An injectable micelle-hydrogel hybrid for localized and prolonged drug delivery in the management of renal fibrosis

Xianyan Qin; Yingying Xu; Xu Zhou; Tao Gong; Zhi-Rong Zhang; Yao Fu

doi:10.1016/j.apsb.2020.10.016

An injectable micelle-hydrogel hybrid for localized and prolonged drug delivery in the management of renal fibrosis

Acta Pharm Sin B. 2021 Mar;11(3):835-847. doi: 10.1016/j.apsb.2020.10.016. Epub 2020 Oct 18.

Authors

Xianyan Qin^{1

2}, Yingying Xu¹, Xu Zhou^{1

3}, Tao Gong¹, Zhi-Rong Zhang¹, Yao Fu¹

Affiliations

¹ Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
² Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
³ Sichuan Provincial Orthopedic Hospital, Chengdu 610041, China.

Abstract

Localized delivery, comparing to systemic drug administration, offers a unique alternative to enhance efficacy, lower dosage, and minimize systemic tissue toxicity by releasing therapeutics locally and specifically to the site of interests. Herein, a localized drug delivery platform ("plum‒pudding" structure) with controlled release and long-acting features is developed through an injectable hydrogel ("pudding") crosslinked via self-assembled triblock polymeric micelles ("plum") to help reduce renal interstitial fibrosis. This strategy achieves controlled and prolonged release of model therapeutics in the kidney for up to three weeks in mice. Following a single injection, local treatments containing either anti-inflammatory small molecule celastrol or anti-TGFβ antibody effectively minimize inflammation while alleviating fibrosis via inhibiting NF-κB signaling pathway or neutralizing TGF-β1 locally. Importantly, the micelle-hydrogel hybrid based localized therapy shows enhanced efficacy without local or systemic toxicity, which may represent a clinically relevant delivery platform in the management of renal interstitial fibrosis.

Keywords: Anti-TGFβ antibody; BSA, bovine serum albumin; CLT, celastrol; Celastrol; Controlled release; Cy5.5-NHS, cyanine 5.5-N-hydroxysuccinimide; DAPI, 4′,6-diamidino-2-phenylindole; DEX, dexamethasone; DiD, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanineperchlorate; ECM, extracellular matrix; EDCI, carbodiimide hydrochloride; ESR, equilibrium swelling ratio; FITC, fluorescein isothiocyanate; G", the loss modulus; G', storage modulus; HA, hyaluronic acid; HASH, thiolated hyaluronic acid; Hydrogel; IL-1β, interleukin 1β; IL-6, interleukin 6; Inflammation; Localized therapy; MOD, mean optical density; NHS, N-hydroxysuccinimide; PDI, polydispersity index; RIF, renal interstitial fibrosis; RSR, real-time swelling ratio; Renal fibrosis; SD, standard deviation; SEM, scanning electron microscopy; TEM, transmission electron microscopy; TGF-β1, transforming growth factor β1; TNF-α, tumor necrosis factor α; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labelling; UUO, unilateral ureteral obstruction; bis-F127-MA, bis-F127-methacrylate; iNOS, nitric oxide synthase; α-SMA, α-smooth muscle actin; “Plum‒pudding” structure.