TY - JOUR
T1 - Inflammation-Responsive Drug-Conjugated Dextran Nanoparticles Enhance Anti-Inflammatory Drug Efficacy
AU - Lee, Sangeun
AU - Stubelius, Alexandra
AU - Hamelmann, Naomi
AU - Tran, Vincent
AU - Almutairi, Adah
N1 - Funding Information:
*E-mail: [email protected]. ORCID Adah Almutairi: 0000-0001-5339-0207 Author Contributions These authors contributed equally. S.L. and A.S. designed the studies. S.L., N.H., and A.S. synthesized the polymers; and S.L. and A.S. engineered the NPs. S.L. conducted the polymer analysis studies including LC−MS, GPC, and TEM of the NPs. A.S. conducted the in vitro studies and analysis. V.T. conducted the NMR studies and analysis. A.A. provided guidance on the overall studies. S.L. and A.S. coauthored the paper. All authors discussed the results and commented on the paper. All authors have given approval to the final version of the manuscript. Funding This work was supported by the Air Force Office of Scientific Research (AFOSR) FA9550-15-1-0273, National Institutes of Health R01EY024134, and the Swedish Research Council’s International Postdoc Grant (AS: 2015-06470). Notes The authors declare no competing financial interest.
Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/11/28
Y1 - 2018/11/28
N2 - Stimuli-responsive nanoparticles (NPs) are especially interesting to enhance the drug delivery specificity for biomedical applications. With the aim to achieve a highly stable and inflammation-specific drug release, we designed a reactive oxygen species (ROS)-responsive dextran-drug conjugate (Nap-Dex). By blending Nap-Dex with the acid-sensitive acetalated dextran polymer, we achieved a dual-responsive NP with high specificity toward the inflammatory environment. The inflammatory environment not only has elevated ROS levels but also has a lower pH than healthy tissues, making pH and ROS highly suitable triggers to target inflammatory diseases. The anti-inflammatory cyclooxygenase inhibitor naproxen was modified with an ROS-responsive phenylboronic acid (PBA) and conjugated onto dextran. The dextran units were functionalized with up to 87% modified naproxen. This resulted in a complete drug release from the polymer within 20 min at 10 mM H 2 O 2 . The dual-responsive NPs reduced the levels of the proinflammatory cytokine IL-6 120 times more efficiently and TNFα 6 times more efficiently than free naproxen from lipopolysaccharide (LPS)-activated macrophages. These additional anti-inflammatory effects were found to be mainly attributed to ROS-scavenging effects. In addition, the model cargo fluorescein diacetate was released in an LPS-induced inflammatory response in vitro. We believe that drug conjugation using PBA can be applied to various drugs and dextran-based materials for enhanced drug efficacy, where this work demonstrates the significance of functionalized carbohydrates polymer-drug conjugates.
AB - Stimuli-responsive nanoparticles (NPs) are especially interesting to enhance the drug delivery specificity for biomedical applications. With the aim to achieve a highly stable and inflammation-specific drug release, we designed a reactive oxygen species (ROS)-responsive dextran-drug conjugate (Nap-Dex). By blending Nap-Dex with the acid-sensitive acetalated dextran polymer, we achieved a dual-responsive NP with high specificity toward the inflammatory environment. The inflammatory environment not only has elevated ROS levels but also has a lower pH than healthy tissues, making pH and ROS highly suitable triggers to target inflammatory diseases. The anti-inflammatory cyclooxygenase inhibitor naproxen was modified with an ROS-responsive phenylboronic acid (PBA) and conjugated onto dextran. The dextran units were functionalized with up to 87% modified naproxen. This resulted in a complete drug release from the polymer within 20 min at 10 mM H 2 O 2 . The dual-responsive NPs reduced the levels of the proinflammatory cytokine IL-6 120 times more efficiently and TNFα 6 times more efficiently than free naproxen from lipopolysaccharide (LPS)-activated macrophages. These additional anti-inflammatory effects were found to be mainly attributed to ROS-scavenging effects. In addition, the model cargo fluorescein diacetate was released in an LPS-induced inflammatory response in vitro. We believe that drug conjugation using PBA can be applied to various drugs and dextran-based materials for enhanced drug efficacy, where this work demonstrates the significance of functionalized carbohydrates polymer-drug conjugates.
KW - Acid-responsive
KW - Dextran
KW - Dual-responsive
KW - Inflammation-responsive
KW - Polymer-drug conjugates
KW - ROS-responsive
KW - 2023 OA procedure
UR - http://www.scopus.com/inward/record.url?scp=85052280728&partnerID=8YFLogxK
U2 - 10.1021/acsami.8b08254
DO - 10.1021/acsami.8b08254
M3 - Article
C2 - 30067018
AN - SCOPUS:85052280728
SN - 1944-8244
VL - 10
SP - 40378
EP - 40387
JO - ACS Applied Materials and Interfaces
JF - ACS Applied Materials and Interfaces
IS - 47
ER -