Matrix metalloproteinase–activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity

Abstract

Matrix metalloproteinase (MMP) -activated prodrugs were formed by coupling MMP-cleavable peptides to doxorubicin. The resulting conjugates were excellent in vitro substrates for MMP-2, -9, and -14. HT1080, a fibrosarcoma cell line, was used as a model system to test these prodrugs because these cells, like tumor stromal fibroblasts, expressed several MMPs. In cultured HT1080 cells, simple MMP-cleavable peptides were primarily metabolized by neprilysin, a membrane-bound metalloproteinase. MMP-selective metabolism in cultured HT1080 cells was obtained by designing conjugates that were good MMP substrates but poor neprilysin substrates. To determine how conjugates were metabolized in animals,

Gelatinase-stimuli strategy enhances the tumor delivery and therapeutic efficacy of docetaxel-loaded poly(ethylene glycol)-poly(ε-caprolactone) nanoparticles

“…Many studies have verified that gelatinases are 'bad' MMPs, playing an important role in numerous malignant tumor behaviors, such as angiogenesis, apoptosis, aggressiveness, metastasis, and poor survival. 17,18 Therefore, gelatinases may be suitable candidates for stimuli-responsive targeted strategies, although MMP-stimuli strategies have been applied to prodrugs, 19 and liposomes. 20,21 Nanoparticles, which have their own advantages on drug delivery, using such strategies are rare.…”

Oral and IV Dosages of Doxorubicin-Methotrexate loaded-Nanoparticles Inhibit Progression of Oral Cancer by Down-Regulation of Matrix Methaloproteinase 2 Expression in Vivo

“…However, it worth to note that Matrix metalloproteinase (MMP)-activated prodrugs could be generated by coupling MMP-cleavable peptides to doxorubicin in order to enhance the specific accumulation of DOX within tumor and also to reduce its toxic effects on healthy cells. MMPs are attractive enzymes that tend to activate prodrugs in the tumor environment because MMPs are intimately connected with tumorigenesis (Albright et al, 2005;Hu et al, 2010).…”

Enhancing cellular uptake of activable cell-penetrating peptide–doxorubicin conjugate by enzymatic cleavage

“…HT-1080 cells were used as overexpressed MMP-2/9 16,23 tumor cell types to study the cellular uptake of activable ACPP-DOX after cell-secreted MMPs trigger cleavage. Innate fluorescence of DOX allowed us to use flow cytometry and confocal microscopy to study penetration and localization of free or conjugated DOX.…”