title: Antitumor properties and toxicity of dextran-methotrexate conjugates are dependent on the molecular weight of the carrier.
abstract: Methotrexate (MTX) is widely utilized in the clinical treatment of many forms of cancer. However, the drug has a short plasma half-life and causes toxic effects on normal proliferating cells. Conjugation with carriers is a possible way to alter these disadvantageous pharmacokinetics. Our aim was to synthesize dextran-MTX (D-MTX) conjugates, using carriers with molecular weights (Mw) ranging from 10 kDa to 500 kDa. Their in vitro and in vivo properties were compared with free MTX. The in vitro studies revealed that D-MTX conjugates had 4- to 10-fold lower antiproliferative effects against neoplastic cell lines compared to free MTX. There was a negative relationship between the Mw of the carrier and the antiproliferative effect of the respective conjugate. The data obtained in a mouse leukemia P388 in vivo model suggested that a lower in vitro antiproliferative effect of the conjugates does not result in diminished antileukemic activity in vivo. The toxicity of the conjugates was greater in comparison with the parent drug and tended to rise with increasing Mw. However, no superiority over free MTX in terms of an antileukemic effect was demonstrated. In particular, the D-MTX conjugate based on the dextran with Mw 10 kDa showed a comparable antileukemic effect with an even lower toxicity than that of free MTX. The data suggest that at least the toxicity of conjugates is dependent on the Mw of the carrier. This fact should be taken into account when designing new anticancer polymer-drug compounds.
authors.affiliation: Laboratory of Experimental Anticancer Therapy, Department of Experimental Oncology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla st., 12, 53-114 Wroclaw, Poland.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Nevozhay
authors.forename: Renata
authors.initials: R
authors.lastname: Budzynska
authors.forename: Urszula
authors.initials: U
authors.lastname: Kanska
authors.forename: Monika
authors.initials: M
authors.lastname: Jagiello
authors.forename: Mohamed Salah
authors.initials: MS
authors.lastname: Omar
authors.forename: Janusz
authors.initials: J
authors.lastname: Boratynski
authors.forename: Adam
authors.initials: A
authors.lastname: Opolski
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003911:Dextrans / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008970:Molecular Weight; D013329:Structure-Activity Relationship
chemical_list: D003911:Dextrans; D004337:Drug Carriers; C050526:dextran T70-methotrexate conjugate; D008727:Methotrexate