Species-specific optimization of PEG∼SN-38 prodrug pharmacokinetics and antitumor effects in a triple-negative BRCA1-deficient xenograft
Species-specific optimization of PEG∼SN-38 prodrug pharmacokinetics and antitumor effects in a triple-negative BRCA1-deficient xenograft
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DOI：
10.1007/s00280-019-03903-5
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发表时间：
2019-10-01
影响因子：
3
通讯作者：
Santi, Daniel. V.
中科院分区：
文献类型：
--
作者：
Fontaine, Shaun D.;Hann, Byron;Santi, Daniel. V.
Purpose Optimal efficacy of a macromolecular prodrug requires balancing the rate of drug release with the rate of prodrug elimination. Since circulating macromolecules have different elimination rates in different species, a prodrug optimal for one species will likely not be for another. The objectives of this work were (a) to develop an approach to optimize pharmacokinetics of a PEGSN-38 prodrug in a particular species, (b) to use the approach to predict the pharmacokinetics of various prodrugs of SN-38 in the mouse and human, and (c) to develop a PEGSN-38 conjugate that is optimized for mouse tumor models. Methods We developed models that describe the pharmacokinetics of a drug released from a prodrug by the relationship between the rates of drug release and elimination of the prodrug. We tested the model by varying the release rate of SN-38 from PEGSN-38 conjugates in the setting of a constant prodrug elimination rate in the mouse. Finally, we tested the antitumor efficacy of a PEGSN-38 optimized for the mouse. Results Optimization of a PEGSN-38 prodrug was achieved by adjusting the rate of SN-38 release such that the ratio of t(1/2,beta) of released SN-38 to the t(1/2) of prodrug elimination was 0.2-0.8. Using this approach, we could rationalize the efficacy of previous PEGylated SN-38 prodrugs in the mouse and human. Finally, a mouse-optimized PEGSN-38 showed remarkable antitumor activity in BRCA1-deficient MX-1 xenografts; a single dose gave tumor regression, suppression, and shrinkage of massive tumors. Conclusions The efficacy of a macromolecular prodrug can be optimized for a given species by balancing the rate of drug release from the carrier with the rate of prodrug elimination.
