Suppression of colorectal cancer subcutaneous xenograft and experimental lung metastasis using nanoparticle-mediated drug delivery to tumor neovasculature.
Antiangiogenic therapy is a validated approach for colorectal cancer (CRC) treatment. However, diverse adverse effects inevitably appear due to the off-target effect of the approved antiangiogenic inhibitors on the physiological functions and homeostasis. This study was to investigate a new tumor vessel targeting nanoparticulate drug delivery system, F56 peptide conjugated nanoparticles loading vincristine (F56-VCR-NP), for the effective treatment of CRC subcutaneous xenograft and experimental lung metastasis model. The controlled release behavior and in vivo pharmacokinetic profile of F56-VCR-NP were characterized. The tumor vessel targeting and antiangiogenic activity of F56-VCR-NP was evaluated in human umbilical vein endothelial cells (HUVEC, a classical cell model mimicking tumor vascular EC), subcutaneous human HCT-15 xenograft in immunodeficient nude mice, and experimental CT-26 lung metastasis model in immunocompetent mice. The therapeutic efficacy (animal survival and toxicity) was further investigated in the model of CT-26 lung metastasis in mice. F56-VCR-NP could achieve 30-day controlled drug release in PBS (pH 7.4) and exhibited favorable long-circulating feature in vivo. F56-VCR-NP could accurately target the CRC neovasculature and elicit nanoparticle internalization in the tumor vascular EC, where the antiangiogenic VCR-induced dramatic EC apoptosis and necrosis of CRC tissue. F56-VCR-NP significantly prolonged the mouse survival with no obvious toxicity (weight loss and anepithymia) in the CT-26 lung metastasis mice model, and this pronounced antitumor effect was closely related with the decreased microvessel density in the metastases. The present nanoparticle-based targeted antiangiogenic therapy may provide a new promising approach for the therapy of CRC and lung metastasis, which deserves further translational research.
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Chao
C
Wang
Mei
M
Zhao
Ya-Rong
YR
Liu
Xin
X
Luan
Ying-Yun
YY
Guan
Qin
Q
Lu
De-Hong
DH
Yu
Fan
F
Bai
Hong-Zhuan
HZ
Chen
Chao
C
Fang
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D016503:Drug Delivery Systems; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D014750:Vincristine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D009842:Oligopeptides; C488235:peptide F56; D014750:Vincristine
Antiangiogenic therapy; Colorectal cancer; Lung metastasis; Nanoparticles; Tumor neovasculature