Abstract
Cyclopeptidic chemotherapeutic prodrugs (cPCPs) are macromolecular protease-sensitive doxorubicin (DOX) prodrugs synthesized from a cyclodecapeptidic scaffold, termed Regioselectively Addressable Functionalized Template (RAFT). In order to increase the chemotherapeutic potential of DOX and limit its toxicity, we used a Cathepsin B (Cat B)-sensitive prodrug concept for its targeted release since this enzyme is frequently overexpressed in cancer cells. Copper-free “click” chemistry was used to synthesize cPCPs containing up to four DOX moieties tethered to the upper face of the scaffold through a Cat B-cleavable peptidic linker (GAGRRAAG). On the lower part, PEG 5, 10 and 20 kDa and a fifth peptidyl DOX moiety were grafted in order to improve the solubility, bioavailability and pharmacokinetic profiles of the compound. In vitro results on HT1080 human fibrosarcoma cells showed that cPCPs display a delayed action that consists of a cell cycle arrest in the G2 phase comparable to DOX alone, and increased cell membrane permeability.
Highlights
Chemotherapy remains the first option for cancer treatment in most patients
Regioselectively Addressable Functionalized Template (RAFT) scaffolds containing DOX bound via the Cathepsin B (Cat B)-cleavable spacer were prepared by a fivepeptide was functionalized with DBCO-NHS ester and its carboxylic end was attached to the amino step synthetic procedure employing copper-free click chemistry, namely strain-promoted alkynegroup of azide by standard chemistry
Conclusions chemotherapeutic prodrugs (cPCPs) composed from a cyclodecapeptide RAFT scaffold were successfully synthesized with the appropriate number of DOX—attached via a Cat B-cleavable peptide linker—and PEG moieties
Summary
Chemotherapy remains the first option for cancer treatment in most patients. Its goal is to deliver a maximal dose of an anti-cancer agent to the tumor site with minimal toxicity to other tissues. Most chemotherapeutic drugs are of low molecular weight and low water solubility. Once administered, they do not differentiate between tumor and healthy cells, leading to severe side effects. They do not differentiate between tumor and healthy cells, leading to severe side effects To overcome these drawbacks, macromolecular (mostly polymeric) prodrug systems composed of a scaffold to which an anti-cancer drug is attached were explored [1]. In order to tackle this problem, we selected a Regioselectively Addressable Functionalized Template (RAFTs, see Figure 1). These RAFTs are macromolecular scaffolds containing two separate addressable domains
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