Nanoparticles that do not compete with endogenous ligands - Molecular characterization in vitro, acute safety in canine, and interspecies pharmacokinetics modeling to humans.
Nanoparticles that do not compete with endogenous ligands - Molecular characterization in vitro, acute safety in canine, and interspecies pharmacokinetics modeling to humans.
复制标题
DOI：
10.1016/j.jconrel.2021.02.009
复制
发表时间：
2021-04-10
期刊：
影响因子：
--
通讯作者：
Kumar MNVR
中科院分区：
文献类型：
--
作者：
Zou D;Arora M;Ganugula R;Kumar M;Scott EM;Shah D;Kumar MNVR
绝大多数（如果不是所有的话）受体介导的药物递送系统利用与生理模拟配体缀合的纳米颗粒，测试仅限于体外和啮齿动物模型。在这份报告中，我们提出了第一次，转铁蛋白受体1（TfR 1）靶向聚合物纳米粒子（简称，P2 Ns-GA），不与内源性转铁蛋白竞争，并作为一个通用的平台，口服药物输送的全谱表征。基于内吞作用抑制剂和受体敲低，P2 Ns-GA的细胞摄取是网格蛋白介导的并且依赖于TfR 1表达，但是其他运输机制，特别是涉及小窝/脂筏的那些机制，也可以发挥作用。用疏水性多酚尿石素A（UA）证明了P2 Ns-GA在促进包封化合物的口服生物利用度中的效用。当与普通UA或无配体纳米颗粒中的UA相比时，UA负载的P2 Ns-GA在健康犬中导致显著更高的血浆浓度，口服给药后没有观察到不良健康影响。最后，使用大鼠和狗的数据集开发了半机械药代动力学模型，以定量评估P2 Ns-GA对UA口服生物利用度的影响。将该模型按人体异速生长比例缩放，以模拟口服给药后普通UA和负载UA的P2 Ns-GA的临床药代动力学。
A vast majority, if not all of the receptor-mediated drug delivery systems utilize nanoparticles that are conjugated to physiological mimic ligands, with testing restricted to in vitro and rodent models. In this report, we present for the first time, a full spectrum characterization of transferrin receptor 1 (TfR1)-targeted polymeric nanoparticles (abbreviated, P2Ns-GA) that do not compete with endogenous transferrin, and serve as a versatile platform for oral drug delivery. Based on endocytosis inhibitors and receptor knockdown, the cellular uptake of P2Ns-GA is clathrin-mediated and dependent on TfR1 expression, but other trafficking mechanisms, particularly those involving caveolae/lipid rafts, can also play a role. The utility of P2Ns-GA in promoting the oral bioavailability of encapsulated com-pounds is demonstrated with a hydrophobic polyphenol, urolithin A (UA). When compared against plain UA or UA in ligand-free nanoparticles, UA-loaded P2Ns-GA led to markedly higher plasma concentrations among healthy canines, with no adverse health effects observed after oral dosing. Finally, a semi-mechanistic pharmacokinetic model was developed using both rat and dog datasets to quantitatively evaluate the effect of P2Ns-GA on oral bioavailability of UA. The model was allometrically scaled to humans to simulate clinical pharmacokinetics of plain UA and UA-loaded P2Ns-GA following oral administration.
登录
查看更多内容
影响因子：
16.1
作者：
Agoram, B;Woltosz, WS;Bolger, MB
通讯作者：
Bolger, MB
影响因子：
20.8
作者：
Andreux, Penelope A.;Blanco-Bose, William;Rinsch, Chris
通讯作者：
Rinsch, Chris
影响因子：
29.4
作者：
BANERJEE, D;FLANAGAN, PR;VALBERG, LS
通讯作者：
VALBERG, LS
影响因子：
10.8
作者：
Chalasani, Kishore B.;Russell-Jones, Gregory J.;Jain, Sanjay K.
通讯作者：
Jain, Sanjay K.
影响因子：
4.7
作者：
Arora, M.;Ganugula, R.;Kumar, M. N. V. Ravi
通讯作者：
Kumar, M. N. V. Ravi