@article{65659,
  abstract     = {{Over the past decades, nanoparticulate drug carrier systems have emerged as promising tools in medicine. A persistent challenge in current pharmacotherapy is the limited selectivity of active pharmaceutical ingredients, resulting in undesirable side effects. Smart drug delivery systems, which release encapsulated active pharmaceutical ingredients in response to specific stimuli, offer a potential solution by enabling controlled drug release. This approach can be particularly relevant for exploiting biochemical differences between extracellular and intracellular environments. In this study, self-immolative polydisulfide based polymers manufactured from dithiothreitol were processed into nanoparticle formulations to respond preferentially to elevated glutathione levels, which are characteristic of intracellular environments and are often increased in tumor cells. The influence of polymer chain length on the physicochemical properties of the resulting nanoparticles was investigated. Lumogen® Red was incorporated as a model substance to determine the loading capacity of the carrier system. Degradation was characterized using dynamic light scattering and asymmetric flow field-flow fractionation, as well as by imaging techniques such as atomic force microscopy. Selective release of the embedded substance was demonstrated at elevated glutathione concentrations, while no significant release was observed at extracellularly relevant levels (10 µM glutathione), where the behavior was comparable to the buffer control. Increased release was observed under intracellularly relevant conditions (2 – 10 mM glutathione). These findings support a redox-responsive behavior under intracellular-like conditions. The latter was proven for primary fibroblasts and the cancer cell lines BT-474, MCF-7 and SK-BR-3 by quantification of intracellular low molecular weight thiols. The nanoparticle uptake was confirmed in the investigated cell lines by visualization via confocal laser scanning microscopy. Via lysosomal staining it was shown that nanoparticles accumulate in lysosomes. Furthermore, the carrier system itself showed no cytotoxic properties in cell culture studies against the four different cell types. The developed system is a suitable and very promising smart drug delivery system in the context of controlled drug release.}},
  author       = {{Kramer, Maurice and Horky, Corinna and Völlmecke, Katharina and Mulac-Hahnen, Dennis and Herrmann, Fabian and Kuckling, Dirk and Langer, Klaus}},
  issn         = {{2949-8295}},
  journal      = {{Next Nanotechnology}},
  keywords     = {{Nanoparticles, Smart drug delivery, Controlled release, Self-immolative polymers, Tumor targeting}},
  publisher    = {{Elsevier BV}},
  title        = {{{Smart drug delivery systems for potential targeted cancer therapy: Exploiting increased glutathione levels in tumor microenvironments}}},
  doi          = {{10.1016/j.nxnano.2026.100510}},
  volume       = {{9}},
  year         = {{2026}},
}

@article{64884,
  abstract     = {{To address the challenges associated with poor drug solubility and uncontrolled drug release in conventional dosage forms, a combination of polymer design and advanced drug delivery approaches has been employed. The development of pH-responsive nanoparticles for controlled and selective drug release represents a notable advance in adaptive nanomedicine. This study explores the design of a pH-responsive polymer, poly(1,4-phenyleneacetone dimethylene ketal) (PPADK). Additionally, the incorporation of light-responsive ortho-nitrobenzyl groups (o-NB-PPADK) enhanced the degradation upon exposure to light. Based on the polymer, nanoparticles were prepared using the solvent displacement method. The fluorescence dye Lumogen® Red was incorporated as a model substance. The nanoparticles were characterized by dynamic light scattering to determine their hydrodynamic diameter and size distribution, and the surface charge was analyzed. Atomic force microscopy was used to visualize the surface morphology. The nanoparticles remained stable under physiological pH conditions while exhibiting accelerated degradation and substance release in acidic environment, a property potentially exploitable for tumor targeting. Further enhanced degradation and correspondingly increased release was achieved by incorporating light-responsive elements in the polymer structure.
The cytotoxicity of these newly designed nanoparticles was evaluated in cell culture using a breast cancer cell line. These results support the potential of o-NB-PPADK nanoparticles as a possible candidate for selective and effective cancer therapy, combining stimuli-responsive degradation mechanisms for improved therapeutic outcomes.}},
  author       = {{Kramer, Maurice and van der Linde, Matthias and Hönscheid, Lisa and Horky, Corinna and Völlmecke, Katharina and Mulac, Dennis and Herrmann, Fabian and Kuckling, Dirk and Langer, Klaus}},
  issn         = {{0378-5173}},
  journal      = {{International Journal of Pharmaceutics}},
  keywords     = {{Nanoparticles, Drug delivery, Controlled release, Stimuli-responsiveTumor targeting}},
  publisher    = {{Elsevier BV}},
  title        = {{{Enlightening release strategies: Accelerated nanoparticle degradation and substance release utilizing light- and pH-responsive polymers}}},
  doi          = {{10.1016/j.ijpharm.2025.126127}},
  volume       = {{684}},
  year         = {{2025}},
}

@article{35657,
  abstract     = {{The controlled delivery of active pharmaceutical ingredients to the site of disease represents a major challenge in drug therapy. Particularly when drugs have to be transported across biological barriers, suitable drug delivery systems are of importance. In recent years responsive delivery systems have been developed which enable a controlled drug release depending on internal or external stimuli such as changes in pH, redox environment or light and temperature. In some studies delivery systems with reactivity against two different stimuli were established either to enhance the response by synergies of the stimuli or to broaden the window of possible trigger events. In the present review numerous exciting developments of pH-, light- and redox-cleavable polymers suitable for the preparation of smart delivery systems are described. The review discusses the different stimuli that can be used for a controlled drug release of polymer-based delivery systems. It puts a focus on the different polymers described for the preparation of stimuli-sensitive systems, their preparation techniques as well as their stimuli-responsive degradation. © 2022 The Authors. Polymer International published by John Wiley & Sons Ltd on behalf of Society of Industrial Chemistry.}},
  author       = {{Rust, Tarik and Jung, Dimitri and Langer, Klaus and Kuckling, Dirk}},
  issn         = {{0959-8103}},
  journal      = {{Polymer International}},
  keywords     = {{drug delivery system, stimuli, polymer, cleavable}},
  number       = {{1}},
  pages        = {{5--19}},
  publisher    = {{Wiley}},
  title        = {{{Stimuli‐accelerated polymeric drug delivery systems}}},
  doi          = {{10.1002/pi.6474}},
  volume       = {{72}},
  year         = {{2023}},
}

@article{59620,
  author       = {{Rust, Tarik and Jung, Dimitri and Hoppe, Axel and Schoppa, Timo and Langer, Klaus and Kuckling, Dirk}},
  issn         = {{2637-6105}},
  journal      = {{ACS Applied Polymer Materials}},
  keywords     = {{backbone-degradable, light-responsive, redox-responsive, drug delivery, nanoparticles}},
  number       = {{8}},
  pages        = {{3831--3842}},
  publisher    = {{American Chemical Society (ACS)}},
  title        = {{{Backbone-Degradable (Co-)Polymers for Light-Triggered Drug Delivery}}},
  doi          = {{10.1021/acsapm.1c00411}},
  volume       = {{3}},
  year         = {{2021}},
}