title: Dual fluorescent HPMA copolymers for passive tumor targeting with pH-sensitive drug release II: impact of release rate on biodistribution.
abstract: In recent years, polymer drug carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with pH-triggered drug release have shown enhanced uptake in solid tumors and excellent antitumor activity. Here, the impact of the structure of the acid-labile spacer between the drug and the polymer carrier on the biodistribution of both the drug and the carrier was studied using in vivo noninvasive multispectral optical imaging of dual fluorescently labeled HPMA copolymers. Five different spacers containing a pH-sensitive hydrazone bond were synthesized and used to combine a fluorescent model drug with a polymer backbone, conjugated with another non-releasable fluorescent dye. Two copolymers differing in polymer chain structure (linear and star-like) and molecular weight (30 and 200kDa) were used to distinguish between carriers with molecular weights above and below the limit for renal filtration. The rate of model drug release from the conjugates was determined in vitro. The biodistributions of the six most promising conjugates were investigated in vivo in athymic nude mice inoculated with human colon carcinoma xenograft. The structure of the spacer in the vicinity of the hydrazone bond significantly influenced the release rate of the model drug. The slow release rate of a pyridyl group bearing spacer resulted in a greater amount of the model drug being transported to the tumor, which was independent of the carrier structure. The results of this study emphasize the importance of careful selection of the structure and appropriate spacer when designing polymer conjugates intended for passive tumor targeting.
authors.affiliation: Institute of Macromolecular Chemistry AS CR, v.v.i., Heyrovský Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Chytil
authors.forename: Stefan
authors.initials: S
authors.lastname: Hoffmann
authors.forename: Lucie
authors.initials: L
authors.lastname: Schindler
authors.forename: Libor
authors.initials: L
authors.lastname: Kostka
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.forename: Henrike
authors.initials: H
authors.lastname: Caysa
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
authors.forename: Karsten
authors.initials: K
authors.lastname: Mäder
authors.forename: Tomáš
authors.initials: T
authors.lastname: Etrych
mesh_terms: D000178:Acrylamides / Q000032:analysis*; D000818:Animals; D002232:Carbocyanines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003692:Delayed-Action Preparations / Q000032:analysis*; D005456:Fluorescent Dyes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D014018:Tissue Distribution
chemical_list: D000178:Acrylamides; D002232:Carbocyanines; C573549:DY-676; D003692:Delayed-Action Preparations; D005456:Fluorescent Dyes; D007211:Indoles; C032976:N-(2-hydroxypropyl)methacrylamide
keywords: HPMA copolymers; Multispectral optical imaging; Passive tumor targeting; Tumor accumulation; Xenograft tumor model; pH-responsive drug release