Multifunctional Tumor-Targeting Cathepsin B-Sensitive Gemcitabine Prodrug Covalently Targets Albumin in Situ and Improves Cancer Therapy

Abstract

We report a new type of amide bond-bearing cathepsin B-sensitive gemcitabine (GEM) prodrugs, capable of in situ covalently targeting circulating albumin and then making a hitchhike to the tumor. Specially, less plasma-enzyme deactivation, long plasma half-life, independence on nucleoside transporters, outstanding tumor targeting, and site-specific drug release are achieved, and as such these multifunctional advantages contribute to the dramatically increased in vivo antitumor efficacy.

A Comparative Study on Albumin-Binding Molecules for Targeted Tumor Delivery through Covalent and Noncovalent Approach

“…Recently, various albumin-binding prodrugs have been also developed in cancer treatment. − This is because albumin-binding prodrugs could bind strongly to albumin in the blood, and albumin-binding prodrugs have a tendency to intrinsically accumulate at targeted tumor tissues . Also, endothelial transcytosis via 60 kDa glycoprotein (gp60) or albondin further facilitates penetration of albumin-binding prodrugs to the tumor tissue. , Moreover, various cancer cells such as breast, prostate, and colon cancer cells actively take up albumins, since the albumin is used as the energy source of the cells under a condition of cellular stress. , Therefore, many albumin-binding molecules, such as albumin-binding peptides, fatty acids, and chemical maleimide groups, have served as efficient albumin-binding molecules for developing various albumin-binding prodrugs in cancer treatment .…”

Enzyme-activated prodrugs and their release mechanisms for the treatment of cancer

“…In addition, the author also determined tumor-free GEM accumulation in 4T1-tumor-bearing mice to demonstrate the importance of the cathepsin-B-sensitive ligand. 87…”

“…In addition, the author also determined tumor-free GEM accumulation in 4T1-tumor-bearing mice to demonstrate the importance of the cathepsin-B-sensitive ligand. 87 Kim et al developed prodrug 47 that is similar to the abovementioned prodrug. They combined the anticancer drug DOX with cathepsin-B-cleavable peptide (FRRG) and albuminbinding moiety.…”

Photoactivated In Situ Generation of Near Infrared Cyanines for Spatiotemporally Controlled Fluorescence Imaging in Living Cells

“…In the same microenvironment (i.e., lysosomes) BSA‐Cy5 and Am‐Cy5 are assumed to have comparable fluorescence quantum yields, which makes it possible to estimate the amount of Am‐Cy5 according to the BSA‐Cy5 based standard curve from BSA‐Cy5 treated cells after removal of extracellular medium and various‐fold dilutions (Figures 5 c,d). On the basis that tumor cells could uptake 20 % BSA‐Cy5 after 30‐min incubation, [31] the Am‐Cy5 generated from TMI in cells was calculated as approximately 0.16 μM. Therefore, roughly 0.5 % of total TMI was converted into Am‐Cy5.…”