Dendrimer/Copper(II) Complex-Mediated siRNA Delivery Disrupts Lactate Metabolism to Reprogram the Local Immune Microenvironment against Tumor Growth and Metastasis.

Autor: Gao Y; State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China., Li A; State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China., Li Y; State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China., Guo H; Department of Radiology, Shanghai Songjiang District Central Hospital, Shanghai 201600, China., He L; State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China., Li K; Department of Radiology, Shanghai Songjiang District Central Hospital, Shanghai 201600, China., Shcharbin D; Institute of Biophysics and Cell Engineering of NASB, Akademicheskaja 27, 220072 Minsk, Belarus., Shi X; State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China., Shen M; State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, China.
Jazyk: angličtina
Zdroj: Biomacromolecules [Biomacromolecules] 2024 Dec 09; Vol. 25 (12), pp. 7995-8005. Date of Electronic Publication: 2024 Nov 21.
DOI: 10.1021/acs.biomac.4c01249
Abstrakt: Solid tumors reprogram metabolic pathways to meet their biosynthesis demands, resulting in elevated levels of metabolites in the tumor microenvironment (TME), including lactate. Excessive accumulation and active transportation of lactate within the TME drives tumor progression, metastasis, and immunosuppression. Interruption of TME lactate metabolism is expected to restore antitumor responses and sensitize tumor immunotherapy. Herein, we developed phenylboronic acid- and pyridine-modified poly(amidoamine) dendrimer/copper(II) (Cu(II)) complexes, namely, D-Cu complexes, to deliver monocarboxylate transporter 4 siRNA (siMCT4) and disrupt the tumor lactate shuttle. The D-Cu complexes are shown to have a Cu(II)-mediated chemodynamic effect and T 1 -weighted magnetic resonance imaging potential ( r 1 relaxivity = 1.19 mM -1 s -1 ), enabling effective siMCT4 delivery to inhibit lactate efflux within cancer cells. In combination with a CD11b immune agonist, the treatment of D-Cu/siMCT4 polyplexes in a mouse breast tumor model alleviates local TME immunosuppression, leading to excellent inhibition of both primary tumor growth and lung metastasis.
Databáze: MEDLINE