Thermosensitive hyaluronic acid-manganese-capsaicin complex nanogel improving NKG 2 D/CAR-T melanoma treatment through adjusting tumor microenvironment.

Autor: Wang W; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 211198 Nanjing, China., Ma X; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 211198 Nanjing, China., Gu W; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 211198 Nanjing, China., Xu H; Nanjing KAEDI Biotherapeutics Co. Ltd., Nanjing 210043, China., Zhang Z; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine,100 Shizi Road, Nanjing, Jiangsu, 210028, China., Dai H; Nanjing KAEDI Biotherapeutics Co. Ltd., Nanjing 210043, China. Electronic address: paul.dai@kaedibio.com., Wu H; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 211198 Nanjing, China. Electronic address: hy_wu@cpu.edu.cn., Lv H; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 211198 Nanjing, China. Electronic address: lvhuixia@163.com.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Nov; Vol. 281 (Pt 3), pp. 136397. Date of Electronic Publication: 2024 Oct 09.
DOI: 10.1016/j.ijbiomac.2024.136397
Abstrakt: Intratumorally injection of CAR-T cells to treat melanoma can reduce the incidence of systemic side effects and ensure an adequate concentration of CAR-T cells. However, few targeting ligands and hostile tumor microenvironment (TME) inhibit the CAR-T cells' survival and infiltration. An in situ hyaluronic acid‑manganese-capsaicin complex nanogel (HA-Mn-CAP Gel) was designed by forming complex nanogel based on the main skeleton material of hyaluronic acid (HA). It targeted CD44 and TRPV 1 receptors through HA and CAP, concentrated and released Mn at melanoma, subsequently relieving the hypoxia in the tumor and increasing the expression of CAR-T cells' specific ligands. Cell experiments showed that HA-Mn-CAP Gel significantly enhanced the expression of representative NKG 2 D ligands (MICA/B and ULBP 2/5/6 ) >2.7 times on A375 melanoma cells. Sequential administration of HA-Mn-CAP Gel and NKG 2 D/CAR-T increased the tumor inhibition rate about 1.5 times that of the NKG 2 D/CAR-T group in melanoma-bearing NSG mice. The results of immunohistochemistry and immunofluorescence assays showed that the combined HA-Mn-CAP Gel and NKG 2 D/CAR-T significantly increased the proliferation and infiltration of T cells, especially for CD8 + cells. Therefore, the new promising strategy of increasing the target ligand expression and adjusting TME before administering CAR-T cells is suitable for treating solid tumors.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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