Disulfonated tetraphenyl chlorin (TPCS2a)-induced photochemical internalisation of bleomycin in patients with solid malignancies: a phase 1, dose-escalation, first-in-man trial

Sultan, Ahmed A.; Jerjes, Waseem; Berg, Kristian; Høgset, Anders; Mosse, Charles A.; Hamoudi, Rifat; Hamdoon, Zaid; Simeon, Celia; Carnell, Dawn; Förster, Martin; Hopper, Colin

doi:10.1016/s1470-2045(16)30224-8

Cited by 88 publications

(89 citation statements)

References 36 publications

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“…Owing to its size (c. 2 nm in diameter) saporin is prone to entrapment and degradation within lysosomes following endocytosis, thus severely restricting its cytotoxicity when administered directly 45 . The KB human oral epidermoid carcinoma cell line was used for these studies since head and neck cancer is one of the main clinical targets for PCI 7 . Treatment with saporin alone at 20 nM resulted in a small reduction in viability at <20%, as shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Berg and colleagues found that only the amphiphilic disulfonated derivative was effective for PCI, whereas the more water soluble and less amphiphilic symmetrical tetrasulfonated derivative was ineffective, since it partitions to the aqueous compartment 12 . The same considerations have prompted the development of a disulfonated chlorin photosensitiser for clinical PCI 7 . The endolysosomal localisation of the disulfonated derivative is accounted for by uptake via adsorptive endocytosis.…”

Section: Introductionmentioning

confidence: 96%

“…The PCI technique uses visible light excitation in combination with a co-administered photosensitiser (PS) and is designed specifically to address the problem of sequestration of bioactive agents in endolysosomes, so it could also be applied not only to cancer but also non-cancerous lesions. PCI has proven effective in a wide range of experimental cancer models, including multidrug resistant cancer cells 6 , and has shown promising results in a clinical trial of head and neck cancer, using the chemotherapeutic agent bleomycin 7 . Although this entrapment is particularly problematic for nano-sized and macromolecular agents, some smaller drugs such as the chemotherapeutic agent doxorubicin may also become protonated and entrapped in acidic lysosomes owing to their weakly basic nature.…”

Section: Introductionmentioning

confidence: 99%

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Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines

Yaghini

Dondi

Tewari

et al. 2017

Sci Rep

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A major problem with many promising nano-sized biotherapeutics including macromolecules is that owing to their size they are subject to cellular uptake via endocytosis, and become entrapped and then degraded within endolysosomes, which can significantly impair their therapeutic efficacy. Photochemical internalisation (PCI) is a technique for inducing cytosolic release of the entrapped agents that harnesses sub-lethal photodynamic therapy (PDT) using a photosensitiser that localises in endolysosomal membranes. Using light to trigger reactive oxygen species-mediated rupture of the photosensitised endolysosomal membranes, the spatio-temporal selectivity of PCI then enables cytosolic release of the agents at the selected time after administration so that they can reach their intracellular targets. However, conventional photosensitisers used clinically for PDT are ineffective for photochemical internalisation owing to their sub-optimal intracellular localisation. In this work we demonstrate that such a photosensitiser, chlorin e6, can be repurposed for PCI by conjugating the chlorin to a cell penetrating peptide, using bioorthogonal ligation chemistry. The peptide conjugation enables targeting of endosomal membranes so that light-triggered cytosolic release of an entrapped nano-sized cytotoxin can be achieved with consequent improvement in cytotoxicity. The photoproperties of the chlorin moiety are also conserved, with comparable singlet oxygen quantum yields found to the free chlorin.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines

Yaghini

Dondi

Tewari

et al. 2017

Sci Rep

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“…20 Recent clinical studies have demonstrated both the feasibility and safety of PCI for the treatment of advanced and recurrent solid malignancies. 21 …”

Section: Introductionmentioning

confidence: 99%

Flexible synthesis of cationic peptide–porphyrin derivatives for light-triggered drug delivery and photodynamic therapy

et al. 2016

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“…In addition to the toxic effect of the released drug, lysosomal enzymes are also released triggering cell apoptosis. In particular, PCI of Bleomycin (BLM) has proven highly effective in a host of in vitro and in vivo models and was used in a clinical study on head and neck tumors [6–10]. …”

Section: Introductionmentioning

confidence: 99%

Enhancing the effects of chemotherapy by combined macrophage-mediated photothermal therapy (PTT) and photochemical internalization (PCI)

Nair

Christie

et al. 2018

Lasers Med Sci

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Light-based treatment modalities such as photothermal therapy (PTT) or photochemical internalization (PCI) have been well documented both experimentally and clinically to enhance the efficacy of chemotherapy. The main purpose of this study was to examine the cytotoxic effects of silica-gold nanoshell (AuNS)-loaded macrophage-mediated (Ma) PTT and bleomycin BLM-PCI on monolayers of squamous cell carcinoma cells. The two modalities were applied separately and in simultaneous combination. Two different wavelengths of light were employed simultaneously, one to activate a highly efficient PCI photosensitizer, AlPcSa (670 nm) and the other for the Ma-mediated PTT (810 nm), to evaluate the combined effects of these modalities. The results clearly demonstrated that macrophages could ingest sufficient numbers of silica-gold nanoshells for efficient near infrared (NIR) activated PTT. A significant synergistic effect of simultaneously applied combined PTT and PCI, compared to each modality applied separately, was achieved. Light-driven therapies have the advantage of site specificity, non-invasive and non-toxic application, require inexpensive equipment and can be given as repetitive treatment protocols.

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Disulfonated tetraphenyl chlorin (TPCS2a)-induced photochemical internalisation of bleomycin in patients with solid malignancies: a phase 1, dose-escalation, first-in-man trial

Cited by 88 publications

References 36 publications

Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines

Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines

Flexible synthesis of cationic peptide–porphyrin derivatives for light-triggered drug delivery and photodynamic therapy

Enhancing the effects of chemotherapy by combined macrophage-mediated photothermal therapy (PTT) and photochemical internalization (PCI)

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