Enhanced antitumor and anti-metastasis by VEGFR2-targeted doxorubicin immunoliposome synergy with NK cell activation.

IF 3 3区医学 Q2 ONCOLOGY Investigational New Drugs Pub Date : 2023-10-01 Epub Date: 2023-08-05 DOI:10.1007/s10637-023-01372-5

Mingzhu Pan, Yali Liu, Tian Sang, Jiajun Xie, Huishu Lin, Jianpeng Wei, Shuai Shao, Yanying Zheng, Juan Zhang

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Abstract

Liposomal doxorubicin exhibits stronger drug accumulation at the tumor site due to the Enhanced Permeability and Retention (EPR) effect. However, the prognosis for the patient is poor due to this drug's lack of targeting and tumor metastasis during treatment. Vascular epidermal growth factor receptor (VEGFR2) plays an important role in angiogenesis and cancer metastasis. To enhance antitumor efficacy of PEGylated liposomal doxorubicin, we constructed a VEGFR2-targeted and doxorubicin-loaded immunoliposome (Lipo-DOX-C00) by conjugating a VEGFR2-specific, single chain antibody fragment to DSPE-PEG2000-MAL, and then we inserted the antibody-conjugated polymer into liposomal doxorubicin (Lipo-DOX). The immunoliposome was formed uniformly with high affinity for VEGFR2. In vitro, Lipo-DOX-C00 enhanced doxorubicin internalization into LLC and 4T1 cells compared with non-conjugated, liposomal doxorubicin. In vivo, Lipo-DOX-C00 delivered DOX to tumor tissues effectively, which exhibited an improved antitumor and anti-metastasis efficacy in both LLC subcutaneous tumor models and 4T1 tumor models. In addition, the combined therapy of a VEGFR2-MICA bispecific antibody (JZC01) and Lipo-DOX-C00 achieved enhanced inhibition of cancer growth and metastasis due to activation of the immune system. Our study provides a promising approach to clinical application of liposomal doxorubicin.

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VEGFR2靶向阿霉素免疫脂质体与NK细胞活化协同作用增强抗肿瘤和抗转移能力。

脂质体阿霉素由于增强的渗透性和滞留性（EPR）效应而在肿瘤部位表现出更强的药物积聚。然而，由于该药物在治疗过程中缺乏靶向性和肿瘤转移，患者的预后较差。血管表皮生长因子受体（VEGFR2）在血管生成和癌症转移中起重要作用。为了增强聚乙二醇化阿霉素脂质体的抗肿瘤效力，我们通过将VEGFR2特异性单链抗体片段与DSPE-PEG2000-MAL偶联，构建了VEGFR2靶向和负载阿霉素的免疫脂质体（Lipo-DOX-C00），然后我们将抗体偶联的聚合物插入阿霉素脂质体（Lipo-DOX）中。免疫脂质体形成均匀，对VEGFR2具有高亲和力。在体外，与非缀合的脂质体阿霉素相比，Lipo-DOX-C00增强了阿霉素内化到LLC和4T1细胞中。在体内，Lipo-DOX-C00有效地将DOX递送到肿瘤组织，在LLC皮下肿瘤模型和4T1肿瘤模型中都表现出提高的抗肿瘤和抗转移功效。此外，VEGFR2-MICA双特异性抗体（JZC01）和Lipo-DOX-C00的联合治疗由于免疫系统的激活而实现了对癌症生长和转移的增强抑制。我们的研究为阿霉素脂质体的临床应用提供了一种有前景的途径。

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来源期刊

Investigational New Drugs 医学-药学

CiteScore

7.60

自引率

0.00%

发文量

121

审稿时长

1 months

期刊介绍： The development of new anticancer agents is one of the most rapidly changing aspects of cancer research. Investigational New Drugs provides a forum for the rapid dissemination of information on new anticancer agents. The papers published are of interest to the medical chemist, toxicologist, pharmacist, pharmacologist, biostatistician and clinical oncologist. Investigational New Drugs provides the fastest possible publication of new discoveries and results for the whole community of scientists developing anticancer agents.