title: Arginine-Modified Nanostructured Lipid Carriers with Charge-Reversal and pH-Sensitive Membranolytic Properties for Anticancer Drug Delivery.
abstract: The ability to escape endo/lysosomal trafficking is critically important to prevent entrapment of nanomedicines in lysosomes and to achieve maximum therapeutic efficacy of drugs delivered to cells through endocytosis. In this study, a novel pH-sensitive chitosan carrier with the ability to reverse its charge during endo/lysosomal trafficking is developed as a way of improving lysosomal disruption. N-Arginine-N-octyl chitosan (AOCS) is synthesized by grafting l-arginine onto carboxymethyl chitosan. The AOCS is used to modify the surface of nanostructured lipid carriers (NLC) to prepare pH-sensitive charge-reversal lysosomolytic nanocarriers (ANLC). The ANLC is loaded with 10-hydroxycamptothecin (HCPT). The results show that ANLC is able to reverse surface zeta potential from negative to positive at lysosomal pH, which contributes to improved release of encapsulated drugs into cytoplasm. The lysosomolytic capability of ANLC is confirmed by confocal microscopy and transmission electron microscopy. In vitro studies demonstrate that the anticancer activity of HCPT-loaded ANLC is improved when compared with HCPT-NLC and free HCPT. In vivo pharmacokinetics and tissue distribution analysis show improved delivery of HCPT-ANLC to subcutaneous Heps mouse liver tumors and greatly improved antitumor activity. The results present ANLC as a promising drug delivery carrier for improved antitumor therapy.
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Minjie
authors.initials: M
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Cuiting
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Qiao
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Su
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.|Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: David
authors.initials: D
authors.lastname: Oupický
authors.affiliation: State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Qineng
authors.initials: Q
authors.lastname: Ping
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001120:Arginine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D048271:Chitosan / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D049329:Nanostructures / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D048271:Chitosan; D001120:Arginine; C028098:10-hydroxycamptothecin; D002166:Camptothecin
keywords: charge-reversal; lysosomal disruptive; nanolipid carriers; pH-sensitive