Activatable cell penetrating peptide-conjugated nanoparticles with enhanced permeability for site-specific targeting delivery of anticancer drug.
Based on the powerful cell-penetrating ability of low molecular weight protamine (LMWP) and the overexpression of matrix metalloproteinases in the tumor sites, we constructed an activatable low molecular weight protamine (ALMWP) and modified it onto the surface of poly(ethylene glycol)-poly(lactic acid) nanoparticles to develop a "smart" drug delivery system with enhanced permeability for facilitating site-specific targeting delivery of anticancer drug. The obtained ALMWP-functionalized nanoparticles (ALMWP-NP) with a particle size of 134.0 ± 4.59 nm and a zeta potential of -34.4 ± 2.7 mV, exhibited an enhanced MMP-dependent accumulation in HT-1080 cells via both energy-independent direct translocation and clathrin-mediated, cytoskeleton-dependent endocytosis. Pharmacokinetic and biodistribution study in HT-1080 tumor-bearing mice showed that ALMWP-NP significantly increased the accumulation of paclitaxel (PTX) in the tumor site but not the nontarget tissues. In addition, intratumor distribution analysis demonstrated that more ALMWP-NP penetrated deeply into the tumor parenchyma. As a result, PTX loaded by ALMWP-NP exhibited improved antitumor efficacy over that by unmodified nanoparticles and LMWP-functionalized nanoparticles. The findings suggested that ALMWP-NP could be used as a safe and effective tumor-targeting drug delivery system and opened a new gateway to the application of cell-penetrating peptides for targeted antitumor therapy.
Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, PR China.
Huimin
H
Xia
Guangzhi
G
Gu
Quanyin
Q
Hu
Zhongyang
Z
Liu
Mengyin
M
Jiang
Ting
T
Kang
Deyu
D
Miao
Qingxiang
Q
Song
Lei
L
Yao
Yifan
Y
Tu
Hongzhuan
H
Chen
Xiaoling
X
Gao
Jun
J
Chen
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000008:administration & dosage*; D010539:Permeability / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides