Toxicological profile and safety pharmacology of a single dose of fibroblast activation protein-α-based doxorubicin prodrug

Abstract

Fibroblast activation protein-α (FAPα) is a promising tumor-associated target expressed by reactive stromal fibroblasts in tumor tissue. FAPα has a postprolyl peptidase activity and can specifically cleave N-terminal benzyloxycarbonyl (Z)-blocked peptides, such as the substrate Z-Gly-Pro-AMC. Doxorubicin (DOX) is an effective antitumor drug, but its application is greatly limited by toxic adverse effects owing to poor tumor selectivity. Based on these facts, we previously designed a FAPα-targeting prodrug of doxorubicin (FTPD) which can be selectively hydrolyzed by FAPα. FTPD can retain potent antitumor efficacy and has favorable tumor targeting. The present study aimed to further evaluate the toxicological profile and the safety pharmacological property of FTPD in vitro and in vivo. The cytotoxicity assay showed that FTPD displayed markedly lower cytotoxicity to 3T3 cells and HEK-293 cells compared with DOX. In the short-term toxicity study, mice treated with 25 mg/kg of FTPD showed no obvious change in the appearance and general behavior, and no case of mortality was observed within 14 days. Unlike DOX, FTPD exhibited reduced toxicity to heart, liver, kidney, spleen as well as peripheral white blood cells in mice. Moreover, open file test and general pharmacology study were also conducted correspondingly in mice and beagle dogs. It was found that FTPD may not produce significant pharmacological effects on spontaneous locomotor activity and cardiovascular-respiratory system except for a transient decreasing in systolic blood pressure. Taken together, the results of this work suggest that FTPD has more favorable toxicological profile and better drug safety compared with its parent drug DOX.

Pharmaceutical and Safety Profile Evaluation of Novel Selenocompounds with Noteworthy Anticancer Activity

“…Before their approval to be sold in the market to treat specific diseases, every drug must undergo a series of studies to determine its structure, physicochemical properties, mechanism of action, and side effects [71]. A further requirement for newly synthesized compounds is the precise estimation of their safety profiles: only non-toxic and nonmutagenic derivatives have a chance to reach the further steps of the experiments.…”

Fibroblast Activation Protein-α as a Target in the Bench-to-Bedside Diagnosis and Treatment of Tumors: A Narrative Review

“…Moreover, the same dose of the doxorubicin-conjugated formulation is associated with a 2-fold increase in intratumor accumulation. In the clinical trial stage, it was found that Z-Gly-Pro-Dox is difficult to dissolve in water ( 117 ). Zhang et al.…”

“…The general structure of the prodrug is Z-Gly-Pro-Drug (113)(114)(115)(116)(117)(118)(119)129). It has a small molecular weight, and its toxicity is lower than that of the original drug.…”

“…was found that Z-Gly-Pro-Dox is difficult to dissolve in water (117). Zhang et al (129) designed a nanomicelle system (ZGD-MNs) to promote the systemic administration of Z-Gly-Pro-Dox.…”

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“…In 1960s, a clinical trial was done on the drug and result a successful in treating acute leukemia and lymphoma, and finally a new antibiotic was discovered which named adriamycin which change to doxorubicin. Doxorubicin has a potent antitumor activity more than daunorubicin with a higher therapeutic index [2]. In 1967 the cardiotoxicity due to danurubicin was approved, the greatest risk of doxorubicin-induced toxicity is cardiotoxicity, so administration of doxorubicin should be doselimited [3].…”