Dual-Stage Irradiation of Size-Switchable Albumin Nanocluster for Cascaded Tumor Enhanced Penetration and Photothermal Therapy

He，Peiying1; Lei，Qi1; Yang，Bin2; Shang，Tongyi2; Shi，Jianjun3; Ouyang，Qing4; Wang，Wei3; Xue，Liecong1; Kong，Fanhui1; Li，Zeyu1; Huang，Junda1; Liu，Lihan5; Guo，Jimin6; Brinker，C. Jeffrey6; Liu，Kaisheng7; Zhu，Wei1

2022-09-27

10.1021/acsnano.2c02965

ACS Nano   Impact Factor & Quartile

1936-0851

1936-086X

The triple-negative breast cancer (TNBC) microenvironment makes a feature of aberrant vasculature, high interstitial pressure, and compact extracellular matrix, which combine to reduce the delivery and penetration of therapeutic agents, bringing about incomplete elimination of cancer cells. Herein, employing the tumor penetration strategy of size-shrinkage combined with ligand modification, we constructed a photothermal nanocluster for cascaded deep penetration in tumor parenchyma and efficient eradication of TNBC cells. In our approach, the photothermal agent indocyanine green (ICG) is laded in human serum albumin (HSA), which is cross-linked by a thermally labile azo linker (VA057) and then further modified with a tumor homing/penetrating tLyP-1 peptide (HP), resulting in a TNBC-targeting photothermal-responsive size-switchable albumin nanocluster (ICG@HSA-Azo-HP). Aided by the enhanced permeability and retention effect and guidance of HP, the ca. 149 nm nanoclusters selectively accumulate in the tumor site and then, upon mild irradiation with the 808 nm laser, disintegrate into 11 nm albumin fractions that possess enhanced intratumoral diffusion ability. Meanwhile, HP initiates the CendR pathway among the nutrient-deficient tumor cells and facilitates the transcellular delivery of the nanocluster and its disintegrated fractions for subsequent therapy. By employing this size-shrinkage and peptide-initiated transcytosis strategy, ICG@HSA-Azo-HP possesses excellent penetration capabilities and shows extensive penetration depth in three-dimensional multicellular tumor spheroids after irradiation. Moreover, with a superior photothermal conversion effect, the tumor-penetrating nanocluster can implement effective photothermal therapy throughout the tumor tissue under a second robust irradiation. Both in vivo orthotopic and ectopic TNBC therapy confirmed the efficient tumor inhibition of ICG@HSA-Azo-HP after dual-stage irradiation. The synergistic penetration strategy of on-demanded size-shrinkage and ligand guidance accompanied by clinically feasible NIR irradiation provides a promising approach for deep-penetrating TNBC therapy.

dual-stage irradiation homing peptide photothermal therapy size-switchable nanocluster tumor penetration

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1.MOE International Joint Research Laboratory on Synthetic Biology and Medicines,School of Biology and Biological Engineering,South China University of Technology,Guangzhou,510006,China
2.The Sixth Affiliated Hospital of Guangzhou Medical University,Qingyuan People's Hospital,Department of Biomedical Engineering,School of Basic Medical Sciences,Guangzhou Medical University,Guangzhou,511436,China
3.Science and Technology on Advanced Functional Composites Technology,Aerospace Research Institute of Materials & Processing Technology,Beijing,100076,China
4.Department of Hepatobiliary Surgery,Liver Transplant Center,The General Hospital of Southern Theater,Guangzhou,510010,China
5.Department of Pharmaceutical Sciences and Guangdong,Key Laboratory of New Drug Screening,Southern Medical University,Guangzhou,510515,China
6.Center for Micro-Engineered Materials,Department of Chemical and Biological Engineering,The University of New Mexico,Albuquerque,87131,United States
7.Shenzhen People's Hospital,The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,518020,China

He，Peiying,Lei，Qi,Yang，Bin,et al. Dual-Stage Irradiation of Size-Switchable Albumin Nanocluster for Cascaded Tumor Enhanced Penetration and Photothermal Therapy[J]. ACS Nano,2022,16(9):13919-13932.

He，Peiying.,Lei，Qi.,Yang，Bin.,Shang，Tongyi.,Shi，Jianjun.,...&Zhu，Wei.(2022).Dual-Stage Irradiation of Size-Switchable Albumin Nanocluster for Cascaded Tumor Enhanced Penetration and Photothermal Therapy.ACS Nano,16(9),13919-13932.

He，Peiying,et al."Dual-Stage Irradiation of Size-Switchable Albumin Nanocluster for Cascaded Tumor Enhanced Penetration and Photothermal Therapy".ACS Nano 16.9(2022):13919-13932.