Biodistribution and pharmacokinetic studies of bone-targeting N-(2-hydroxypropyl)methacrylamide copolymer-alendronate conjugates.
The biodistribution and pharmacokinetics of bone-targeting N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-alendronate conjugates were evaluated following intravenous administration of radioiodinated conjugates to young healthy BALB/c mice. The synthesis of a polymerizable and cathepsin K cleavable alendronate derivative, N-methacryloylglycylglycylprolylnorleucylalendronate, enabled the preparation of HPMA copolymer-alendronate conjugates with varying composition. Using the RAFT (reversible addition-fragmentation chain transfer) polymerization technique, four conjugates with different molecular weight and alendronate content and two control HPMA copolymers (without alendronate) with different molecular weight were prepared. The results of biodistribution studies in mice demonstrated a strong binding capacity of alendronate-targeted HPMA copolymer conjugates to bone. Conjugates with low (1.5 mol%) alendronate content exhibited a similar bone deposition capacity as conjugates containing 8.5 mol % of alendronate. The molecular weight was an important factor in the biodistribution of the HPMA copolymer conjugates. More conjugate structures need to be evaluated, but the data suggest that medium molecular weights (50-100 kDa) might be effective drug carriers for bone delivery.
Pan
Huaizhong
H
Department of Pharmaceutics & Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, Utah 84112, USA.
Sima
Monika
M
Kopecková
Pavla
P
Wu
Kuangshi
K
Gao
Songqi
S
Liu
Jihua
J
Wang
Dong
D
Miller
Scott C
SC
Kopecek
Jindrich
J
D019386:Alendronate / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D017886:Durapatite / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011109:Polymethacrylic Acids / Q000737:chemistry*
D011109:Polymethacrylic Acids; C011533:Duxon; D017886:Durapatite; D019386:Alendronate