Doxorubicin Conjugates for Selective Delivery to Tumors

Abstract

With the aim of improving the therapeutic utility of doxorubicin, numerous conjugates or prodrugshave been prepared to be selectively activated at the tumor site while releasing the cytotoxic drug.Among immuno-conjugates representing a widely studied class of doxorubicin derivatives,the clinical development of cBR96-Dox, undoubtedly the most quintessential derivative, was discontinueddue to severe secondary effects. More potent cBR-96 analogues and IMMU-110, another doxorubicin immunoconjugate,are still under study.Antibody-directed prodrug therapy has been designed to overcome some of the problems associatedwith the treatment of solid tumors. Concerning the anthracycline-based prodrugs, two glucuronideconjugates have reached the preclinical level, HMR 1826 and DOX-GA3. Both conjugates were subsequentlyevaluated against several human cancer xenografts without preliminary administration of fusion protein.Among the novelty in ADEPT approaches, one of the most relevant was based on the design of multiplespacer systems.Closely related to ADEPT, new approaches to selectively deliver prodrug-releasing enzymes intumor cells have been still studied or proposed by means of gene (GDEPT), polymer (PDEPT), bacteria(BDEPT), or exploiting endogenous carbohydrate-lectin binding (LEAPT).Activation of conjugates by tumor-associated endogenous enzymes such as prostate specific antigen,plasmin, matrix metalloproteinase, and various extra and intracellular peptidases has also been reported,some of these conjugates like L377,202, a PSA substrate, having reached the clinical level. Doxorubicinpeptide conjugates were also designed to be activated by endopeptidase legumain, and extracellularthimet oligopeptidase to deliver Leu-Dox, known to be cleaved intracellularly by peptidase.A third class of conjugates has been designed for receptor-mediated targeted delivery,including folate, somatostatin, bombesin, LHRH receptors or integrin and lectin.Transportation of doxorubicin with peptide vectors has been simultaneously investigated to overcomethe problem of penetration in the brain or the problem of multidrug resistance.