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Synergistic antitumor efficacy of PD-1-conjugated PTX- and ZSQ-loaded nanoliposomes against multidrug-resistant liver cancers

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Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor chemotherapeutic efficiency due to multidrug resistance (MDR); it is very important to develop a targeted nanocarrier for the treatment of HCC. In this study, a programmed death ligand 1 (PD-L1)–conjugated nanoliposome was constructed for co-delivery of paclitaxel (PTX) and P-glycoprotein (P-gp) inhibitor zosuquidar (ZSQ) to overcome MDR in human HCC cells and tumors in vivo. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to examine the nanoparticles morphology and size; PD-1-conjugated PTX and ZSQ-loaded nanoliposomes (PD-PZLP) revealed a spherical shape with a size of 139.5 ± 10.7 nm. Then, the physicochemical properties, as well as the drug loading capacity, release profile, cellular uptake, and cytotoxicity of the dual drug-encapsulated nanoliposomes were characterized. PD-PZLP displayed a high drug loading capacity of 20 ~ 30% for both PTX and ZSQ; the drug release of PTX and ZSQ in pH 5.0 was significantly faster than in pH 7.4. Cellular uptake study demonstrated PD-PZLP had higher internalization efficiency than non-targeted PZLP. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and reactive oxygen species (ROS) analysis demonstrated that PD-PZLP triggered an excessive ROS reaction and cell apoptosis compared with that of free PTX or ZSQ, which was also consistent with the cell antiproliferative effects in MTT assay. Furthermore, PD-PZLP could enhance synergistic antitumor effects on 7721/ADM xenograft tumor model, which also significantly alleviated hepatotoxicity as evident from the decreased aspartate transaminase (AST) and alanine transaminase (ALT) levels. Overall, PD-PZLP exhibited high loading capacity, significant synergistic effects, promising antitumor efficacy, and the lowest toxicity, which provide a promising strategy to overcome MDR in HCC.

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Availability of data and materials

The datasets used or analyzed during the current study are available from the corresponding author.

Abbreviations

HCC:

Hepatocellular carcinoma

MDR:

Multidrug resistance

P-gp:

P-glycoprotein

PTX:

Paclitaxel

ZSQ:

Zosuquidar

PD-L1:

Programmed death ligand1

PD-PZLP:

PD-L1-conjugated PTX and ZSQ-loaded nanoliposomes

ROS:

Reactive oxygen species

EPR:

Enhanced permeation and retention

NTA:

Nanoparticle tracking analysis

TEM:

Transmission electron microscope

HPLC:

High-performance liquid chromatography system

PBS:

Phosphate-buffered saline

DAPI:

4,6-Diamidino-2-phenylindole

PFA:

Paraformaldehyde

CLSM:

confocal laser scanning microscope

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gels

PVDF:

Polyvinylidene fluoride

CI:

Combination index

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

IHC:

Immunohistochemical

AST:

Aspartate transaminase

ALT:

Alanine transaminase

TBST:

Tris‑buffered saline with Tween 20

ECL:

enhanced chemiluminescence

mAb:

monoclonal antibodies

FITC:

Fluorescein Isothiocyanate

DCFH-DA:

dichlorofluorescin diacetate

DAB:

diaminebenzidine

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Funding

All sources of funding were supported by the Medical and Health Project of Suzhou High-tech district (2018Z006).

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Author notes

  1. Mingjia Gu and Fang Yin are first authors to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, China

    Mingjia Gu & Jiebin Zhu

  2. Institute for Intestinal Diseases, Shanghai Tenth People’s Hospital, Shanghai, China

    Fang Yin

  3. Department of Dermatology, The People’s Hospital of Rushan, Weihai, China

    Yuening Qin

  4. The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, China

    Yali Tian, Hanjing Shen & Jiebin Zhu

  5. College of Food Science and Engineering of Qingdao Agricultural University, Qingdao, China

    Xinjie Xiu

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  1. Mingjia Gu
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  4. Yali Tian
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Contributions

Mingjia Gu and Fang Yin: conceptualization, methodology, investigation, writing — original draft. Yuening Qin and Yali Tian: methodology, data curation; formal analysis, validation; Xinjie Xiu and Hanjing Shen: software; supervision, visualization. Jiebin Zhu: conceptualization, writing — review and editing, supervision, project administration. All persons mentioned above have made substantial contributions to the work in the manuscript.

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Correspondence to Jiebin Zhu.

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Gu, M., Yin, F., Qin, Y. et al. Synergistic antitumor efficacy of PD-1-conjugated PTX- and ZSQ-loaded nanoliposomes against multidrug-resistant liver cancers. Drug Deliv. and Transl. Res. 12, 2550–2560 (2022). https://doi.org/10.1007/s13346-021-01106-1

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