Colon-specific 9-aminocamptothecin-HPMA copolymer conjugates containing a 1,6-elimination spacer.
N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-9-aminocamptothecin (9-AC) conjugate for oral colon-specific drug delivery was designed, synthesized, and characterized. The drug, 9-AC, was attached to the polymer carrier via a spacer containing a combination of an aromatic azo bond and a 4-aminobenzylcarbamate group. The design of the spacer ensured a fast and highly efficient release of unmodified 9-AC from the polymer in the colon by azo bond cleavage followed by a 1,6-elimination mechanism. An in vitro degradation study indicated that this conjugate was stable in simulated upper GI tract conditions, including small intestine (SI) contents, SI mucosa suspension, and in PBS (pH 1.5 and 7.4). A fast release of the unmodified drug (85+/-10% of 9-AC in 12 h) was detected in rat cecal contents. This drug delivery system has potential in the treatment of colon cancer.
Gao
Song-Qi
SQ
Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, Utah 84112, USA.
Lu
Zheng-Rong
ZR
Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, Utah 84112, USA.
Petri
Boris
B
Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, Utah 84112, USA.
Kopečková
Pavla
P
Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, Utah 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, Utah 84112, USA.
Kopeček
Jindřich
J
Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, Utah 84112, USA; Department of Bioengineering, University of Utah, Salt Lake City, Utah 84112, USA. Electronic address: Jindrich.Kopecek@m.cc.utah.edu.
D000818:Animals; D002021:Buffers; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000378:metabolism*; D016503:Drug Delivery Systems; D007202:Indicators and Reagents; D007413:Intestinal Mucosa / Q000378:metabolism; D007420:Intestine, Large / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D008689:Methacrylates / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013050:Spectrometry, Fluorescence
D002021:Buffers; D007202:Indicators and Reagents; D008689:Methacrylates; C080125:9-aminocamptothecin; C032802:hydroxypropyl methacrylate; D002166:Camptothecin