title: Doxorubicin-loaded amphiphilic polypeptide-based nanoparticles as an efficient drug delivery system for cancer therapy.
abstract: An amphiphilic anionic copolymer, methoxy poly(ethylene glycol)-b-poly(l-glutamic acid-co-l-phenylalanine) (mPEG-b-P(Glu-co-Phe)), with three functionalized domains, was synthesized and used as a nanovehicle for cationic anticancer drug doxorubicin hydrochloride (DOX·HCl) delivery via electrostatic interactions for cancer treatment. The three domains displayed distinct functions: PEG block chain for prolonged circulation; poly(phenylalanine) domain for stabilizing the nanoparticle construct through hydrophobic/aromatic interactions; and the poly(glutamic acid) domain for providing electrostatic interactions with the cationic drug to be loaded. The copolymer could self-assemble into micellar-type nanoparticles, and DOX was successfully loaded into the interior of nanoparticles by simple mixing of DOX·HCl and the copolymer in the aqueous phase. DOX-loaded mPEG-b-P(Glu-co-Phe) nanoparticles (DOX-NP) had a superior drug-loading content (DLC) (21.7%), a high loading efficiency (almost 98%) and a pH-triggered release of DOX. The size of DOX-NP was ∼140 nm, as determined by dynamic light scattering measurements and transmission electron microscopy. In vitro assays showed that DOX-NP exhibited higher cell proliferation inhibition and higher cell uptake in A549 cell lines compared with free DOX·HCl. Maximum tolerated dose (MTD) studies showed that DOX-NP demonstrated an excellent safety profile with a significantly higher MTD (15 mg DOX kg(-1)) than that of free DOX·HCl (5 mg DOX kg(-1)). The in vivo studies on the subcutaneous non-small cell lung cancer (A549) xenograft nude mice model confirmed that DOX-NP showed significant antitumor activity and reduced side effects, and then enhanced tumor accumulation as a result of the prolonged circulation in blood and the enhanced permeation and retention effect, compared with free DOX, indicating its great potential for cancer therapy.
authors: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China; University of Chinese Academy of Sciences, Beijing 100039, China.
authors: Shixian
authors: S
authors: Lv
authors: Mingqiang
authors: M
authors: Li
authors: Zhaohui
authors: Z
authors: Tang
authors: Wantong
authors: W
authors: Song
authors: Hai
authors: H
authors: Sun
authors: Huaiyu
authors: H
authors: Liu
authors: Xuesi
authors: X
authors: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D012996:Solutions; D013501:Surface-Active Agents / Q000737:chemistry*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D012996:Solutions; D013501:Surface-Active Agents; C477046:monomethoxypolyethylene glycol-glutamic acid; D018698:Glutamic Acid; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Doxorubicin hydrochloride; Drug delivery; Electrostatic interaction; Poly(amino acids); pH sensitive