Enhanced affinity bifunctional bisphosphonates for targeted delivery of therapeutic agents to bone.
Enhanced affinity bifunctional bisphosphonates for targeted delivery of therapeutic agents to bone.
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DOI：
10.1021/bc2003132
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发表时间：
2011-12-21
影响因子：
4.7
通讯作者：
Bachas, Leonidas G.
中科院分区：
文献类型：
--
作者：
Yewle, Jivan N.;Puleo, David A.;Bachas, Leonidas G.
糖尿病对世界人口和经济产生重大影响。尽管有几种治疗剂和治疗方法可用于解决骨疾病，但由于它们在非靶向部位的吸收和相关的副作用，它们没有得到充分利用。主动靶向控制给药是治疗此类疾病的理想方法。由于已知双膦酸盐对骨具有高亲和力并且被广泛用于治疗骨质疏松症，因此它们非常适合用于靶向骨的药物。在这项研究中，治疗剂的骨吸收部位和伤口愈合部位的靶向递送进行了探索。为了实现这一目标，合成了具有不同长度间隔基的双功能肼双膦酸盐（HBP），并研究了它们对骨骼的亲和力增强。晶体生长抑制研究表明，这些HBPs具有高亲和力的羟基磷灰石，与较短的间隔HBPs结合强于阿仑膦酸钠的羟基磷灰石。HBP不影响MC 3 T3-E1前成骨细胞的增殖，不诱导细胞凋亡，并且在测试的浓度范围内（10−6 - 10−4 M）没有细胞毒性。此外，药物可以通过腙键连接到HBP，所述腙键在骨吸收和伤口愈合部位的低pH下可裂解，导致药物释放。这是证明使用羟基磷灰石作为骨的模型材料和4-硝基苯甲醛作为模型药物。这项研究表明，这些HBPs可用于治疗剂的骨靶向输送。
Skeletal diseases have a major impact on the worldwide population and economy. Although several therapeutic agents and treatments are available for addressing bone diseases, they are not being fully utilized because of their uptake in non-targeted sites and related side effects. Active targeting with controlled delivery is an ideal approach for treatment of such diseases. Because bisphosphonates are known to have high affinity to bone and are being widely used in treatment of osteoporosis, they are well-suited for drug targeting to bone. In this study, a targeted delivery of therapeutic agent to resorption sites and wound healing sites of bone was explored. Towards this goal, bifunctional hydrazine-bisphosphonates (HBPs), with spacers of various lengths, were synthesized and studied for their enhanced affinity to bone. Crystal growth inhibition studies showed that these HBPs have high affinity to hydroxyapatite, and HBPs with shorter spacers bind stronger than alendronate to hydroxyapatite. The HBPs did not affect proliferation of MC3T3-E1 pre-osteoblasts, did not induce apoptosis, and were not cytotoxic at the concentration range tested (10−6 - 10−4 M). Furthermore, drugs can be linked to the HBPs through a hydrazone linkage that is cleavable at the low pH of bone resorption and wound healing sites, leading to release of the drug. This was demonstrated using hydroxyapatite as a model material of bone and 4-nitrobenzaldehyde as a model drug. This study suggests that these HBPs could be used for targeted delivery of therapeutic agents to bone.
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