Institute of Biophysics and Cellular Engineering of NASB, Minsk, Belarus.
Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
J Control Release. 2014 May 10;181:40-52. doi: 10.1016/j.jconrel.2014.02.021. Epub 2014 Mar 4.
This paper reviews the biodistribution, toxicity and pharmacokinetics of pure dendrimers and their complexes with nucleic acids (dendriplexes) in animals, including mice, rats, rabbits, and guinea pigs. Methods and results will both be discussed. The paradigm about dendrimers' toxicity based on in vitro studies should be revised; almost all dendrimers of low and middle generations are non-toxic in vivo, despite showing some cytotoxic effects in vitro. Only the high generations of unmodified cationic dendrimers in high doses have some toxicity in vivo. Modifications of dendrimers decrease their toxicity, even when this has already been acceptable with regard to unmodified dendrimers. Several undesirable effects following administration of unmodified cationic dendrimers diminish during prolonged dosing because of the development of counteracting mechanisms. Disturbances tend to return to normal levels during the recovery period after dendrimers have ceased to be administered to animals. Neutralization of the surface charge of dendrimers in their dendriplexes leads to less toxicity in vivo. Although dendrimers and dendriplexes accumulate temporarily in liver, pancreas, heart, and kidneys, they do not do permanent damage to them, i.e. the risk of irreversible damage or malfunction of these internal organs is slight. Chemical modifications of dendrimers determine the desired location of multifunctional dendrimer-based conjugates and dendriplexes in a targeted organ. Clearance of dendrimers also strongly depends on their chemical structure. When nucleic acids are complexed with dendrimers (forming so-called dendriplexes), they are more stable, having longer circulation times than free and PEI-complexed ones. Dendrimers are highly efficient in transfection and can be targeted to any organ, e.g. brain, lung and kidneys. The vast majority of dendrimers and dendriplexes are non-immunogenic. To sum up, these promising results from in vivo studies open up the possibility of dendrimers being applied as a new generation of nano-therapeutic agents in medicine, especially in human gene therapy.
本文综述了纯树枝状大分子及其与核酸复合物（树枝状聚合物）在动物（包括小鼠、大鼠、兔和豚鼠）体内的生物分布、毒性和药代动力学。方法和结果将一并讨论。基于体外研究的关于树枝状大分子毒性的范例应该得到修正；除了少数几批未经修饰的高代数阳离子树枝状大分子在高剂量下具有一定的体内毒性外，几乎所有低代数和中代数的树枝状大分子在体内均无毒性，尽管它们在体外具有一定的细胞毒性。树枝状大分子的修饰降低了其毒性，即使对未经修饰的树枝状大分子而言，毒性也已经可以接受。在给予未经修饰的阳离子树枝状大分子后，一些不良反应在延长给药期间会减少，因为机体产生了对抗机制。在停止给予动物树枝状大分子后，恢复期内，紊乱会恢复到正常水平。在树枝状聚合物中中和树枝状大分子的表面电荷会导致体内毒性降低。虽然树枝状大分子和树枝状聚合物会在肝脏、胰腺、心脏和肾脏中暂时积聚，但它们不会对这些器官造成永久性损害，即这些内部器官发生不可逆转的损伤或功能障碍的风险很小。树枝状大分子的化学修饰决定了多功能树枝状大分子缀合物和树枝状聚合物在靶向器官中的理想位置。树枝状大分子的清除也强烈依赖于它们的化学结构。当核酸与树枝状大分子（形成所谓的树枝状聚合物）复合时，它们比游离的和与聚乙烯亚胺复合的核酸更稳定，具有更长的循环时间。树枝状大分子在转染方面非常有效，可以靶向任何器官，如脑、肺和肾脏。绝大多数树枝状大分子和树枝状聚合物是非免疫原性的。总之，这些体内研究的有希望的结果为树枝状大分子作为新一代纳米治疗剂在医学，特别是在人类基因治疗中的应用开辟了可能性。
