title: Spacer length impacts the efficacy of targeted docetaxel conjugates in prostate-specific membrane antigen expressing prostate cancer.
abstract: Combination of targeted delivery and controlled release is a powerful technique for cancer treatment. In this paper, we describe the design, synthesis, structure validation and biological properties of targeted and non-targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-docetaxel conjugates. Docetaxel (DTX) was conjugated to HPMA copolymer via a tetrapeptide spacer (-GFLG-). 3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA) was used as the targeting moiety to actively deliver DTX for treatment of Prostate-Specific Membrane Antigen (PSMA) expressing prostate cancer. Short and long spacer DUPA monomers were prepared, and four HPMA copolymer--DTX conjugates (non-targeted, two targeted with short spacer of different molecular weight and targeted with long spacer) were prepared via Reversible Addition-Fragmentation Chain Transfer (RAFT) copolymerization. Following confirmation of PSMA expression on C4-2 cell line, the DTX conjugates' in vitro cytotoxicity was tested against C4-2 tumor cells and their anticancer efficacies were assessed in nude mice bearing s.c. human prostate adenocarcinoma C4-2 xenografts. The in vivo results show that the spacer length between targeting moieties and HPMA copolymer backbone can significantly affect the treatment efficacy of DTX conjugates against C4-2 tumor bearing nu/nu mice. Moreover, histological analysis indicated that the DUPA-targeted DTX conjugate with longer spacer had no toxicity in major organs of treated mice.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD .
authors.forename: Zheng-Hong
authors.initials: ZH
authors.lastname: Peng
authors.forename: Monika
authors.initials: M
authors.lastname: Sima
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: Salama
authors.forename: Pavla
authors.initials: P
authors.lastname: Kopečková
authors.forename: Jindřich
authors.initials: J
authors.lastname: Kopeček
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D000077143:Docetaxel; D016503:Drug Delivery Systems; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism; D005977:Glutarates / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D009842:Oligopeptides / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: C544380:2-(3-(1,3-dicarboxypropyl)ureido)pentanedioic acid; D000178:Acrylamides; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D005977:Glutarates; D009842:Oligopeptides; D011108:Polymers; D043823:Taxoids; D000077143:Docetaxel; D014508:Urea; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; C032976:N-(2-hydroxypropyl)methacrylamide