Photoinduced Endosomal Escape Mechanism: A View from Photochemical Internalization Mediated by CPP-Photosensitizer Conjugates

Abstract

Endosomal escape in cell-penetrating peptide (CPP)-based drug/macromolecule delivery systems is frequently insufficient. The CPP-fused molecules tend to remain trapped inside endosomes and end up being degraded rather than delivered into the cytosol. One of the methods for endosomal escape of CPP-fused molecules is photochemical internalization (PCI), which is based on the use of light and a photosensitizer and relies on photoinduced endosomal membrane destabilization to release the cargo molecule. Currently, it remains unclear how this delivery strategy behaves after photostimulation. Recent findings, including our studies using CPP-cargo-photosensitizer conjugates, have shed light on the photoinduced endosomal escape mechanism. In this review, we discuss the structural design of CPP-photosensitizer and CPP-cargo-photosensitizer conjugates, and the PCI mechanism underlying their application.

Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line

“…For example, the first generation Ps such as hematoporphyrin derivative localizes diffusely in the cytomembrane and porfimer (Photofrin ® ) localizes to the Golgi apparatus and the endoplasmic reticulum [44,45], while the second generation Ps such as meta-tetrahydroxy-phenylchlorin (Foscan ® ), 5-ALA, and N-aspartyl chlorin e6 accumulates in the Golgi apparatus and endoplasmic reticulum, mitochondria, and lysosome, respectively [46][47][48]. In order for effective PCI to occur, the preferential uptake by endocytosis and accumulation of Ps in the endo-lysosomal axis is a crucial requisite [49,50]; these can be mediated by the conjugation of cell penetrating peptide or low density lipoprotein to the Ps, or through the use of Ps in the form of nanocomposites or nanoparticles [51][52][53]. In this study, the latter approach was utilized through the formation of PAMAM(G5) Ns incorporating both Etop and PpIX.…”

Unprotonatable and ROS‐Sensitive Nanocarrier for NIR Spatially Activated siRNA Therapy with Synergistic Drug Effect

“…[32,33] Photosensitizers (PSs)-based PCI can effectively disrupt endo-lysosomal membrane through oxidation of PSs-induced ROS under near infrared (NIR) irradiation. [34,35] Besides, complete siRNA release from the nanocarrier into the cytoplasm is necessary to maximize the gene inhibition effect of siRNA. The conventional cationic carriers such as PEI and liposomes cannot completely release siRNA into the cytoplasm, which limits the therapeutic efficacy of siRNA.…”

“…[ 32,33 ] Photosensitizers (PSs)‐based PCI can effectively disrupt endo‐lysosomal membrane through oxidation of PSs‐induced ROS under near infrared (NIR) irradiation. [ 34,35 ]…”

A Photosensitized Singlet Oxygen (1O2) Toolbox for Bio-Organic Applications: Tailoring 1O2 Generation for DNA and Protein Labelling, Targeting and Biosensing

“…By conjugating a porphyrine derivative (ce6) to the TAT sequence or other positively charged CPP’s, they were able to demonstrate the previously mentioned hypothesis. T. Ohtsuki et al [ 261 ] recently wrote a good review that covers this topic in more detail,…”