Conjugates of cytotoxic agents with RGD peptides (Arg-Gly-Asp) addressed to αβ, αβ and αβ integrin receptors overexpressed by cancer cells, have recently gained attention as potential selective anticancer chemotherapeutics. In this review, the design and the development of RGD conjugates coupled to different small molecules including known cytotoxic drugs and natural products will be discussed.
There is a growing interest for the discovery of new cancer-targeted delivery systems for drug delivery and diagnosis. A synopsis of the bibliographic data will be presented on bombesin, neurotensin, octreotide, Arg-Gly-Asp, luteinizing hormone-releasing hormone and other peptides. Many of them have reached the clinics for therapeutic or diagnostic purposes, and have been utilized as carriers of known cytotoxic agents such as doxorubicin, paclitaxel, cisplatin, methotrexate or dyes and radioisotopes. In our article, recent advances in the development of peptides as carriers of cytotoxic drugs or radiometals will be analyzed.
The c(RGDyK) conjugates of POPAM demonstrated better inhibitory effects and selectivity compared with c(RGDyK) and POPAM. The c(RGDyK) conjugates of 5-FUA demonstrated diverse inhibitory effects compared with c(RGDyK) and 5-FUA related to the levels of integrin expression, the conjugate stability and sensitivity of cancer cells to 5-FUA.
Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: c(RGDyK)-based conjugates of gemcitabine (GEM) with the carbonate and carbamate linkages in the 6-OH group of GEM were synthesized for the targeted delivery of GEM to integrin α v β 3 , overexpressing cancer cells to increase the stability as well as the tumor delivery of GEM and minimize common side effects associated with GEM treatment. Competitive cell uptake experiments demonstrated that conjugate TC113 could be internalized by A549 cells through integrin α v β 3 . Among the synthesized conjugates, TC113 bearing the carbamate linker was stable in human plasma and was further assessed in an in vivo pharmacokinetic study. TC113 appeared to be relatively stable, releasing GEM slowly into blood, while it showed potent antiproliferative properties against WM266.4 and A549 cells. The encouraging data presented in this study with respect to TC113 provide a promising keystone for further investigation of this GEM conjugate with potential future clinical applications.
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