title: 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.
abstract: 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.
authors.affiliation: Taiwan Semiconductor Manufacturing Company, Hsinchu, 30010, Taiwan.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Su
authors.affiliation: College of Materials Science and Opto-Electronic Technology, University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Ching-Shu
authors.initials: CS
authors.lastname: Yen
authors.affiliation: Department of Materials Sciences and Engineering, National Chiao Tung University, Hsinchu, 30010, Taiwan.
authors.forename: Chih-Sheng
authors.initials: CS
authors.lastname: Chiang
authors.affiliation: Department of Materials Sciences and Engineering, National Chiao Tung University, Hsinchu, 30010, Taiwan.
authors.forename: Chin-Hao
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: Department of Materials Sciences and Engineering, National Chiao Tung University, Hsinchu, 30010, Taiwan.
authors.forename: San-Yuan
authors.initials: SY
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D018938:Caco-2 Cells; D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D004317:Doxorubicin / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D004705:Endocytosis / Q000187:drug effects; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008024:Ligands; D008055:Lipids / Q000737:chemistry*; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D055672:Static Electricity; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008024:Ligands; D008055:Lipids; D010455:Peptides; D004317:Doxorubicin; D048271:Chitosan
keywords: Drug targeting; Lyp-1; Multistage continuous targeting delivery; Oral Administration; RGD