Tumor Microenvironment Remodeling-Mediated Sequential Drug Delivery Potentiates Treatment Efficacy

Yajun Xu; Jianlin Lv; Fuyao Liu; Jinqiang Wang; Ya Liu; Chaoying Kong; Yanran Li; Na Shen; Zhen Gu; Zhaohui Tang; Xuesi Chen

doi:10.1002/adma.202312493

Tumor Microenvironment Remodeling-Mediated Sequential Drug Delivery Potentiates Treatment Efficacy

Adv Mater. 2024 Mar 5:e2312493. doi: 10.1002/adma.202312493. Online ahead of print.

Authors

Yajun Xu^{1

2

3}, Jianlin Lv^{1

2

3}, Fuyao Liu^{4

5

6}, Jinqiang Wang^{4

5

6}, Ya Liu^{1

2

3}, Chaoying Kong^{1

2

3}, Yanran Li^{1

2

3}, Na Shen^{1

3}, Zhen Gu^{4

5

6

7}, Zhaohui Tang^{1

2

3}, Xuesi Chen^{1

2

3}

Affiliations

¹ Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China.
² School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China.
³ Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, China.
⁴ National Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
⁵ Jinhua Institute of Zhejiang University, Jinhua, 321037, China.
⁶ Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Provincial, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
⁷ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.

PMID: 38444177
DOI: 10.1002/adma.202312493

Abstract

Toll-like receptor 7/8 agonists, such as imidazoquinolines (IMDQs), are promising for the de novo priming of antitumor immunity. However, their systemic administration is severely limited due to the off-target toxicity. Here, this work describes a sequential drug delivery strategy. The formulation is composed of two sequential modules: a tumor microenvironment remodeling nanocarrier (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4, termed CA4-NPs) and an immunotherapy nanocarrier (apcitide peptide-decorated poly(l-glutamic acid)-graft-IMDQ-N₃ conjugate, termed apcitide-PLG-IMDQ-N₃ ). CA4-NPs, as a vascular disrupting agent, are utilized to remodel the tumor microenvironment for enhancing tumor coagulation and hypoxia. Subsequently, the apcitide-PLG-IMDQ-N₃ could identify and target tumor coagulation through the binding of surface apcitide peptide to the GPIIb-IIIa on activated platelets. Afterward, IMDQ is activated selectively through the conversion of "-N₃ " to "-NH₂ " in the presence of hypoxia. The biodistribution results confirm their high tumor uptake of activated IMDQ (22.66%ID/g). By augmenting the priming and immunologic memory of tumor-specific CD8⁺ T cells, 4T1 and CT26 tumors with a size of ≈500 mm³ are eradicated without recurrence in mouse models.

Keywords: TLR agonist; coagulation; drug delivery; imidazoquinoline; tumor hypoxia; vascular disrupting agent.

Abstract

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