McCoy Colin P, Morrow Ryan J, Edwards Christopher R, Jones David S, Gorman Sean P
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
Bioconjug Chem. 2007 Jan-Feb;18(1):209-15. doi: 10.1021/bc060238y.
To give the first demonstration of neighboring group-controlled drug delivery rates, a series of novel, polymerizable ester drug conjugates was synthesized and fully characterized. The monomers are suitable for copolymerization in biomaterials where control of drug release rate is critical to prophylaxis or obviation of infection. The incorporation of neighboring group moieties differing in nucleophilicity, geometry, and steric bulk in the conjugates allowed the rate of ester hydrolysis, and hence drug liberation, to be rationally and widely controlled. Solutions (2.5 x 10-5 mol dm-3) of ester conjugates of nalidixic acid incorporating pyridyl, amino, and phenyl neighboring groups hydrolyzed according to first-order kinetics, with rate constants between 3.00 +/- 0.12 x 10-5 s -1 (fastest) and 4.50 +/- 0.31 x 10- 6 s-1 (slowest). The hydrolysis was characterized using UV-visible spectroscopy. When copolymerized with poly(methyl methacrylate), free drug was shown to elute from the resulting materials, with the rate of release being controlled by the nature of the conjugate, as in solution. The controlled molecular architecture demonstrated by this system offers an attractive class of drug conjugate for the delivery of drugs from polymeric biomaterials such as bone cements in terms of both sustained, prolonged drug release and minimization of mechanical compromise as a result of release. We consider these results to be the rationale for the development of "designer" drug release biomaterials, where the rate of required release can be controlled by predetermined molecular architecture.
为了首次展示邻基控制的药物释放速率，合成并全面表征了一系列新型的可聚合酯类药物共轭物。这些单体适用于生物材料的共聚，在这些生物材料中，药物释放速率的控制对于预防或避免感染至关重要。在共轭物中引入亲核性、几何形状和空间体积不同的邻基部分，使得酯水解速率以及药物释放能够得到合理且广泛的控制。含有吡啶基、氨基和苯基邻基的萘啶酸酯共轭物的溶液（2.5×10⁻⁵ mol dm⁻³）按照一级动力学进行水解，速率常数在3.00±0.12×10⁻⁵ s⁻¹（最快）和4.50±0.31×10⁻⁶ s⁻¹（最慢）之间。水解过程通过紫外可见光谱进行表征。当与聚甲基丙烯酸甲酯共聚时，游离药物从所得材料中洗脱，释放速率如同在溶液中一样由共轭物的性质控制。该系统所展示的可控分子结构为从诸如骨水泥等聚合物生物材料中递送药物提供了一类有吸引力的药物共轭物，在持续、延长药物释放以及使释放导致的机械性能损害最小化方面均有优势。我们认为这些结果是开发“定制”药物释放生物材料的理论依据，在这种材料中，所需的释放速率可以通过预先确定的分子结构来控制。
