Evaluation of the tumor targeting of a FAPα-based doxorubicin prodrug

Abstract

Fibroblast activation protein-α (FAPα) is a tumor-associated antigen uniquely expressed by reactive stromal fibroblasts in the majority of human epithelial tumors. FAPα also possesses both post-prolyl peptidase and endopeptidase activities. Consequently, FAPα is increasingly considered as a potential pan-tumor target for designing tumor-targeted prodrugs. We previously conjugated Doxorubicin (Dox) with a FAPα-specific dipeptide (Z-Gly-Pro) to develop a FAPα-targeting prodrug of Dox (FTPD). The aim of current work was to validate the tumor targeting of this targeted-delivery strategy. The results demonstrated that FTPD could effectually release Dox upon the hydrolysis of FAPα as well as the incubation with tumor homogenate of FAPα-positive tumor (4T1 tumor), while it was highly stable in mouse plasma and a variety of tissue homogenates including heart, liver, and so on. And the FAPα-cleaved FTPD exhibited significantly higher cytotoxicity against 4T1 cells in vitro than the uncatalyzed prodrug. Additionally, FTPD produced similar antitumor efficacy in 4T1 tumor-bearing mice to free Dox without obvious cardiotoxic effect. Moreover, subsequent study indicated that the accumulation of FTPD reduced significantly in the heart compared to free Dox. These findings suggest that such FAPα-based prodrug strategy is promising to achieve targeted delivery of antitumor agents.

Lymph cancer chemotherapy: delivery of doxorubicin-gemcitabine prodrug and vincristine by nanostructured lipid carriers

“…Dicyclohexylcarbodiimide, N-hydroxysuccinimide, and N,N-Diisopropylethylamine (1:1:2, molar ratio) were then sequentially added into the DMSO solution. 32 The reaction mixture was stirred at 600 rpm at room temperature for 4 h in the dark. Finally, DOX-GEM was obtained via rotary evaporation method and purification by HPLC.…”

Mixed nanomicelles as potential carriers for systemic delivery of Z-GP-Dox, an FAPα-based doxorubicin prodrug: formulation and pharmacokinetic evaluation

“…27 The plasma cardiac output (Q co ) for rats was calculated as 2.69 L/hour. The mass balance equations (1)(2)(3)(4)(5)(6)(7)(8) for the model are shown as follows: …”

“…2 However, the insoluble nature of Z-GP-Dox becomes a significant barrier to drug administration, particularly when it comes to clinical trials. Therefore, it would be of great value to solve the solubility problem and achieve systemic delivery of this promising anticancer prodrug.…”

“…However, Z-GP-Dox can release doxorubicin in an opportune manner upon hydrolysis of FAPα or incubation with an FAPα-positive tumor homogenate. 2 In a previous study, we found that Z-GP-Dox shows significantly lower accumulation than doxorubicin in the heart at all time points, but showed higher accumulation in tumor tissue. Generally, nanocarriers achieve passive tumor targeting via the enhanced permeation and retention effect.…”

Proteases As Selective Activators Of Triggered Drug Release: A Potential Answer To The Problem Of Biomaterial-Associated Infections?

“…In a recent study, Huang et al [7] utilized the highly selective expression and the specific proteolytic activity of fibroblast activation protein-α (FAP-α) to construct a tumor targeting of FAP-α-based doxorubicin prodrug (Z-Gly-Pro-doxorubicin). It was found that FAP-α selective expressed on the surface of tumour-associated fibroblasts while not detected in normal adult tissues except tissues of healing wound [8].…”