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Research Article

Enzyme-activatable disk-shaped nanocarriers augment tumor permeability for breast cancer combination therapy

Hanming Zhang1, Honglin Gao1, Yicong Zhang1, Yikun Han1, Qing Lin1, Tao Gong1, Xun Sun1, Zhirong Zhang1, Ling Zhang2( ), Shiqi Huang2( )
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Med-X Center for Materials, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China
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Graphical Abstract

The current work designed a disc-shaped nano-system to co-deliver hydroxycamptothecin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein. These disc-shaped nanoparticles can be triggered charge reversal under the catalytic hydrolysis at tumor sites, and then the transcellular transport of nanoparticles was enabled through endocytosis and transcytosis mechanism, with superior penetration capacity compared to ubiquitous spherical liposomes, ultimately possessing satisfactory anti-tumor therapeutic efficacy.

Abstract

Unique physiopathological characteristics of tumor tissues impose obstacles to the sufficient penetration of traditional nanomedicines, resulting in undesirable drug delivery efficacy and therapeutic outcomes. Here, we constructed TRAIL-[ND-HCPT]GAC, a synergistic hydroxycamptothecin (HCPT) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein co-loaded disk-shaped nanocarrier with γ-glutamyl transpeptidase responsiveness. When the novel nanodisks extravasated into the tumor interstitium, the γ-glutamyl transpeptidase overexpressed on the tumor cell membranes cleaved the γ-glutamyl portions of the nanodisk surface to produce positively charged amino groups. As a result, the cationic nanodisks possessed stronger tumor infiltration ability through transcytosis than anionic nanodisks. HCPT and TRAIL exerted synergistic antitumor effects with better overall therapeutic efficacy. This TRAIL-[ND-HCPT]GAC system performed significantly better than free HCPT and remarkably prolonged the survival of breast tumor-bearing mice with no significant toxicity.

Keywords

tumor penetrationcombination therapycharge reversalγ-glutamyl transpeptidasenanodisk

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Nano Research
Volume 17 Issue 7,
July 2024
Pages 6400-6410
DOI: 10.1007/s12274-024-6608-3
Cite this article:
Zhang H, Gao H, Zhang Y, et al. Enzyme-activatable disk-shaped nanocarriers augment tumor permeability for breast cancer combination therapy. Nano Research, 2024, 17(7): 6400-6410. https://doi.org/10.1007/s12274-024-6608-3
Topics:
Chemotherapy Drug deliveryDrug therapyLiposomesNanoparticlesNanospheres NanostructuresSpheresTargeted drug deliveryTumors

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Received: 27 December 2023
Revised: 04 March 2024
Accepted: 07 March 2024
Published: 04 April 2024
© Tsinghua University Press 2024
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