title: Partly PEGylated polyamidoamine dendrimer for tumor-selective targeting of doxorubicin: the effects of PEGylation degree and drug conjugation style.
abstract: Partly PEGylated polyamidoamine (PAMAM) dendrimers were used as the carrier for tumor-selective targeting of the anticancer drug doxorubicin (DOX). Acid-sensitive cis-aconityl linkage or acid-insensitive succinic linkage was introduced between DOX and polymeric carriers to produce PPCD or PPSD conjugates, respectively. DOX release from PPCD conjugates followed an acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PPCD conjugates against murine B16 melanoma cells increased with, while cellular uptake decreased with increasing PEGylation degree. PPSD conjugates released negligible drug at any tested pH condition and were less cytotoxic. Confocal laser scanning microscopy confirmed the acid-sensitive release of DOX from PPCD conjugates in the lysosomes and the entrance into nuclei. Pharmacokinetic and biodistribution studies demonstrated that increasing PEGylation degree resulted in reduced liver and splenic accumulation, longer circulation time and more tumor accumulation of the conjugates. Although PPSD conjugates showed more tumor accumulation than PPCD conjugates at the same PEGylation degree, the acid-sensitive DOX release from PPCD conjugates ensured higher concentration of free DOX in tumor and more pronounced antitumor activity. Besides, the antitumor activity of PPCD conjugates increased with increasing PEGylation degree. Overall, PPCD conjugate with the highest PEGylation would be a promising candidate for solid tumor therapy.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan Univeristy, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Saijie
authors.initials: S
authors.lastname: Zhu
authors.forename: Minghuang
authors.initials: M
authors.lastname: Hong
authors.forename: Guotao
authors.initials: G
authors.lastname: Tang
authors.forename: Lili
authors.initials: L
authors.lastname: Qian
authors.forename: Jiayuan
authors.initials: J
authors.lastname: Lin
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Pei
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods; D008422:Materials Testing; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011073:Polyamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D011073:Polyamines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin