| Autor: |
Zhang Y; IMM Institute of Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden., Lundberg P; Materials Research Laboratory, University of California, Santa Barbara, CA 93106, USA., Diether M; IMM Institute of Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden., Porsch C; KTH Royal Institute of Technology, School of Chemical Science and Engineering, Department of Fibre and Polymer Technology, SE-100 44, Stockholm, Sweden., Janson C; Materials Research Laboratory, University of California, Santa Barbara, CA 93106, USA., Lynd NA; Materials Research Laboratory, University of California, Santa Barbara, CA 93106, USA., Ducani C; Swedish Medical Nanoscience Center, Department of Neuroscience, Karolinska Institutet, SE-171 77, Stockholm, Sweden., Malkoch M; KTH Royal Institute of Technology, School of Chemical Science and Engineering, Department of Fibre and Polymer Technology, SE-100 44, Stockholm, Sweden., Malmström E; KTH Royal Institute of Technology, School of Chemical Science and Engineering, Department of Fibre and Polymer Technology, SE-100 44, Stockholm, Sweden., Hawker CJ; Materials Research Laboratory, University of California, Santa Barbara, CA 93106, USA., Nyström AM; IMM Institute of Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden. |
| Abstrakt: |
Histamine functionalized block copolymers based on poly(allyl glycidyl ether)- b -poly(ethylene oxide) (PAGE- b -PEO) were prepared with different ratios of histamine and octyl or benzyl groups using UV-initiated thiol-ene click chemistry. At neutral pH, the histamine units are uncharged and hydrophobic, while in acidic environments, such as in the endosome, lysosomes, or extracellular sites of tumours, the histamine groups are positively charged and hydrophilic. pH responsible polymer drug delivery systems is a promising route to site specific delivery of drugs and offers the potential to avoid side effects of systemic treatment. Our detailed in vitro experiments of the efficacy of drug delivery and the intracellular localization characteristics of this library of NPs in 2D and 3D cultures of breast cancer revealed that the 50% histamine-modified polymer loaded with DOX exhibited rapid accumulation in the nucleus of free DOX within 2 h. Confocal studies showed enhanced mitochondrial localization and lysosomal escape when compared to controls. From these combined studies, it was shown that by accurately tuning the structure of the initial block copolymers, the resulting self-assembled NPs can be designed to exploit histamine as an endosomal escape trigger and the octyl/benzyl units give rise to a hydrophobic core resulting in highly efficacious drug delivery systems (DDS) with control over intracellular localization. Optimization and rational control of the intracellular localization of both DDS and the parent drug can give nanomedicines a substantial increase in efficacy and should be explored in future studies. |
