Development of Photoremovable Linkers as a Novel Strategy to Improve the Pharmacokinetics of Drug Conjugates and Their Potential Application in Antibody–Drug Conjugates for Cancer Therapy

Abstract

Although there have been extensive research and progress on the discovery of anticancer drug over the years, the application of these drugs as stand-alone therapy has been limited by their off-target toxicities, poor pharmacokinetic properties, and low therapeutic index. Targeted drug delivery, especially drug conjugate, has been recognized as a technology that can bring forth a new generation of therapeutics with improved efficacy and reduced side effects for cancer treatment. The linker in a drug conjugate is of essential importance because it impacts the circulation time of the conjugate and the release of the drug for full activity at the target site. Recently, the light-triggered linker has attracted a lot of attention due to its spatiotemporal controllability and attractive prospects of improving the overall pharmacokinetics of the conjugate. In this paper, the latest developments of UV- and IR-triggered linkers and their application and potential in drug conjugate development are reviewed. Some of the most-well-researched photoresponsive structural moieties, such as UV-triggered coumarin, ortho-nitrobenzyl group (ONB), thioacetal ortho-nitrobenzaldehyde (TNB), photocaged C40-oxidized abasic site (PC4AP), and IR-triggered cyanine and BODIPY, are included for discussion. These photoremovable linkers show better physical and chemical stabilities and can undergo rapid cleavage upon irradiation. Very importantly, the drug conjugates containing these linkers exhibit reduced off-target toxicity and overall better pharmacokinetic properties. The progress on photoactive antibody–drug conjugates, such as antibody–drug conjugates (ADC) and antibody–photoabsorber conjugate (APC), as precision medicine in clinical cancer treatment is highlighted.

Nano‐Biotechnology and Challenges of Drug Delivery System in Cancer Treatment Pathway: Review Article

“…As a result, some drugs might not work with the nano drug delivery technology. These systems may rapidly breakdown the ligand by proteins and enzymes typically found in blood plasma, activating the medication earlier and speeding up blood flow [30–32] …”

“…Since protein drug attached nanostructures are generally quite tiny (10 nm), their lengthy in vivo half-lives make it easier to transport them to the specific tumor location. [31] The targeting capacity of protein-drug attached nanoparticles has recently been improved by the addition of antibody proteins. [32] It can be challenging to attach to a protein basis because of some medications' structural sensitivity, which is one of the fundamental problems with protein-based nanostructures.…”

“…This obstacle has been solved by more recent technology, such protein-drug conjugated systems with linkers that remain intact until the nanostructures arrive at the intended location. [31] This technology lessens the negative side effects of therapy on the body and leads to the regulated and controllable release of medicinal compounds. Since protein drug attached nanostructures are generally quite tiny (10 nm), their lengthy in vivo half-lives make it easier to transport them to the specific tumor location.…”

“…This could lead to the early release of the drug because its destructible interface is readily degraded by proteases and altered factors in the blood. This obstacle has been solved by more recent technology, such protein‐drug conjugated systems with linkers that remain intact until the nanostructures arrive at the intended location [31] . This technology lessens the negative side effects of therapy on the body and leads to the regulated and controllable release of medicinal compounds.…”

Spektroskopische Charakterisierung von Halbleiter-Quantenpunkten und deren Hybridsystemen

“…Auch heute gehören oNB Derivate noch zu den am häufigsten eingesetzten photolabilen Schutzgruppen. Neben oNB [60][61][62][63][64] , finden auch Cumarin-basierte Moleküle [54,56,60,62,[65][66][67][68] , auf BODIPY basierende Verbindungen [54,[68][69][70][71] sowie Nitrodibenzofurane (NDBF) [55,60,72] Anwendung als photolabile Schutzgruppen. Über Modifikationen an den Strukturen können die optischen sowie die photolytischen Eigenschaften beeinflusst werden (vgl.…”