Direct Photocontrol of Peptidomimetics: An Alternative to Oxygen‐Dependent Photodynamic Cancer Therapy

Abstract

Conventional photodynamic treatment strategies are based on the principle of activating molecular oxygen in situ by light, mediated by a photosensitizer, which leads to the generation of reactive oxygen species and thereby causes cell death. A diarylethene-derived peptidomimetic is presented that is suitable for photodynamic cancer therapy without any involvement of oxygen. This light-sensitive molecule is not a mediator but is itself the cytotoxic agent. As a derivative of the cyclic amphiphilic peptide gramicidin S, the peptidomimetic exists in two thermally stable photoforms that are interconvertible by light of different wavelengths. The isomer generated by visible light shows much stronger toxicity against tumor cells than the UV-generated isomer. First in vivo applications are demonstrated on a tumor animal model to illustrate how the peptidomimetic can be administered in the less toxic form and then activated locally in a solid tumor by visible light.

Facile synthesis of photoactive diaryl(hetaryl)cyclopentenes by ionic hydrogenation

“…Besides, it is of interest to study this family of diarylethenes in order to develop different types of light-controlling materials and devices. [11][12][13][14][15][16][17] In addition, the elaboration of an alternative and effective synthetic protocol is one of the major challenges in modern organic synthesis having a high priority in the development of new technologies and smart materials. [18][19][20] However, the synthesis of these compounds remains a difficult task and has a lot of limitations.…”

Light-controllable dithienylethene-modified cyclic peptides: photoswitching the in vivo toxicity in zebrafish embryos

“…Compared to the ring-closed (deactivated, OFF) photoform, the ring-open (active, ON) isomer of 2 indeed displayed a much stronger in vitro toxicity against several tumor cell lines [29,30]. Using the photoswitchable analogue 2 in an allograft mouse model, the first in vivo photopharmacology application for a DAE-derived peptide as an anticancer agent has been demonstrated [29]. In order to optimize 2, we have recently performed a structure-activity relationship (SAR) study using a library of photoswitchable derivatives of 2 [30].…”

“…This natural antimicrobial agent has an amphipathic structure, whose functional mechanism is attributed to the permeabilization of bacterial membranes, with considerable side-effects also on eukaryotic cell membranes [27,28]. Compared to the ring-closed (deactivated, OFF) photoform, the ring-open (active, ON) isomer of 2 indeed displayed a much stronger in vitro toxicity against several tumor cell lines [29,30]. Using the photoswitchable analogue 2 in an allograft mouse model, the first in vivo photopharmacology application for a DAE-derived peptide as an anticancer agent has been demonstrated [29].…”

Targeted Nanoswitchable Inhibitors of Protein–Protein Interactions Involved in Apoptosis

“…In addition to classical targeting methods (based, for example, on tumor molecularm arkers), an active field of research is focusedo ns elf-propelling nano-and microbots that are remotelyo rs elf-driven to the target. [2][3][4] Other approaches involve using focalized light to locally heat biologically targeted nanoparticles, [5] generating reactive oxygen species chemically or genetically, [6] redoxb iology, [7] and nanoswitching the pharmacological action of small molecules [8] and peptidomimetics [9] using photochromic actuators. Compared to gene therapies and micro-and nanoparticles, the photopharmacological approachm ight benefitf rom well-established medical, industrial and regulatory procedures of pharmacology and is compatible with clinically available phototherapies.…”

“…[18] If only one of these conformationsi sa ble to inhibito renhance ac ertain PPI, the peptide can be used to photomodulate that interaction at the targeted location and dosage. [9,19] Progress in drug delivery is hampered by al ack of efficient strategies to target drugsw ithh igh specificity and precise spatiotemporalr egulation. The remote control of nanoparticles and drugs with light allows regulationo ft heir action site and dosage.…”