title: Multifunctional lactobionic acid-modified dendrimers for targeted drug delivery to liver cancer cells: investigating the role played by PEG spacer.
abstract: We report the development of a lactobionic acid (LA)-modified multifunctional dendrimer-based carrier system for targeted therapy of liver cancer cells overexpressing asialoglycoprotein receptors. In this study, generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were sequentially modified with fluorescein isothiocyanate (FI) and LA (or polyethylene glycol (PEG)-linked LA, PEG-LA), followed by acetylation of the remaining dendrimer terminal amines. The synthesized G5.NHAc-FI-LA or G5.NHAc-FI-PEG-LA conjugates (NHAc denotes acetamide groups) were used to encapsulate a model anticancer drug doxorubicin (DOX). We show that both conjugates are able to encapsulate approximately 5.0 DOX molecules within each dendrimer and the formed dendrimer/DOX complexes are stable under different pH conditions and different aqueous media. The G5.NHAc-FI-PEG-LA conjugate appears to have a better cytocompatibility, enables a slightly faster DOX release rate, and displays better liver cancer cell targeting ability than the G5.NHAc-FI-LA conjugate without PEG under similar experimental conditions. Importantly, the developed G5.NHAc-FI-PEG-LA/DOX complexes are able to specifically inhibit the growth of the target cells with a better efficiency than the G5.NHAc-FI-LA/DOX complexes at a relatively high DOX concentration. Our results suggest a key role played by the PEG spacer that affords the dendrimer platform with enhanced targeting and therapeutic efficacy of cancer cells. The developed LA-modified multifunctional dendrimer conjugate with a PEG spacer may be used as a delivery system for targeted liver cancer therapy and offers new opportunities in the design of multifunctional drug carriers for targeted cancer therapy applications.
authors.affiliation: College of Chemistry, Chemical Engineering and Biotechnology, and ‡State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University , Shanghai 201620, People's Republic of China.
authors.forename: Fanfan
authors.initials: F
authors.lastname: Fu
authors.forename: Yilun
authors.initials: Y
authors.lastname: Wu
authors.forename: Jingyi
authors.initials: J
authors.lastname: Zhu
authors.forename: Shihui
authors.initials: S
authors.lastname: Wen
authors.forename: Mingwu
authors.initials: M
authors.lastname: Shen
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Shi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry*; D004187:Disaccharides / Q000737:chemistry*; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; D004187:Disaccharides; D004337:Drug Carriers; C104700:PAMAM Starburst; D011092:Polyethylene Glycols; C005608:lactobionic acid; D004317:Doxorubicin
keywords: PAMAM dendrimers; PEG spacer; doxorubicin; lactobionic acid; targeted cancer therapy