Mitochondria-Targeted Photodynamic Therapy with a Galactodendritic Chlorin to Enhance Cell Death in Resistant Bladder Cancer Cells

Pereira, Patrícia M. R.; Silva, Sandrina; Bispo, Mafalda; Zuzarte, Mónica; Gomes, Célia; Girão, Henrique; Cavaleiro, José A. S.; Ribeiro, Carlos; Tomé, João P. C.; Fernandes, Rosa

doi:10.1021/acs.bioconjchem.6b00519

Cited by 38 publications

(49 citation statements)

References 41 publications

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“…There is growing interest in the development of porphyrinoids conjugated with sugars such as glucose and galactose as new PSs for the PDT of cancer [6, 10, 11, 13, 35, 36]. Galectin-1 and GLUT1 are glyco-binding proteins overexpressed in cancer cells [37, 38] that play a key role in the uptake and photo-toxicity of with galactose- and glucose- porphyrin conjugates [11, 39, 40].…”

Section: Resultsmentioning

confidence: 99%

Cancer cell spheroids are a better screen for the photodynamic efficiency of glycosylated photosensitizers

et al. 2017

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Photodynamic Therapy (PDT) relies on the use of non-toxic photosensitizers that are locally and selectively activated by light to induce cell death or apoptosis through reactive oxygen species generation. The conjugation of porphyrinoids with sugars that target cancer is increasingly viewed as an effective way to increase the selectivity of PDT. To date, in vitro PDT efficacy is mostly screened using two-dimensional monolayer cultures. Compared to monolayer cultures, three-dimensional spheroid cultures have unique spatial distributions of nutrients, metabolites, oxygen and signalling molecules; therefore better mimic in vivo conditions. We obtained 0.05 mm3 spheroids with four different human tumor cell lines (HCT-116, MCF-7, UM-UC-3 and HeLa) with appropriate sizes for screening PDT agents. We observed that detachment from monolayer culture and growth as tumor spheroids was accompanied by changes in glucose metabolism, endogenous ROS levels, galectin-1 and glucose transporter GLUT1 protein levels. We compared the phototoxic responses of a porphyrin conjugated with four glucose molecules (PorGlu4) in monolayer and spheroid cultures. The uptake and phototoxicity of PorGlu4 is highly dependent on the monolayer versus spheroid model used and on the different levels of GLUT1 protein expressed by these in vitro platforms. This study demonstrates that HCT-116, MCF-7, UM-UC-3 and HeLa spheroids afford a more rational platform for the screening of new glycosylated-photosensitizers compared to monolayer cultures of these cancer cells.

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Section: Resultsmentioning

confidence: 99%

Cancer cell spheroids are a better screen for the photodynamic efficiency of glycosylated photosensitizers

et al. 2017

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“…[5] Although PDT has numerous advantages, its broader acceptance in clinical practice is restricted mainly due to the limited penetration depth of the visible light through tissues, lack of cancer cell selectivity and reduced level of oxygen in most of the solid tumors (tissue hypoxia). [8] On the other side, subcellular localization of PSs particularly to the MT can address the problems related to hypoxia [9] and enhance the PDT effect [10][11][12][13] since MT play important roles in cell respiration, oxygen metabolism and apoptosis signalling. [6,7] In this context, organelletargeted and red/near-IR absorbing PSs are highly promising.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria‐Targeting Selenophene‐Modified BODIPY‐Based Photosensitizers for the Treatment of Hypoxic Cancer Cells

et al. 2019

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Two red-absorbing, water-soluble and mitochondria (MT)targeting selenophene-substituted BODIPY-based photosensitizers (PSs) were realized (BODÀ Se, BODÀ SeÀ I), and their potential as photodynamic therapy (PDT) agents were evaluated. BODÀ SeÀ I showed higher 1 O 2 generation yield thanks to the enhanced heavy-atom effect, and this derivative was further tested in detail in cell culture studies under both normoxic and hypoxic conditions. BODÀ SeÀ I not only effectively functioned under hypoxic conditions, but also showed highly selective photocytotoxicity towards cancer cells. The selectivity is believed to arise from differences in mitochondrial membrane potentials of healthy and cancerous cells. To the best of our knowledge, this marks the first example of a MT-targeted BODIPY PS that functions under hypoxic conditions. Remarkably, thanks to the design strategy, all these properties where realized by a compound that was synthesized in only five steps with 32 % overall yield. Hence, this material holds great promise for the realization of next-generation PDT drugs for the treatment of hypoxic solid tumors.

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“…GOMES, MARIA G.P.M.S. NEVES and JOSÉ A.S. CAVALEIRO Considering these promising works, in 2016 it was reported the synthesis of the chlorin derivative Chl-Gal 8 46 also conjugated with galactodendritic units (Figure 36) (Pereira et al 2016a). The synthetic approach was also based on the nucleophilic substitution by the galacto-dendridic unit 43 of the p-fluorine atoms of the chlorin ChlF 20 ; this chlorin was obtained from TPPF 20 through a 1,3-dipolar cycloaddition process as it was previously described by Cavaleiro´s group (Silva et al 1999(Silva et al , 2005.…”

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“…The synthetic approach was also based on the nucleophilic substitution by the galacto-dendridic unit 43 of the p-fluorine atoms of the chlorin ChlF 20 ; this chlorin was obtained from TPPF 20 through a 1,3-dipolar cycloaddition process as it was previously described by Cavaleiro´s group (Silva et al 1999(Silva et al , 2005. The results showed that this chlorin has excellent photostability, high ability to generate singlet oxygen and to interact with the proteins galectin-1 and human serum albumin (HSA) (Pereira et al 2016a). Besides the Chl-Gal 8 46 exhibits high absorption in the red region of the electromagnetic spectrum where tissue light penetration is rather high, which is an important requirement for PDT (Senge and Brandt 2011, Lu et al 2015, Agostinis et al 2011.…”

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“…The subcellular localization studies revealed that the enhanced phototoxicity in HT-1376 cancer cells seems to be due to the ability of Chl-Gal 8 46 to accumulate in the mitochondria, via glucose transporter 1 (GLUT1), in the period between single and repeated irradiation. A PDT treatment using an extra dose of light irradiation and Chl-Gal 8 46 as PS represents a promising strategy in treating resistant cancers in a clinical setting (Pereira et al 2016a). …”

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Cancer, Photodynamic Therapy and Porphyrin-Type Derivatives

Gomes

Cavaleiro

2018

An. Acad. Bras. Ciênc.

113

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This review has two parts. The first one gives an approach to interdisciplinary studies against cancer carried out by many scientists using porphyrin-type substrates as photosensitizers in PDT. Intensive studies were performed for almost six decades. The successes really started in 1993 with the first formulation patented under the trade name Photofrin, which was immediately approved in several countries to treat certain types of cancer. Photofrin is still used although certain negative features soon became well known. That has motivated the search for better new photosensitizers. Several ones were developed, evaluated and a few of them had clinical approval. This group includes porphyrin derivatives and pro-drugs (aminolevulinic acid and its alkyl esters). Oncological, dermatological and ophthalmic applications are now taking place for the benefit of mankind. The second part of this review is related with the work carried out in Aveiro at the authors University on the synthesis and biological evaluation of several potential PDT photosensitizers. Not only new synthetic methodologies mainly for porphyrins and chlorins were developed but also other related macrocycles of the phthalocyanine and corrole types have entered in the same "pipeline". In vivo and in vitro biological evaluations also took place under interdisciplinary studies.

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Mitochondria-Targeted Photodynamic Therapy with a Galactodendritic Chlorin to Enhance Cell Death in Resistant Bladder Cancer Cells

Cited by 38 publications

References 41 publications

Cancer cell spheroids are a better screen for the photodynamic efficiency of glycosylated photosensitizers

Cancer cell spheroids are a better screen for the photodynamic efficiency of glycosylated photosensitizers

Mitochondria‐Targeting Selenophene‐Modified BODIPY‐Based Photosensitizers for the Treatment of Hypoxic Cancer Cells

Cancer, Photodynamic Therapy and Porphyrin-Type Derivatives

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