Targeted dendrimeric anticancer prodrug: a methotrexate-folic acid-poly(amidoamine) conjugate and a novel, rapid, "one pot" synthetic approach.
A targeted dendrimeric anticancer prodrug, a conjugate of generation 5 (G5) polyamidoamine (PAMAM) dendrimer, folic acid (FA), and methotrexate (MTX), has been successfully synthesized by using a novel "one pot" approach which is simple, reproducible, and feasible for large-scale synthesis. All dendrimer products have been characterized by (1)H NMR, MALDI-TOF, GPC, and HPLC. With this new method, the ratio of FA versus MTX attached to the dendrimer can be easily tuned to achieve the desired therapeutic effect. A new analytical approach for calculating the numbers of FA and MTX attached to the dendrimer has been established. In vitro studies performed on FA receptor-expressing KB cells show that the new conjugate has a similar affinity and cytotoxic potency to G5-FA-MTX synthesized using the traditional multiple-step approach.
Michigan Nanotechnology Institute for Medicine and Biological Sciences, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109.
Yuehua
Y
Zhang
Thommey P
TP
Thomas
Ankur
A
Desai
Hong
H
Zong
Pascale R
PR
Leroueil
Istvan J
IJ
Majoros
James R
JR
Baker
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005492:Folic Acid / Q000737:chemistry*; D006801:Humans; D007624:KB Cells; D008727:Methotrexate / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011073:Polyamines / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D050091:Dendrimers; C531249:Poly(amidoamine); D011073:Polyamines; D011355:Prodrugs; D005492:Folic Acid; D008727:Methotrexate