Multistage Continuous Targeting with Quantitatively Controlled Peptides on Chitosan‐Lipid Nanoparticles with Multicore–Shell Nanoarchitecture for Enhanced Orally Administrated Anticancer In Vitro and In Vivo

• Published in: Macromolecular bioscience 2017-02, Vol.17 (2), p.1600260-n/a
• Main Authors: Su, Chia‐Wei, Yen, Ching‐Shu, Chiang, Chih‐Sheng, Hsu, Chin‐Hao, Chen, San‐Yuan
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anticancer properties; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antitumor activity; Bioavailability; Biocompatibility; Caco-2 Cells; Cancer; Cell Death - drug effects; Cell Membrane Permeability - drug effects; Chitosan; Chitosan - chemistry; Conjugation; Cytotoxicity; Doxorubicin - pharmacology; Drug Carriers - chemistry; Drug delivery; Drug delivery systems; Drug targeting; Endocytosis - drug effects; Enterocytes - drug effects; Enterocytes - metabolism; Epithelium; Female; Humans; In vivo methods and tests; Lecithin; Ligands; Lipids; Lipids - chemistry; Lyp‐1; M cells; Mice, Inbred BALB C; Micelles; Microscopy, Fluorescence; Multistage; Multistage continuous targeting delivery; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Oral Administration; Peptides; Peptides - chemistry; Peptides - pharmacokinetics; Peptides - pharmacology; Permeability; Polysaccharides; Reverse micelles; RGD; Static Electricity; Studies; Therapy; Tissue Distribution - drug effects; Toxicity; Triglycerides
• ISSN: 1616-5187; 1616-5195
• DOI: 10.1002/mabi.201600260

A DOX‐loaded polysaccharide‐lecithin reverse micelles triglyceride‐based oral delivery nanocarrier (D‐PL/TG NPs) conjugated with (i) RGD peptide for targeting to β1 integrin of M cells and (ii) Lyp‐1 peptide for targeting to the p32 receptor of MDA‐MB‐231 cells is used to investigate the multistage continuous targeting capabilities of these peptide‐conjugated nanocarriers (GLD‐PL/TG NPs) for tumor therapy. Variations in the targeting efficacy and pharmacokinetic properties are investigated by quantitatively controlling the surface density of different peptides on the nanoparticles. In vitro permeability in a human follicle‐associated epithelium model and cytotoxicity against MDA‐MB‐231 cells indicate that the nanocarriers conjugated with high RGD peptide concentrations display a higher permeability due to the existence of M cells with higher transcytosis activity, but a higher concentration of conjugated Lyp‐1 peptide exhibits the lowest cell viability. Being benefited from specific targeting of peptide conjugation, improved bioavailability and enhanced tumor accumulation are achieved by the GLD‐PL/TG NPs, leading to better antitumor efficacy. The results of in vivo biodistribution and antitumor studies reveal that the effect of LyP‐1 peptide is more predominant than that of RGD peptide. This proof of multistage continuous targeting may open the door to a new generation of oral drug delivery systems in targeted cancer therapy. A multistage continuous targeting with an optimal ratio of Lyp‐1 to RGD peptides on triglyceride‐based oral drug nanocarrier achieves an improved bioavailability and antitumor efficacy.