Abstract
Gene-directed enzyme prodrug therapy (GDEPT) has been intensively studied as a promising new strategy of prodrug delivery, with its main advantages being represented by an enhanced efficacy and a reduced off-target toxicity of the active drug. In recent years, numerous therapeutic systems based on GDEPT strategy have entered clinical trials. In order to deliver the desired gene at a specific site of action, this therapeutic approach uses vectors divided in two major categories, viral vectors and non-viral vectors, with the latter being represented by chemical delivery agents. There is considerable interest in the development of non-viral vectors due to their decreased immunogenicity, higher specificity, ease of synthesis and greater flexibility for subsequent modulations. Dendrimers used as delivery vehicles offer many advantages, such as: nanoscale size, precise molecular weight, increased solubility, high load capacity, high bioavailability and low immunogenicity. The aim of the present work was to provide a comprehensive overview of the recent advances regarding the use of dendrimers as non-viral carriers in the GDEPT therapy.
Highlights
Antibody Directed Enzyme Prodrug Therapy (ADEPT) = the enzyme is vectorized by antibodies or catalyzed directly by antibodies, towards antigens expressed on tumor cells [4,5]
The current review addresses the Gene-directed enzyme prodrug therapy (GDEPT) strategy with the presentation of vectors used for the targeting and release of active molecules
PAMAM G4 dendrimers with Arg terminal groups were developed as efficient nanovectors for the functional delivery of Messenger RNA (mRNA) to capitalize on the unique properties of poly(amidoamine) dendrimers with triethanolamine nucleus (TEA) [223,224]
Summary
During the research process for the development of new therapies, different strategies have been addressed, including prodrugs that can be transported and activated in the vicinity of targeted areas, combined with certain genes, enzymes or proteins, for an accurate and effective delivery of the drug to the target site or at the level of tissues or receptors, thereby increasing the selectivity of drugs for specific cellular targets, and consecutively increasing their therapeutic effect and decreasing the incidence of side effects. Selective activation of a drug at the level of the target tissue by exogenous enzymes or enzymes expressed at the target site can be achieved through the following strategies, using prodrugs and various vectors [1,2,3]. Virus Directed Enzyme Prodrug Therapy (VDEPT) = uses viral vectors to provide the gene encoding an enzyme which can trigger the activation reaction of a cytotoxic agent following systemic administration [6,7]. Polymer Directed Enzyme Prodrug Therapy (PDEPT) = passive targeting approach using a prodrug-conjugated polymer, followed by the administration of an enzymepolymer conjugate, to achieve site-specific activation [8]. The current review addresses the GDEPT strategy with the presentation of vectors used for the targeting and release of active molecules. The cytotoxicity of dendrimers is presented, together with different structural modulation strategies that have been studied in the scientific literature to improve their safety profile and efficacy
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