Deepened cellular/subcellular interface penetration and enhanced antitumor efficacy of cyclic peptidic ligand-decorated accelerating active targeted nanomedicines

Acceleration and improvement of penetration across cell-membrane interfaces of active targeted nanotherapeutics into tumor cells would improve tumor-therapy efficacy by overcoming the issue of poor drug penetration. Cell-penetrating peptides, especially synthetic polyarginine, have shown promise in...

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Bibliographic Details
Published in:International journal of nanomedicine 2018-01, Vol.13, p.5537-5559
Main Authors: Shi, Nian-Qiu, Li, Yan, Zhang, Yong, Li, Zheng-Qiang, Qi, Xian-Rong
Format: Article
Language:English
Subjects:
Amino acids
Animals
Anthracyclines
Antibiotics, Antineoplastic - administration & dosage
Antibiotics, Antineoplastic - chemistry
Apoptosis - drug effects
Arginine
Asparagine
Biomarkers
Biomedical materials
Cancer therapies
Cell-Penetrating Peptides
Cyclic asparagine-glycine-arginine (cNGR)
Doxorubicin - administration & dosage
Doxorubicin - analogs & derivatives
Doxorubicin - chemistry
Doxorubicin - pharmacology
Drug Delivery Systems
Female
Fibrosarcoma - drug therapy
Fibrosarcoma - pathology
Glycine
Glycols (Class of compounds)
Heparan sulfate
Humans
Laboratories
Life sciences
Ligands
Lipids
Medical research
Mice
Mice, Inbred BALB C
Mice, Nude
Microscopy
Multifunctional nanomedicines
Nanomedicine
Nanoparticles
Original Research
Penetration and tumor therapy
Peptides
Peptides - chemistry
Peptides, Cyclic - chemistry
Polyethylene glycol
Polyethylene Glycols - administration & dosage
Polyethylene Glycols - chemistry
Polyethylene Glycols - pharmacology
Polyols
Tandem inserted nona-arginine (tiR9)
Tumor Cells, Cultured
Tumors
Xenograft Model Antitumor Assays
“Accelerating” active targeting nanotherapeutics
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Summary:Acceleration and improvement of penetration across cell-membrane interfaces of active targeted nanotherapeutics into tumor cells would improve tumor-therapy efficacy by overcoming the issue of poor drug penetration. Cell-penetrating peptides, especially synthetic polyarginine, have shown promise in facilitating cargo delivery. However, it is unknown whether polyarginine can work to overcome the membrane interface in an inserted pattern for cyclic peptide ligand-mediated active targeting drug delivery. Here, we conducted a study to test the hypothesis that tandem-insert nona-arginine (tiR ) can act as an accelerating component for intracellular internalization, enhance cellular penetration, and promote antitumor efficacy of active targeted cyclic asparagine-glycine-arginine (cNGR)-decorated nanoliposomes. Polyarginine was coupled with the polyethylene glycol (PEG) chain and the cNGR moiety, yielding a cNGR-tiR -PEG -distearoylphosphatidylethanolamine conjugate. The accelerating active targeted liposome (Lip) nanocarrier (cNGR-tiR -Lip-doxorubicin [Dox]) constructed in this study held suitable physiochemical features, such as appropriate particle size of ~150 nm and sustained-release profiles. Subsequently, tiR was shown to enhance cellular drug delivery of Dox-loaded active targeted systems (cNGR-Lip-Dox) significantly. Layer-by-layer confocal microscopy indicated that the tandem-insert polyarginine accelerated active targeted system entry into deeper intracellular regions based on observations at marginal and center locations. tiR enhanced the penetration depth of cNGR-Lip-coumarin 6 through subcellular membrane barriers and caused its specific accumulation in mitochondria, endoplasmic reticulum, and Golgi apparatus. It was also obvious that cNGR-tiR -Lip-Dox induced enhanced apoptosis and activated caspase 3/7. Moreover, compared with cNGR-Lip-Dox, cNGR-tiR -Lip-Dox induced a significantly higher antiproliferative effect and markedly suppressed tumor growth in HT1080-bearing nude mice. This active tumor-targeting nanocarrier incorporating a tandem-insert polyarginine (tiR ) as an accelerating motif shows promise as an effective drug-delivery system to accelerate translocation of drugs across tumor-cell/subcellular membrane barriers to achieve improved specific tumor therapy.
ISSN:1178-2013
1176-9114
1178-2013
DOI:10.2147/IJN.S172556