Construction of targeting-clickable and tumor-cleavable polyurethane nanomicelles for multifunctional intracellular drug delivery.
New strategies for the construction of versatile nanovehicles to overcome the multiple challenges of targeted delivery are urgently needed for cancer therapy. To address these needs, we developed a novel targeting-clickable and tumor-cleavable polyurethane nanomicelle for multifunctional delivery of antitumor drugs. The polyurethane was synthesized from biodegradable poly(ε-caprolactone) (PCL) and L-lysine ethyl ester diisocyanate (LDI), further extended by a new designed L-cystine-derivatized chain extender bearing a redox-responsive disulfide bond and clickable alkynyl groups (Cys-PA), and finally terminated by a detachable methoxyl-poly(ethylene glycol) with a highly pH-sensitive benzoic-imine linkage (BPEG). The obtained polymers show attractive self-assembly characteristics and stimuli-responsiveness, good cytocompatibility, and high loading capacity for doxorubicin (DOX). Furthermore, folic acid (FA) as a model targeting ligand was conjugated to the polyurethane micelles via an efficient click reaction. The decoration of FA results in an enhanced cellular uptake and improved drug efficacy toward FA-receptor positive HeLa cancer cells in vitro. As a proof-of-concept, this work provides a facile approach to the design of extracellularly activatable nanocarriers for tumor-targeted and programmed intracellular drug delivery.
College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University , Chengdu 610065, China.
Nijia
N
Song
Mingming
M
Ding
Zhicheng
Z
Pan
Jiehua
J
Li
Lijuan
L
Zhou
Hong
H
Tan
Qiang
Q
Fu
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry; D004317:Doxorubicin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005492:Folic Acid / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008823:Micelles; D053769:Nanocapsules / Q000737:chemistry*; D011140:Polyurethanes / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
D000903:Antibiotics, Antineoplastic; D008823:Micelles; D053769:Nanocapsules; D011140:Polyurethanes; D004317:Doxorubicin; D005492:Folic Acid