Pharmacokinetics and delivery of tat and tat-protein conjugates to tissues in vivo
Pharmacokinetics and delivery of tat and tat-protein conjugates to tissues in vivo
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DOI：
10.1021/bc0155061
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发表时间：
2001-11-01
影响因子：
4.7
通讯作者：
Pardridge, WM
中科院分区：
文献类型：
--
作者：
Lee, HJ;Pardridge, WM
治疗性蛋白质的体内膜渗透可以通过将蛋白质与阳离子输入肽（例如人免疫缺陷病毒的达特蛋白）缀合来增强。器官摄取（表示为每克组织注射剂量（ID）的百分比）是膜渗透性和血浆浓度曲线下面积（AUC）的函数，AUC是血浆药代动力学的函数。本研究的目的是检查达特肽对模型外源蛋白链霉亲和素的血浆AUC的影响，并检查血浆AUC的变化影响蛋白质的器官摄取（%ID/g）的程度。达特蛋白的阳离子部分由富含赖氨酸/亮氨酸的序列组成，命名为达特（48-58）。将该阳离子肽的生物素类似物tat-生物素放射性碘标记并静脉内注射到大鼠中，与或不与链霉亲和素缀合。未结合的tat-生物素肽几乎立即被所有组织从血浆中清除，全身清除率非常高，为29 +/- 4 mL/min/kg，全身分布容积高，为4160 m2 +/- 450 mL/kg。tat-生物素/链霉亲和素缀合物的血浆清除率为1.37 +/-0.01 mL/min/kg，相对于未缀合的达特肽的清除率降低，但高于未缀合的链霉亲和素的血浆清除率0.058 +/-0.005 mL/min/kg。阳离子输入肽如tat 48 -58与较高分子量蛋白质的缀合导致蛋白质从循环中去除的速率显著增加，这反映在降低的血浆AUC中。总之，蛋白质的达特缀合对膜渗透和血浆AUC具有相反的作用。因此，器官%ID/g的增加与蛋白质达特缀合引起的膜渗透增加不成比例。
The membrane permeation in vivo of therapeutic proteins may be enhanced by conjugation of the protein to cationic import peptides, such as the tat protein of the human immune deficiency virus. The organ uptake, expressed as a percent of injected dose (ID) per gram of tissue, is a function of both membrane permeability and the area under the plasma concentration curve (AUC), which is a function of the plasma pharmacokinetics. The purpose of the present studies was to examine the effect of the tat peptide on the plasma AUC of a model exogenous protein, streptavidin, and to examine the extent to which changes in the plasma AUC influence organ uptake (%ID/g) of the protein. The cationic portion of the tat protein is comprised of a lysine/arginine-rich sequence, designated tat(48-58). A biotin analogue of this cationic peptide, tat-biotin, was radioiodinated and injected intravenously into rats with or without conjugation to, streptavidin. The unconjugated tat-biotin peptide was nearly instantaneously cleared from plasma by all tissues with a very high systemic clearance of 29 +/- 4 mL/min/kg and a high systemic volume of distribution of 4160 m +/- 450 mL/kg. The plasma clearance of the tat-biotin/streptavidin conjugate, 1.37 +/- 0.01 mL/min/kg, was reduced relative to the clearance of unconjugated tat peptide, but was higher than the plasma clearance of the unconjugated streptavidin, 0.058 +/- 0.005 mL/min/kg. Conjugation of cationic import peptides such as tat48-58 to higher molecular weight proteins results in a marked increase in the rate of removal of the protein from the circulation, which is reflected in the reduced plasma AUC. In summary, tat conjugation of a protein has opposing effects on membrane permeation and the plasma AUC. Therefore, the organ %ID/g is not increased in proportion to the increase in membrane permeation caused by tat conjugation of proteins.