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

Abstract

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.

Coupling Chlorin e6 to the surface of Nanoscale Gas Vesicles strongly enhances their intracellular delivery and photodynamic killing of cancer cells

“…5a-e). This cytoplasmic distribution pattern has been observed for other Ce6-conjugates and nanoparticles 13,25 .…”

Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases

“…Chlorin e 6 is a porphyrin derivative of interest in PDT capable of generating singlet oxygen. By conjugating chlorin e 6 to a cell penetrating peptide, Eggleston et al (Yaghini et al, 2017 ) reported that such porphyrin-like molecules can efficiently be used in PDT and employed in photo-induced cellular internalization, which is a new technology to increase the intracellular delivery and efficacy of nano-sized biotherapeutics. This work opened the way to the use of porphyrins not only as effective near infrared dyes for bioimaging or therapeutic agents but also as promoters of drug delivery (Yaghini et al, 2017 ).…”

Chlorin e6-Coated Superparamagnetic Iron Oxide Nanoparticle (SPION) Nanoclusters as a Theranostic Agent for Dual-Mode Imaging and Photodynamic Therapy

“…Furthermore, sharp Soret and Q bands are observed for Ce6 in protic solvents except for water 14,29 . To improve the poor water solubility of Ce6 for PDT, various kinds of nano-sized drug carriers such as nano-graphene 20 and gold vesicles 21 , or PS-conjugates with polyvinylpyrrolidone (PVP) 24,30,31 , human serum albumin 2 , polymeric micelles 32 , silica 22 , peptides 33 , glucamine (BLC 1010) 34 , and Ce6-conjugates with superparamagnetic iron oxide nanoparticles (SPIONs) by multistep chemical reactions 35–37 have been developed. Unfortunately, Ce6’s characteristic PDT properties are often suppressed when incorporated into nanocarriers due to quenching 38–41 .…”