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ABSTRACT
Introduction: Prodrugs have been used to improve the selectivity and efficacy of cancer therapy by targeting unique abnormal markers that are overexpressed by cancer cells and are absent in normal tissues. In this context, different strategies have been exploited and new ones are being developed each year.
Areas covered: In this review, an integrated view of the potential use of prodrugs in targeted cancer therapy is provided. Passive and active strategies are discussed in light of the advantages of each one and some successful examples are provided, as well as the clinical status of several prodrugs. Among them, antibody-drug conjugates (ADCs) are the most commonly used. However, several drawbacks, including limited prodrug uptake, poor pharmacokinetics, immunogenicity problems, difficulties in selective targeting and gene expression, and optimized bystander effects limit their clinical applications. Expert opinion: Despite the efforts of different companies and research groups, several drawbacks, such as the lack of relevant in vivo models, complexity of the human metabolism, and economic limitations, have hampered the development of new prodrugs for targeted cancer therapy. As a result, we believe that the combination of prodrugs with cancer nanotechnology and other newly developed approaches, such as aptamer-conjugated nanomaterials, are efficient strategies.
Trial registration: ClinicalTrials.gov identifier: NCT02049905.
Trial registration: ClinicalTrials.gov identifier: NCT02049905.
Trial registration: ClinicalTrials.gov identifier: NCT02014844.
Trial registration: ClinicalTrials.gov identifier: NCT02029430.
Trial registration: ClinicalTrials.gov identifier: NCT01706835.
Article highlights
This review provides the most commonly used strategies in the development of prodrugs for targeted cancer therapy, including those based on the tumor microenvironment, antibody-drug conjugates (ADCs), antibody-directed enzyme prodrug therapy (ADEPT), and gene-directed enzyme prodrug therapy (GDEPT);
The results of clinical and preclinical studies with a variety of prodrug systems demonstrate their potential use and the ability to enhance their efficacy and reduce their toxic effects in conventional therapy;
Nanotechnology is emerging as a promising and helpful strategy for the targeting of tumor cells to improve drug availability, for the accumulation of prodrugs at specific sites/tissues, and for a controlled drug release, among others;
ADC-based therapy is the most prominent as it is simpler and economically viable. On the other hand, despite being very promising in their concepts, ADEPT and GDEPT are more complex than ADC systems, and several drawbacks, including immunogenicity, their non-specific distribution, and cell permeability, limit their clinical development and in vivo applications.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.