Design of self-immolative linkers for tumour-activated prodrug therapy.
The main drawback of most cancer chemotherapy is its relatively low ability to target tumour cells versus normal cells. As a consequence, chemotherapy is usually connected with severe side effects due to the toxicity of traditional cytostatic agents towards normal tissues. A few years ago, the site-specific activation of non-toxic prodrugs in tumours has been proposed in order to enhance the selectivity for the killing of cancer cells. Within this framework, most of the prodrugs that have been designed were three part compounds comprising trigger, linker and effector units. The main function of the linker is to release the effector unit after selective trigger activation via a spontaneous chemical breakdown. However, its structure also affects significantly many prodrug properties such as stability, pharmacokinetic, organ distribution, bioavailability or trigger activation. This review, focussed on the linker unit, is an update of our previous article published in 2002. It deals with recent advances in the design of prodrug linkers including new delivery systems such as elongated linkers or self-immolative dendrimers.
Tranoy-Opalinski
I
I
Université de Poitiers, UMR-CNRS 6514, SRSN, 40 avenue du Recteur Pineau, 86022 Poitiers, France.
Fernandes
A
A
Thomas
M
M
Gesson
J-P
JP
Papot
S
S
D003500:Cyclization; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D015195:Drug Design; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011355:Prodrugs