeric nanoparticle with Forster resonance energy transfer (FRET) effect and chemo-photodynamic properties was fabricated as the drug vehicle. An amphiphilic polymer of cyclo(RGDfCSH) (cRGD)-poly(ethylene glycol) (PEG)-Poly(l-histidine) (PH)-poly(ε-caprolactone) (PCL)-Protoporphyrin (Por)-acting as both a photosensitizer for photodynamic therapy (PDT) and absorption of acceptor in FRET was synthesized and self-assembled into polymeric nanoparticles with epirubicin (EPI)-acting as an antitumor drug for chemotherapy and fluorescence of donor in FRET. Spherical EPI-loaded nanoparticles with the average size of 150 ± 2.4 nm was procured with negatively charged surface, pH sensitivity and high drug loading content (14.9 ± 1.5%). The cellular uptake of EPI-loaded cRGD-PEG-PH-PCL-Por was monitored in real time by the FRET effect between EPI and cRGD-PEG-PH-PCL-Por. The polymeric nanoparticles combined PDT and chemotherapy showed significant anticancer activity both in vitro (IC50 = 0.47 μg/mL) and better therapeutic efficacy than that of free EPI in vivo. Conclusions This work provided a versatile strategy to fabricate nanoassemblies for intracellular tracking of drug release and synergistic chemo-photodynamic therapy.

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Ruthenium Complexes for 1- and 2-Photon Photodynamic Therapy: From In Silico Prediction to In Vivo Applications

10.26434/chemrxiv.11767995.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Johannes Karges ◽

Shi Kuang ◽

Federica Maschietto ◽

Olivier Blacque ◽

Ilaria Ciofini ◽

...

Keyword(s):

Photodynamic Therapy ◽

In Silico ◽

Aqueous Solubility ◽

The Body ◽

Photon Absorption ◽

Multicellular Tumor Spheroids ◽

Spectral Window ◽

Photon Excitation ◽

Polypyridine Complexes

<div>The use of photodynamic therapy (PDT) against cancer has received increasing attention overthe recent years. However, the application of the currently approved photosensitizers (PSs) is somehow limited by their poor aqueous solubility, aggregation, photobleaching and slow clearance from the body. To overcome these limitations, there is a need for the development of new classes of PSs with ruthenium(II) polypyridine complexes currently gaining momentum. However, these compounds generally lack significant absorption in the biological spectral window, limiting their application to treat deep-seated or large tumors. To overcome this drawback, ruthenium(II) polypyridine complexes designed in silico with (E,E’)-4,4´-bisstyryl 2,2´-bipyridine ligands showed impressive 1- and 2-Photon absorption up to a magnitude higher than the ones published so far. While non-toxic in the dark, these compounds were found phototoxic in various 2D monolayer cells, 3D multicellular tumor spheroids and be able to eradicate a multiresistant tumor inside a mouse model upon clinically relevant 1-Photon and 2 Photon excitation.</div>

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Synthesis, electrochemistry, and ligand substitution reactions of conducting copolymer films of ruthenium polypyridine complexes and aromatic heterocycles

Canadian Journal of Chemistry ◽

10.1139/v91-099 ◽

1991 ◽

Vol 69 (4) ◽

pp. 653-660 ◽

Cited By ~ 12

Author(s):

Jolanta Ochmanska ◽

Peter G. Pickup

Keyword(s):

Aqueous Media ◽

Aqua Complex ◽

Substitution Reactions ◽

Copolymer Films ◽

Ru Complex ◽

Chloride Ligand ◽

Polypyridine Complexes ◽

Ruthenium Polypyridine ◽

Water Ligands ◽

Perchlorate Complex

Conducting films containing ruthenium complexes of the general formula [Ru(2,2′-bipyridine)2(pmp)X]2+ (pmp = 3-(pyrrol-1-ylmethyl)pyridine, X = Cl−, ClO4−, pmp, CH3CN, or H2O) have been prepared by copolymerization of the Ru complex monomer with pyrrole, 3-methylthiophene, 1-methyl-3-(pyrrol-1-ylmethyl)pyridinium(1+), or 2,2′-bithiophene. The immobilized complexes exhibit rapid and reversible electrochemistry in acetonitrile. The perchlorate and water ligands are rapidly substituted to give the acetonitrile complex, while the chloride ligand is replaced more slowly. In aqueous media, both the perchlorate complex and chloride yield an aqua complex. The substitution rate of the chloride ligand is again low but is enhanced by photolysis. No substitution reactions were observed for the acetonitrile or pmp ligands under a variety of conditions tested. Infrared spectroscopy and fast atom bombardment mass spectroscopy indicate that attempts to isolate [Ru(bp)2(pmp)(ClO4)]+ as a solid in fact give the aqua complex. The perchlorate complex may also rearrange to the aqua complex in polymer films. Films containing the aqua complex were not useful for electrocatalytic oxidation because of the instability of the conducting polymer matrix at low pH and the inactivity of the complex at higher pH values. Key words: polythiophene, polypyrrole, electropolymerization, metallopolymer.

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Porphylipoprotein Accumulation and Porphylipoprotein Photodynamic Therapy Effects Involving Cancer Cell-Specific Cytotoxicity

International Journal of Molecular Sciences ◽

10.3390/ijms22147306 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7306

Author(s):

Hiromi Kurokawa ◽

Hiromu Ito ◽

Hirofumi Matsui

Keyword(s):

Reactive Oxygen Species ◽

Photodynamic Therapy ◽

Cancer Cell ◽

Reactive Oxygen ◽

Cancer Tissue ◽

Oxygen Species ◽

Normal Tissues ◽

Specific Cytotoxicity ◽

Specific Accumulation

In photodynamic therapy (PDT) for neoplasms, photosensitizers selectively accumulate in cancer tissue. Upon excitation with light of an optimal wavelength, the photosensitizer and surrounding molecules generate reactive oxygen species, resulting in cancer cell-specific cytotoxicity. Porphylipoprotein (PLP) has a porphyrin-based nanostructure. The porphyrin moiety of PLP is quenched because of its structure. When PLP is disrupted, the stacked porphyrins are separated into single molecules and act as photosensitizers. Unless PLP is disrupted, there is no photosensitive disorder in normal tissues. PLP can attenuate the photosensitive disorder compared with other photosensitizers and is ideal for use as a photosensitizer. However, the efficacy of PLP has not yet been evaluated. In this study, the mechanism of cancer cell-specific accumulation of PLP and its cytotoxic effect on cholangiocarcinoma cells were evaluated. The effects were investigated on normal and cancer-like mutant cells. The cytotoxicity effect of PLP PDT in cancer cells was significantly stronger than in normal cells. In addition, reactive oxygen species regulated intracellular PLP accumulation. The cytotoxic effects were also investigated using a cholangiocarcinoma cell line. The cytotoxicity of PLP PDT was significantly higher than that of laserphyrin-based PDT, a conventional type of PDT. PLP PDT could also inhibit tumor growth in vivo.

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