Targeting CDK4/6 in glioblastoma via in situ injection of a cellulose-based hydrogel

Xia Zhang; Like Ning; Hongshuai Wu; Suisui Yang; Ziyi Hu; Wenhong Wang; Yuandong Cao; Hongliang Xin; Chaoqun You; Fan Lin

doi:10.1039/D3NR00378G

Targeting CDK4/6 in glioblastoma via in situ injection of a cellulose-based hydrogel†

Xia Zhang,‡^ab Like Ning,‡^a Hongshuai Wu,

‡^c Suisui Yang,^a Ziyi Hu,^a Wenhong Wang,^d Yuandong Cao,^e Hongliang Xin,*^f Chaoqun You

*^g and Fan Lin

*^ahi

Author affiliations

* Corresponding authors

^a Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China
E-mail: linfee@me.com

^b Department of Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

^c Department of Central Laboratory, The Affiliated Jiangyin Hospital of Nantong University, Jiangyin, Jiangsu, China

^d College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, Zhejiang, China

^e Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

^f Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China
E-mail: xhl@njmu.edu.cn

^g Jiangsu Key Lab for the Chemistry and Utilization of Agro-Forest Biomass, College of Chemical Engineering, Nanjing Forestry University, Nanjing, Jiangsu, China
E-mail: chemyoucq@njfu.edu.cn

^h Institute for Brain Tumors & Key Laboratory of Rare Metabolic Diseases, Nanjing Medical University, Nanjing, Jiangsu, China

ⁱ Department of Gastroenterology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, China

Abstract

Despite aggressive treatments, including surgery, chemotherapy and radiotherapy, the prognosis of glioblastoma (GBM) remains poor, and tumor recurrence is inevitable. The FDA-approved CDK4/6 inhibitor palbociclib (PB) showed interesting anti-GBM effects, but its brain penetration is limited by the blood–brain barrier. The aim of this project is to find whether the cellulose-based hydrogel via in situ injection could provide an alternative route to PB brain delivery and generate sufficient drug exposure in orthotopic GBM. In brief, PB was encapsulated in a cellulose nanocrystal network structure crosslinked by polydopamine via divalent Cu²⁺ and hexadecylamine. The formed hydrogel (PB@PH/Cu-CNCs) exhibited sustained drug retention and acid-responsive network de-polymerization for controlled release in vivo. Specifically, the released Cu²⁺ catalyzed a Fenton-like reaction to generate reactive oxygen species (ROS), which was further enhanced by PB, and consequently, irreversible senescence and apoptosis were induced in GBM cells. Finally, PB@PH/Cu-CNCs demonstrated a more potent anti-GBM effect than those treated with free PB or PH/Cu-CNCs (drug-free hydrogel) in cultured cells or in an orthotopic glioma model. These results prove that the injection of the PB-loaded hydrogel in situ is an effective strategy to deliver the CDK4/6 inhibitor into the brain and its anti-GBM effect can be further enhanced by combining Cu²⁺-mediated Fenton-like reaction.

Nanoscale

Targeting CDK4/6 in glioblastoma via in situ injection of a cellulose-based hydrogel†

Abstract

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Targeting CDK4/6 in glioblastoma via in situ injection of a cellulose-based hydrogel

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