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Combination of metronomic administration and target delivery strategies to improve the anti-angiogenic and anti-tumor effects of triptolide

  • Xin-jun Cai
  • Wei-dong Fei
  • Ying-ying Xu
  • Hong Xu
  • Gao-yi Yang
  • Jia-wei Cao
  • Jian-jun Ni
  • Zeng WangEmail author
Original Article
  • 28 Downloads

Abstract

The metronomic administration of a low-dose cytotoxic agent with no prolonged drug-free breaks is an anti-angiogenic cancer treatment method. The use of nano-formulations in this manner enhances anti-tumor efficacy and reduces toxicity by inhibiting angiogenic activity, reduces adverse effects, and changes the biodistribution of TP in the body, steering TP away from potentially endangering healthy tissues. The present study uses liposomes and Asn-Gly-Arg (NGR) peptide conjugated aminopeptidase N(APN)-targeted liposomes for triptolide (TP), as a model for the investigation of targeted metronomic administration and subsequent effects on the toxicity profile and efficacy of the chemotherapeutic agent. Metronomic NGR-PEG-TP-LPs have been found to have enhanced anti-tumor activity, a phenomenon that is attributed to an increase in angiogenic inhibition properties. In vitro experiments demonstrate that the viability, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) are obviously suppressed in comparison with that of other treatment groups. In vivo experiments also demonstrate that the anti-tumor efficacy of targeted metronomic administration is superior to that of liposome-administered treatments given at maximum tolerated dose (MTD) schemes, as is evidenced by markedly decreased tumor volume, vessel density, and the volume of circulating endothelial progenitor cells (CEPCs) in serum. Moreover, we observed that the metronomic administration of NGR-PEG-TP-LPs could elevate thrombospondin-1 (TSP-1) expression in tumors, a finding that is consistent with the promotion of TSP-1 secretion specifically from HUVECs. Additionally, metronomic NGR-PEG-TP-LPs have minimal drug-associated toxicity (weight loss, hepatotoxicity and nephrotoxicity in mice). Our research demonstrates the significance of targeted metronomic administration using liposomes for anti-angiogenic cancer therapy.

Keywords

Liposomes Metronomic administration Anti-angiogenic Anti-tumor effect 

Notes

Funding information

This work was supported by the Chinese Medicine Science and Technology Plan of Zhejiang Province (NO 2015ZA148, 2017ZA109), the Natural Science Foundation of Zhejiang Province (NO Q18H290004, NO LYY18H300001), Hangzhou City Science and Technology Project Planning Guide (2015YD21), and Talent Training Program of Zhejiang Cancer Hospital.

Compliance with ethical standards

All procedures related with animal handling and care were carried out under strict compliance with governmental and institutional protocols.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Controlled Release Society 2019

Authors and Affiliations

  1. 1.Department of PharmacyZhejiang Chinese Medicine and Western Medicine Integrated HospitalHangzhouPeople’s Republic of China
  2. 2.Department of Pharmacy, Women’s HospitalZhejiang University School of MedicineHangzhouChina
  3. 3.Department of Gastroenterology and HepatologyZhejiang Chinese Medicine and Western Medicine Integrated HospitalHangzhouPeople’s Republic of China
  4. 4.Department of UltrasoudZhejiang Chinese Medicine and Western Medicine Integrated HospitalHangzhouPeople’s Republic of China
  5. 5.Department of PharmacyInstitute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer HospitalHangzhouPeople’s Republic of China

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