Journal
ACS APPLIED MATERIALS & INTERFACES
Volume 12, Issue 48, Pages 53598-53614Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsami.0c13023
Keywords
VEGF; micelles; FRET; siRNA delivery; chitosan
Funding
- National Natural Science Foundation of China [81660681, 81202467]
- Natural Science Foundation of Guangxi Province of China [2018GXNSFAA294080]
- Guangxi First-class Discipline Project for Pharmaceutical Sciences [GXFCDP-PS-2018]
- Joint Cultivation Base of Inovation & Entrepreneurship for Pharmaceutical Postgraduates [20170703]
- Postgraduate Research & Practice Innovation Program of Jiangsu Province [KYCX18_2436]
- Science and Technology Projects of Nantong City [JC2018024]
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Targeting vascular endothelial growth factor (VEGF) using small interfering RNA (siVEGF) has shown great potential in inhibiting the growth, proliferation, and migration of tumors by reducing the proliferation of blood vessels. On the basis of bionic principles, a novel pH-responsive and virus mimetic shell-sheddable chitosan (CS) micelles (CMs) as siRNA delivery system was introduced in this study. The cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) modified poly(enthylene glycol) (PEG) was conjugated to the HA2 modified chitosan via a hydrazone linkage (cRGD-PEG-Hz-CS-HA2). The cRGD-PEG-Hz-CS-HA2 conjugate could form micelles by interacting with the complex of octanal, Boc-L-lysine, and 9-D-arginine (9R) (octyl-Lys-9R) as a hydrophodic core forming agent, termed as cRGD-PEG-Hz-CS-HA2/octyl-Lys-9R (abbreviated as cRGD/HA2/Hz-CMs).The CMs modified with cRGD can accurately target glioma cells (U87MG cells) with high expression of avfi3. The payloads of siVEGF were packed into the core of cRGD/HA2/Hz-CMs via electrostatic interaction and hydrophobic interaction. The intracellular cargo release was achieved by the pH-responsive lysis of the hydrazone bond in acidic environment of endosome. Moreover, the exposed HA2, as a pH-sensitive membrane-disruptive peptide, assists the escape of the carriers from endosome into cytosol. In addition, cRGD/HA2/Hz-CMs can effectively deliver siVEGF and silence VEGF gene expression in U87MG cells, leading to the significant tumor growth inhibition. This study demonstrates that cRGD/HA2/Hz-CMs can deliver and release siVEGF in a controlled manner, which was traced by the fluorescence resonance energy transfer (FRET) system in order to achieve RNAi-based antiangiogenic treatment of cancer in vivo.
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